Abstract
Infection is a serious adverse event limiting LVAD therapy in advanced heart failure patients, but a reliable means to identify patients at increased risk of infection is still lacking. We hypothesized that pre-operative elevated levels of plasma Oncostatin M (OSM), a cytokine marker of leukocyte activation and inflammation, would be predictive of subsequent infection. We measured plasma OSM in 41 LVAD patients one day before LVAD implantation and post-operatively over two months. Pre-operative plasma OSM levels were normal in 27 patients (Group A, 4.9 ± 3.2 pg/mL) but elevated in 14 patients (Group B, 1649.0 ± 458.9 pg/mL) (p=0.003). Early post-operative levels rose in both groups and declined rapidly in Group A, with Group B declining slowly over two months. Significantly more infections developed in Group B than Group A patients over two months post-implantation (p=0.004). No other routine clinical assessment or laboratory testing afforded this differentiation. These findings suggest that pre-operative plasma OSM levels may assist in identifying patients at increased risk of infections after LVAD implantation.
Keywords: Biomarker, Cytokines, Heart failure, Hemocompatibility, Infection, Inflammation, LVAD, Oncostatin M, OSM
Introduction
Advanced heart failure has a mortality rate greater than cancer.1 Left Ventricular Assist Devices (LVADs) offer a life-defining option for patients with advanced heart failure.2,3 With improving outcomes, LVAD implantation has become widely adopted as a bridge to heart transplantation or as a life-long alternative to transplantation necessitated by limited donor heart availability.2-5
LVAD recipients experience improved life expectancy and quality of life but remain at risk for infections.2-5 Despite encouraging reports with the recently released HeartMate 3 Left Ventricular Assist Device (HM3, Abbott, Santa Clara, CA) demonstrating excellent survival and significant improvements in pump thrombosis and stroke, the development of post-implant infections remains challenging.2-5 Predictors for risk of infection in LVAD recipients have been sought but to date remain unreliable.6,7
We hypothesized that plasma Oncostatin M (OSM), a sensitive indicator of an activated state of inflammation, could be predictive of infections in LVAD recipients. This cytokine, a member of the IL-6 family, was first purified in phorbol-12-myristate-13-acetate (PMA)-treated histiocytic lymphoma cell line, U-937.8,9 It is synthesized by neutrophils, monocytes, T lymphocytes and macrophages.10,11 Its synthesis, intra-cellular trafficking, release mechanisms and the critical roles it plays in inflammation and infection have been well described.10-13 Among its multiple leukocyte cell sources, neutrophils are unique as they store OSM in their gelatinase and secretory granules11,14 which release their contents following neutrophil activation more readily than other types of neutrophil granules (azurophilic and specific granules).15 Subsequent to neutrophil activation, these granules are readily mobilized to fuse with the cell plasma membrane and subsequently release their contents extracellularly.16,17 This route of rapid release of OSM into plasma accommodates an immediate response of neutrophils to their activation without waiting for the transcription of de novo OSM.
Considering that neutrophils are the most abundant type of leukocytes and that they are endowed with this unique pathway for OSM release, we anticipated that the release of OSM would serve as a uniquely sensitive indicator of an active state of inflammation indicative of a predisposition to infection. Given that, we hypothesized that an increase in plasma OSM levels could serve as a more sensitive predictor of infection risk than previously proposed biomarkers.6,7
To test this hypothesis, we performed serial measurements of plasma OSM levels prior to LVAD implantation and for two months following. We then studied the relationship between OSM levels and the development of post-operative infection.
Methods
Patient population
A total of 41 LVAD recipients were enrolled under research protocols approved by the healthcare system Institutional Review Board (IRB) and in compliance with the International Society for Heart and Lung Transplantation (ISHLT) Ethics. Patients were selected randomly, enrolling approximately one third of all patients receiving LVADs during the time course of study. Once enrolled in the study, no patients were excluded thereafter. The LVADs implanted included HeartMate 3 (n=28, Abbott, Santa Clara CA), HeartMate II (n=12, Abbott) and HeartWare (n=1, Medtronic, Minneapolis MN). Table 1 outlines the basic characteristics of these patients.
