Introduction
The global prevalence of heart failure is increasing, driven by aging and rising cardiovascular risk factors. The accessibility of left ventricular mechanical assist devices (LVADs) offers favorable short- and long-term results, making the method one of the preferred therapeutic options, particularly in emergencies [1]. Significant clinical improvement in LVAD patients, including enhanced quality of life and survival, has been reported; however, a relatively high incidence of driveline complications, a major complication affecting patient outcomes, persists [2]. The neutrophils, as the first line of response of the innate immune system, are critical in combating infections. Emerging evidence also suggests their role in the pathophysiology of cardiovascular disease, including heart failure and device-related complications [3, 4].
The study aimed to compare neutrophil extracellular trap (NET) formation measured by serum citrullinated histone 3 (CitH3) concentration in LVAD (H3, Abbot, Illinois, USA) patients with and without driveline infection.
Material and methods
Twenty-five white Caucasian male patients with a median age of 56 (range: 51–62) years who underwent LVAD (HM3 implantation, Abbott Inc., Nathan Lane North, Plymouth, USA) for congestive heart failure secondary to dilated (14 (56%)) and ischemic (11 (44%)) cardiomyopathy were enrolled in the analysis. Preoperative, perioperative, and postoperative clinical characteristics and blood samples for citH3 measurements were collected. Laboratory test, 6-minute walking tests (6MWT), and transthoracic echocardiography were performed during a 1-day hospitalization. The blood samples for citH3 were gathered, and the analysis was performed as described previously [5].
Driveline infection was categorized according to previous definitions [6], including positive microbiological cultures from the driveline site presenting with local redness, swelling, and pain requiring antibiotic therapy.
Statistical analysis
Since the data did not follow a normal distribution, continuous variables were reported as medians and interquartile ranges (IQR: Q1–Q3). Categorical data were presented as counts and percentages. The Mann-Whitney test was used to compare interval parameters between groups, while categorical data were analyzed using a χ2 test of independence. The repeated-measure ANOVA test was applied to compare preoperative and postoperative data. Statistical analysis was performed using JASP statistical software (JASP Team, 2023, Version 0.18.1). A p-value < 0.05 was considered statistically significant.
Results
The mean follow-up time was 242 (296–1277) days. Driveline infection was observed in 7 (28%) patients during outpatient follow-up, comprising group 1, while 18 (72%) patients without driveline infections served as the control group (group 2).
No significant differences were observed in LVAD performance parameters between groups 1 and 2. Median values of radial pump flows were 4629 (1823)/min vs. 5139 (171)/min (p = 0.13), with calculated outputs 4.5 (0.3) vs. 4.5 (0.3) l/min (p = 0.19), and pulsatility indexes of 2.1 (0.2) vs. 2.1 (0.1) (p = 0.95) were not different between groups 1 and 2, respectively. Functional status, assessed by the New York Heart Association (NYHA) classification, was comparable between groups, with 11 (44%) patients classified as NYHA class I and 14 (56%) patients as NYHA class II. Similarly, the 6-minute walking test (6MWT) showed no significant difference between both groups, with a median distance of 375 m (IQR: 349–428) in group 1 versus 384 m (IQR: 363–409) in group 2 (p = 0.83).
In group 1, driveline infections were associated with methicillin-resistant Staphylococcus aureus (MRSA) in 5 (71%) patients and Pseudomonas aeruginosa (PE) in 2 (29%) patients, as possible causative factors.
No significant differences were found between group 1 and group 2 in baseline characteristics, including age (p = 0.95), prevalence of diabetes mellitus (p = 0.38), kidney function (p = 0.96), clinical status (p = 0.77), and N-terminal pro-brain natriuretic peptide serum concentration (p = 0.35), Table I.
Table I
Demographic, clinical, and echocardiographic characteristics
[i] ALT – alanine transaminase, AST – aspartate aminotransferase, citH3 – citrullinated histone 3, CRP – C-reactive protein, BMI – body mass index, citH3 – citrullinated histone 3, GFR – glomerular filtration rate, Hb – hemoglobin, IVs – interventricular septum, LA – left atrial diameter, LDH – lactate dehydrogenase, LVEF – left ventricular ejection fraction, LVID – left ventricular diastolic diameter, MR – mitral regurgitation, NYHA – New York Heart Association, NT-pro-BNP – N-terminal pro–B-type natriuretic peptide, Plt – platelets, RVDD – right ventricular diastolic diameter, n – number, TAPSE – tricuspid annular plane systolic excursion, TR – tricuspid regurgitation, SD – standard deviation, Q – quartiles, WBC – white blood count.
The preoperative right catheterization revealed a median cardiac index of 2.02 l/min/m2 (IQR: 1.7–2.1), median pulmonary vascular resistance of 315 dyn·s/m5 (IQR: 142–404) and median pulmonary artery pressure of 35 mm Hg (IQR: 21–49). Postoperative serum citH3 concentration, a biomarker of NET formation, was significantly higher in group 1 (median 3217 pg/ml (IQR: 2792–3306) compared with group 2 (median 408 pg/ml, IQR: 241–1498), p = 0.049.
Neither the preoperative citH3 concentration (median 2262 pg/ml, IQR: 1554–2525 in group 1 vs. 2569 pg/ml, IQR: 2031–2788 in group 2, p = 0.51) nor perioperative results (median 3820 pg/ml, IQR: 3229–4410 in group 1 vs. 4018 pg/ml, IQR: 3659–4802, p = 0.85) distinguished between the groups, as presented in Table I.
Discussion
Our analysis highlights the significant role of driveline infection in promoting a prothrombotic state in LVAD patients. We observed significant differences in CitH3 concentrations in LVAD patients, associated with increased neutrophil extracellular trap formation related to driveline infections. This suggests that driveline infections are linked to NET formation. The immunological system response to heart failure has been previously postulated [7], and our study confirmed elevated preoperative citH3 serum concentration in all LVAD patients, indicating a baseline proinflammatory state. NET formation is known to activate the coagulation cascade, contributing to cardiovascular complications, including thrombosis, which may lead to worse outcomes in LVAD patients [8, 9].
Driveline infections are well-documented complications in LVAD recipients and related to either patient or non-patient factors [10]. Current evidence indicates that driveline infections are often chronic, with pathogen eradication posing a significant challenge. As a result, pharmacotherapy modifications, such as chronic or recurrent antibiotic therapy, are frequently used. According to our study, driveline infections are associated with prothrombotic activation, as evidenced by elevated CitH3 concentrations. This prothrombotic state should warrant clinical attention and may necessitate a more aggressive anticoagulation strategy to reduce thrombotic risk.
In LVAD (HM3) patients with concomitant driveline infection, citH3 can be considered as a potential biomarker for risk stratification. We may suggest that either continuation/adding antiplatelet therapy to VKA or more aggressive oral anticoagulation with an upper limit of international normalized ratio could be advised according to the results from the study.
The results are from a single-center prospective analysis performed on male patients. NET formation was diagnosed based on citrullinated histone 3 serum concentration. The analysis was restricted to the HM3 (Abbott Inc., Nathan Lane North, Plymouth, USA) device.
Conclusions
Driveline infection, though localized, can trigger a systemic inflammatory response mediated by neutrophils, leading to NET formation. Elevated NET formation, as measured by CitH3, is a potential driver of immunothrombotic events in LVAD patients with driveline infections. Our findings suggest that a more aggressive anticoagulation approach in LVAD patients presenting with driveline infection may be required to reduce thrombotic risk. However, the presented hypothesis requires further investigation into a larger group of participants to confirm the clinical implications and optimize therapeutic strategies.