Table 1.
Baseline characteristics of advanced heart failure patients with normal and elevated Oncostatin M (OSM) levels prior to LVAD implantation.
| Group A (n=27) | Group B (n=14) |
p- value |
|
|---|---|---|---|
| Age – years | 58 ± 14 | 64 ± 12 | 0.15a |
| 60 (47 – 70) | 68 (59 – 70) | 0.21b | |
| Gender | |||
| Male | 23 (85.2) | 10 (71.4) | - |
| Female | 4 (14.8) | 4 (28.6) | - |
| Race/ethnicity | |||
| Caucasian | 18 (66.7) | 9 (64.3) | - |
| African American | 6 (22.2) | 2 (14.3) | - |
| Other | 3 (11.1) | 3 (21.4) | - |
| Device type | |||
| HeartMate 3 | 18 (66.7) | 10 (71.4) | 1.00c |
| HeartMate II | 8 (29.6) | 4 (28.6) | 1.00c |
| HeartWare | 1 (3.7) | 0 (0) | 1.00c |
| Body mass index – Kg/m2 | 29 ± 7.8 | 31.7 ± 8.1 | 0.31a |
| 26 (24 – 33) | 29.6 (26.2 – 35.2) | 0.21b | |
| MELD score | 12.8 ± 5 | 14.6 ± 3.8 | 0.19a |
| 12 (9 – 15) | 15 (12.3 – 17) | 0.10b | |
| INTERMACS score | |||
| 1 | 0 (0) | 1 (7) | 0.34c |
| 2 | 6 (22) | 1 (7) | 0.39c |
| 3 | 17 (63) | 11 (79) | 0.48c |
| 4-7 | 4 (14.8) | 1 (7) | 0.65c |
| IABP or Acute MCS/ECMO | 6 (22.2) | 5 (35.7) | 0.46c |
| Ischemic cause of heart failure | 14 (51.2) | 6 (42.9) | 0.59c |
| History of atrial fibrillation | 8 (29.6) | 10 (71.4) | 0.01c |
| History of stroke | 3 (11.1) | 2 (14.3) | 0.56c |
| Previous cardiac surgery | 6 (22.2) | 3 (21.4) | 0.64c |
| Hypertension | 16 (59.3) | 8 (57.1) | 0.90c |
| Diabetes Mellitus | 13 (48.1) | 8 (57.1) | 0.59c |
| History of smoking | 12 (44.4) | 7 (50) | 0.74c |
| Defibrillator | 24 (88.9) | 11 (78.6) | 0.33c |
| Pre-implant HLOS – days | 7 ± 6 | 7 ± 7 | 0.88a |
| Left ventricular ejection fraction – % | 11.7 ± 5 | 14.3 ± 3.9 | 0.07a |
| Arterial blood pressure – mmHg | |||
| Systolic | 111.9 ± 16.4 | 112.3 ± 12.4 | 0.93a |
| Diastolic | 69.1 ± 12.4 | 67 ± 9.3 | 0.55a |
| Mean | 82.4 ± 12.3 | 82.6 ± 8.6 | 0.94a |
| Central venous pressure – mmHg | 8.2 ± 5 | 9.4 ± 4.9 | 0.47a |
| 7 (4 – 12) | 7 (6 – 13.8) | 0.35b | |
| Pulmonary-capillary wedge pressure – mmHg | 18.8 ± 7.5 | 19.4 ± 7.8 | 0.81a |
| 19 (14 – 24) | 20 (12 – 26) | 0.82b | |
| Right ventricle stroke work index – g-m/m2 | 9 ± 3.2 | 9.3 ± 2.8 | 0.70a |
| 9 (6 – 11) | 8.8 (7.6 – 10.9) | 0.73b | |
| Pulmonary artery pulsatility index | 3.4 ± 1.7 | 4.3 ± 2.5 | 0.26a |
| 3.3 (2 – 4.4) | 3.6 (2.8 – 5.5) | 0.35a | |
| Cardiac index – liter/min/m2 of BSA | 2.2 ± 0.7 | 2.3 ± 0.8 | 0.97a |
Group A: normal OSM. Group B: elevated OSM. The data are presented as number (%), mean ± SD or median (Q1 – Q3).
P-values were derived from t-test
Mann-Whitney U test or
Fisher’s exact test.
P-values ≤ 0.05 were considered significant.
Preoperative care of these patients included careful screening for infection and the administration of infection prophylaxis. Routine screening included nasal swab testing for MRSA. With any concern of infection, patients underwent thorough workup including laboratory testing and blood cultures. All patients were devoid of clinical or laboratory findings concerning for infection before implantation. Patients underwent a universal decolonization protocol using chlorhexidine bath daily and intranasal mupirocin twice a day for 5 days prior to implantation.18,19 Patients were admitted to an ICU for hemodynamic optimization and pre-op preparation. Instrumentation was limited to that which was necessary for care and monitoring. Newly inserted Swan-Ganz catheters were placed in the ICU within 48 hours prior to operation.
As controls, 25 healthy subjects were enrolled. Their OSM levels (Mean ± SEM:17.3 ± 7.63 pg/mL; Median: 0 pg/mL) (Figure 1) were within reported values for healthy subjects.20,21
Figure 1. Comparison between the pre-operative plasma Oncostatin M levels in normal subjects and Group A and B patients.
No statistical significance in the baseline plasma Oncostatin M levels between the normal subjects and the Group A patients was noted. In contrast, there was a highly significant difference between the normal subjects and the Group B patients (p=0.004). The difference between Group A and Group B patients was also highly significant (p=0.003).
Blood collection and plasma preparation
Blood samples were collected in commercial vacuum tubes (Vacutainer, BD BioSciences) containing ethylenediaminetetraacetic acid (EDTA) from each patient after obtaining informed consent. A baseline sample was collected pre-operatively within 24 hours prior to LVAD implantation (Day -1). Additional samples were obtained 4-8 hours after implantation (Day 0), at Day 1,2,3, every two days until Day 21 and then weekly until the patient was discharged. Samples were subsequently collected during follow-up clinic visits for 2 months post-implantation.
Within 30 min after collection, blood samples were centrifuged at 1650g for 20 min at 4°C. The plasma was separated and immediately frozen at −80°C. All samples were stored at −80°C until analysis for OSM levels.
Measurement of OSM levels
Measurement of OSM was performed by established methodology using the DuoSet enzyme-linked immunosorbent assay (ELISA) (R&D Systems, Minneapolis MN) on human plasma samples following manufacturer’s recommendation. Controls consisting of pooled human plasma samples, with and without the addition of known concentrations of human OSM, were included in each assay. Each sample was measured in duplicates.
Statistical analysis
Between-group differences were assessed by Student t-test, Mann-Whitney U test or Fisher’s exact test. Freedom from post-operative infection was analyzed by the Kaplan-Meier method, while the Mann-Whitney U test was performed to analyze the difference between groups in the number of infections over 2 months post-implantation. Statistical analysis was performed with the SPSS statistical package (IBM, version 26) and Excel software (Microsoft Office Professional Plus 2010). P-values ≤ 0.05 were considered significant.
Results
Pre-operative OSM levels varied widely among advanced heart failure patients
Pre-operative (Day -1) plasma OSM levels of the advanced heart failure patients varied widely, ranging from 0 to nearly 6000 pg/mL. To shed light on the clinical relevance of variations in pre-operative OSM levels, we divided the patient population into two groups: Group A – patients with normal plasma OSM levels (Mean ± SEM: 4.9 ± 3.2 pg/ml; Median: 0 pg/mL, n=27, 66% of the total patient population); and Group B – those with elevated levels (Mean ± SEM: 1649.0 ± 458.9 pg/mL; Median: 842.6 pg/mL, n=14, 34% of the total patient population). The magnitude and the significance of elevated plasma OSM levels of Group B over Group A patients (p=0.003) and normal subjects (p=0.004) are depicted in Figure 1.
Post-operative profiles of OSM levels differed between Groups
Differences in the post-operative longitudinal profiles of serial plasma OSM levels were observed. In Group A, plasma OSM levels were low at baseline pre-operatively (4.9 ± 3.2 pg/mL), but then sharply increased (1943.1 ± 325.48 pg/mL, p<0.0001), peaking following LVAD implantation (Day 0) and then decreased progressively. Although Group A levels declined towards baseline levels, they remained elevated at 370.3 ± 156.6 pg/mL on Day 60 when compared to the baseline pre-operative levels of 4.9 ± 3.2 pg/ml (p=0.04), thus suggesting persistence of longer-term effects post-LVAD implantation (Figure 2).
Figure 2. Oncostatin M levels in advanced heart failure patients before LVAD implantation and for 60 days post-operatively.
Group A: normal OSM. Group B: elevated OSM. Pre-operative: Day -1. Data points represent mean ± SEM. P-values ≤ 0.05 were considered significant and denoted as * p ≤ 0.05 ** p ≤ 0.005.
In contrast, Group B patients started with markedly elevated OSM baseline pre-operative levels at 1649.0 ± 458.9 pg/mL, then peaked at 2869.6 ± 799.1 pg/mL on Day 2 followed by a slow decline. By Day 40, Group B OSM levels (932.1 ± 201.5 pg/mL) remained significantly higher compared to those of Group A (348.2 ± 137.7 pg/mL, p=0.04). Group B OSM levels continued to decline and by Day 60 (818.0 ± 551.7 pg/mL) they approached the lower Group A levels (370.3 ± 156.6 pg/mL) (Figure 2).
Patients with elevated baseline OSM levels experienced more post-operative infections
All infections that developed in both groups of patients within two months after implantation were identified using the ISHLT guidelines for characterizing infections in patients with LVADs, including LVAD-specific, LVAD-related and non-LVAD infections.22,23 Table 3 lists the types and number of infections observed in both groups.
Table 3.
Post-operative infections in LVAD recipients by type of infection and time of appearance.
| Group A (n=27) | Group B (n=14) | |||
|---|---|---|---|---|
| Type of infection | 0-30 days | 0-60 days | 0-30 days | 0-60 days |
| Pneumonia | 1 | 1 | 2 | 2 |
| Bacteremia | 0 | 1 | 1 | 1 |
| Gynecological infection | 0 | 0 | 1 | 1 |
| Mediastinitis | 0 | 0 | 1 | 1 |
| Urinary tract infection | 0 | 0 | 1 | 2 |
| Wound infection | 0 | 0 | 0 | 1 |
| Total infections | 1 | 2 | 6 | 8 |
| Infection per patient-month | 0.037 | 0.286 | ||
| Group A vs B (0-30 days) | p=0.006 | |||
| Group A vs B (0-60 days) | p=0.006 | |||
Group A: normal OSM (n=27 patients total with 2 patients experiencing 1 infection each). Group B: elevated OSM (n=14 patients total with 4 patients experiencing 1 infection each and 2 patients with 2 infections each). P-values ≤ 0.05 were considered significant.
Over the entire two month-period following implantation, Group B patients experienced more infections (n=8) than Group A (n=2) (Table 3, Mann-Whitney analysis, p=0.006). Most of the infections (75%) occurred in the first 30 days. (Table 3). The incidence of infection in Group B patients with elevated OSM levels pre-operatively was 0.286 per patient-month (8 infections in 14 patients over 2 months) compared with 0.037 per patient-month in Group A (2 infections in 27 patients over 2 months) (Figure 3, Kaplan-Meier analysis, p=0.004). Patients with pre-implant OSM levels above their normal range had a significantly higher prevalence of infections over two months following LVAD implantation.
Figure 3. Freedom from post-operative infections in patients from Group A versus Group B.
Group A: normal OSM. Group B: elevated OSM. Kaplan-Meier analysis in which a p-value ≤ 0.05 was considered significant.
Clinical parameters and basic lab tests did not differ between Groups
Baseline pre-operative clinical and demographic characteristics of patients in Groups A and B were similar, including risk factors for infection, such as Hemoglobin A1C (HbA1C) (p=0.30), diabetes (p=0.59) and BMI (p=0.31) (Table 1 and 2). These alone did not account for observed variations in pre-operative OSM levels as their correlation with BMI (Pearson’s correlation R=−0.096) and HbA1C (R=−0.1) were not significant (p=0.55) and p=0.67 respectively). We found no significant difference between BMI (p=0.44) or HbA1C (p=0.23) of patients with infection and those without infection; nor was there any association with the type of infection.
Table 2.
Pre-operative hematology and biochemistry laboratory values prior to LVAD implantation.
| Group A (n=27) | Group B (n=14) | p-value | |
|---|---|---|---|
| Oncostatin M (pg/mL) | 4.9 ± 3.2 | 1648 ± 458.9 | 0.003 a |
| White blood cells (x103/μL) | 7.2 ± 0.4 | 7.1 ± 0.4 | 0.90a |
| Neutrophils (x103/μL) | 4.8 ± 0.4 | 4.9 ± 0.1 | 0.91a |
| Lymphocytes (x103/μL) | 1.3 ± 0.1 | 1.2 ± 0.1 | 0.52a |
| Monocytes (x103/μL) | 1 ± 0.2 | 0.7 ± 0.1 | 0.27a |
| Neutrophil-lymphocyte ratio | 4.7 ± 0.7 | 5.3 ± 1.1 | 0.63a |
| Platelets (x103/μL) | 167.7 ± 12.1 | 180.4 ± 16.4 | 0.54a |
| Hemoglobin (g/dL) | 12.2 ± 0.3 | 11.8 ± 0.7 | 0.59a |
| Hematocrit (%) | 36.5 ± 0.8 | 35.3 ± 2.2 | 0.63a |
| BNP (pg/mL) | 847 ± 193 | 654 ± 205 | 0.50a |
| Hemoglobin A1C (%) | 6.7 ± 0.3 | 7.2 ± 0.3 | 0.30a |
| 6.2 (6 – 7.7) | 7.1 (6.5 – 8) | 0.15b | |
| ALT (unit/L) | 27 ± 3.6 | 27 ± 5.9 | 0.86a |
| AST (unit/L) | 27 ± 2.9 | 23 ± 1.4 | 0.19a |
| Total Bilirubin (mg/dL) | 1.1 ± 0.1 | 1.1 ± 0.1 | 0.91a |
| Creatinine (mg/dL) | 1.3 ± 0.1 | 1.5 ± 0.1 | 0.06a |
| BUN (mg/dL) | 24.5 ± 1.6 | 23.9 ± 2.4 | 0.82a |
| LDH (U/L) | 316.3 ± 28.7 | 279.5 ± 50.7 | 0.56a |
| Alkaline Phosphatase (unit/L) | 90.3 ± 5.9 | 86.6 ± 9.7 | 0.75a |
Group A: normal OSM. Group B: elevated OSM. The data are presented as mean ± SEM or median (Q1 – Q3).
P-values were derived from t-test or
Mann-Whitney U test
P-values ≤ 0.05 were considered significant.
The degree of right ventricular failure (RVF) did not account for differences in OSM level. Markers such as PAPi (p=0.26) and RVSWI (p=0.70) values were similar between Group A and B (Table 1). These RVF markers were not different between patients with (p=0.17) or without infection (p=0.84).
The only statistically significant finding was the number of patients with a history of atrial fibrillation (AF) in Group A versus Group B (p=0.01). However, there was no difference in OSM levels (p=0.24) or the incidence of infection (p=0.71) between those with or without AF.
Routine pre-operative hematology and biochemistry laboratory tests were not significantly different between Groups A and B (Table 2). Levels of hemoglobin, hematocrit, alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, blood urea nitrogen (BUN), lactate dehydrogenase (LDH) and alkaline phosphatase were also similar over 21 days between the two Groups (Figures S1-8). Furthermore, there was no difference in blood products transfused to patients in the two Groups (Table S1).
Total WBC counts as well as WBC differentials, including neutrophils, lymphocytes, neutrophils/lymphocytes ratios and monocytes, were not different between Groups pre-operatively (Table 2) or post-operatively (Figures 4A-E). However, plasma OSM levels were markedly higher in Group B patients (Figure 2), thus suggesting a higher state of leukocyte activation and greater release of OSM in these patients.
Figures 4 A-E. Longitudinal analysis of leukocyte hematology lab values: Total White Blood Cells (Fig. 4.A), Neutrophils (Fig. 4.B), Lymphocytes (Fig. 4.C), Neutrophils/Lymphocytes ratio (Fig. 4.D), Monocytes (Fig. 4.E).
Group A: normal OSM. Group B: elevated OSM. Pre-operative: Day -1. Data points represent mean ± SEM. No statistically significant differences (p-value ≤ 0.05) were noted.
Discussion
Oncostatin M level as a pre-operative predictor of early post-operative LVAD infection
This is the first known report exploring the potential for Oncostatin M (OSM), a cytokine marker of leukocyte activation, to serve as a pre-operative predictor of risk for infection following LVAD implantation in advanced heart failure patients.
In this study, patients with elevated plasma OSM levels prior to LVAD implantation (Group B; 34% of the total patient population) experienced significantly more early infections following LVAD implantation than those with normal pre-operative OSM levels (Group A; 66% of the total patient population). The incidence of infection in Group B patients with elevated OSM levels pre-operatively was 0.286 per patient-month, substantially higher than the 0.037 per patient-month incidence in Group A. No other parameter among those routinely assessed in the pre-operative evaluation of LVAD candidates served to predict risk for infection, including pre-operative clinical characteristics and hematology or biochemistry laboratory findings. This raises the level of importance of the discovery that OSM, as a laboratory biomarker of inflammation, may have unique predictive potential.
The value of OSM as a predictor, or marker, of infection may extend beyond the pre-operative period into the early post-operative phase. The persistence of markedly elevated OSM levels for the first month beyond the implantation of an LVAD with Group B patients was associated with a higher incidence of infection (n=6 of 8, 75%) in contrast to the second month (n=2 of 8, 25%) during which OSM levels had fallen well below pre-operative levels (Figure 1 and Table 3). This observation is consistent with the relative magnitude of OSM levels having predictive value wherein the higher the OSM level, the higher would be the relative risk of infection. Whether elevated OSM levels subsequent to LVAD implantation represent a predisposition to infection or are elevated as a consequence of a sustained inflammatory state acquired post-operatively will require further study.
Oncostatin M (OSM) has unique characteristics that support its role as a biomarker for infections. It has been well established that OSM synthesis and subsequent release are triggered by the activation of leukocytes in response to infection10-13. Among different types of leukocytes, neutrophils release OSM more rapidly following their activation11-17. Consequently, neutrophils are prominent determinants of plasma OSM levels as they are the most abundant type of leukocytes, capable of releasing OSM rapidly and have relatively rapid turn-over.24 Given the potential value of OSM as a biomarker for infection, further examination of the mechanisms that regulate plasma OSM levels is warranted.
Oncostatin M for assessing patient optimization prior to LVAD implantation
The heart failure field is replete with studies of biomarkers for characterizing the pathophysiology of the disease, its prognosis and targets for therapy. 25-27 While these unique laboratory parameters, such as B-type natriuretic peptide (BNP), are indicative of an advanced state of heart failure with associated risk, they have not found routine use for guiding the best timing for LVAD implantation or for pre-operative optimization.28 Instead, tools such as the INTERMACS level of acuity, well-characterized as predictive of outcomes, are used routinely to guide decisions about timing for implantation, as are clinical assessments of risk factors for right heart failure, end-organ dysfunction, coagulopathy and malnutrition among others.
This study raises the possibility that OSM may serve not only to predict infection risk but may also serve as a useful indicator of the overall inflammatory state of an advanced heart failure patient. That being the case, OSM could potentially serve as a measure by which to guide pre-operative optimization and timing in relationship to a patient’s inflammatory state and risk for infection.
Oncostatin M as an indicator of LVAD hemocompatibility
An intriguing finding of this study is the persistence of elevated levels of OSM, well above normal baseline values, out to 2 months, extending well beyond the generally expected effects of surgery itself. The possibility of sustained LVAD-induced mechanical trauma to blood, invoked by shear forces within the blood pumps, should be considered as an alternative mechanism by which leukocytes are activated and release OSM.
This should not be too surprising given the abundant information now available addressing hemocompatibility limitations with other blood components and associated adverse events with current LVADs.29,30 That LVAD-induced blood trauma may activate, and damage leukocytes has been reported. Increased microparticle formation from leukocytes has been observed in LVAD patients.31 Leukocyte damage, as indicated by microparticle formation and the release of markers of activation, has been demonstrated in laboratory studies of blood flow circuits with LVADs currently in clinical use.32 Early studies employing in vitro simulations of LVAD blood flow conditions on leukocytes of healthy subjects have demonstrated alterations consistent with leukocyte activation.33
Study Limitations
This study is an early observational study limited by the number of patients. Nevertheless, the pre-operative differentiation into two groups based on pre-operative OSM levels as a biomarker for leukocyte activation status and inflammation is evident, and the association of that finding with differences in the incidence of infection is compelling.
We cannot absolutely exclude the possibility that undetected infection was present pre-operatively in those patients who later developed infections, although there were no pre-operative clinical or laboratory findings customarily associated with infection. Had that been the case, however, it most likely would have been limited to a very low incidence given extensive pre-operative screening rigor. Further, the preponderance of infections appeared to have presentations and characteristics suggestive of de novo infections acquired post-operatively. Future studies could include other markers of infection, such as C-reactive protein (CRP) and procalcitonin (PCT), that maybe helpful in identifying subclinical infection.
Conclusion
In conclusion, patients undergoing LVAD implantation who had elevated pre-operative levels of Oncostatin M (OSM), a cytokine marker of leukocyte activation and inflammation, were more likely to develop infections after LVAD implantation. Routine clinical assessments and pre-operative lab tests were not helpful in differentiating patients who would later develop infections from those who did not. These novel findings suggest that OSM measured pre-operatively may potentially serve as a much-needed tool for predicting the risk of infection and prolonged inflammation after LVAD implantation.
These important observations open the door for further studies confirming these early findings, validating the predictive reliability of OSM for pre-operative assessment of infection risk, comparing the performance of OSM to other markers for infection, assessing the utility of OSM as a biomarker for optimizing a patient’s condition prior to LVAD implantation and exploring possible LVAD hemocompatibility-related effects on leukocytes that may contribute to infection.
Supplementary Material
Acknowledgement
We thank INTEGRIS team for the clinical, administrative and research support.
Conflict of Interest and Source of Funding Statement:
Dr. Horstmanshof has served as an advisor for Abbott Medical.
Dr. Long has served as an advisor for Abbott Medical and co-founder of an organization for pre-clinical blood pump research and development.
The other authors declare no conflict of interest.
This work was supported by the National Heart, Lung, and Blood Institute grant R21HL132286-01 and the INTEGRIS Foundation.
Footnotes
Supplemental Data
Figures S 1-8. Longitudinal profile of hemoglobin, hematocrit, alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, blood urea nitrogen (BUN), lactate dehydrogenase (LDH) and alkaline phosphatase levels respectively. The data represent mean ± SEM. No statistically significant differences (p-value ≤ 0.05) were noted.
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