High Baseline Interleukin-6 Linked to Elevated Cardiovascular Risks After TAVI

In an exploratory biomarker substudy of a prospective multicenter cohort, researchers assessed the prognostic value of circulating inflammatory markers in patients undergoing transcatheter aortic valve implantation for severe aortic stenosis. Patients exhibiting high baseline interleukin-6 signal had a statistically significant, more than threefold increased hazard of major adverse cardiac and cerebrovascular events within twelve months after adjusting for age and sex. However, this association was absent in unadjusted analyses, lacked statistical significance in continuous modeling, and proved highly sensitive to cutoff selection. Concurrently, baseline concentrations of soluble interleukin-6 receptor displayed no significant links to twelve-month complications or long-term mortality. The investigators emphasized that while these observations provide biologically plausible insights into post-procedural risk, the findings remain strictly exploratory and hypothesis-generating.

Severe aortic stenosis is a progressive valvular disease that represents the most frequent valve pathology in developed nations, arising predominantly from calcific leaflet degeneration. Because medical therapies cannot alter the natural progression of valve stenosis, mechanical intervention remains the definitive treatment standard. Under joint clinical practice guidelines from the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery, transcatheter aortic valve implantation is generally recommended for patients aged seventy years or older with suitable tricuspid anatomy. Identifying reliable circulating biomarkers capable of predicting clinical outcomes before catheter-based valve deployment could refine clinical decision-making and assist multidisciplinary teams in optimizing therapeutic timing.

Inflammatory signaling cascades are increasingly implicated in the initiation and active propagation of calcific aortic stenosis. Genome-wide association meta-analyses have previously identified the interleukin-6 gene locus as a susceptibility factor implicated in calcific valve pathogenesis. Clinical studies have also demonstrated that pharmacological inhibition of interleukin-6 signaling can reduce circulating concentrations of lipoprotein(a), an established risk factor previously shown by the same research group to correlate with diminished survival following transcatheter valve replacement. These pathophysiological connections motivated the multicenter team to explore whether interleukin-6 and its soluble receptor might offer practical prognostic value.

The research was organized as a biomarker substudy nested within a prospective multicenter parent cohort of individuals diagnosed with severe aortic stenosis. Eligible participants presented with severe obstruction, defined by an aortic valve area under 1.0 square centimeter or an indexed valve area below 0.6 square centimeters per square meter, and were selected for transcatheter implantation by local Heart Teams across three clinical centers. Enrolment took place between December 2018 and September 2021, yielding an analytic substudy cohort of sixty-two patients with available baseline plasma suitable for testing. The formal investigation protocol received ethical approval from the Ethics Committee at the Medical University of Warsaw under references KB/128/2018 and KB/4/A2021, and all participating patients provided written informed consent prior to inclusion.

The median age was 79.5 years, 53.2 percent of participants were female, and the median EuroSCORE II was 3.3. Baseline parameters and operative risk scores were recorded during index hospitalization. When comparing the sixty-two analyzed patients with seventy-eight individuals from the parent prospective cohort who lacked stored plasma samples, investigators noted minor baseline imbalances, particularly in operative risk calculations and echocardiographic findings.

Venous blood samples drawn at baseline during the index hospitalization were double-centrifuged at 2500 times gravity for fifteen minutes at twenty degrees Celsius to prepare platelet-depleted plasma, which was stored at minus twenty degrees Celsius. Laboratory testing was performed centrally several years later using coded samples, without knowledge of patient clinical outcomes. Interleukin-6 and soluble receptor levels were quantified using commercial enzyme-linked immunosorbent assay kits from Abcam, models ab178013 and ab46029, run in duplicate technical replicates under uniform laboratory conditions. For the soluble receptor, sample concentrations were interpolated against a seven-point serial dilution standard curve using a four-parameter logistic model, with manufacturer-reported inter-assay coefficients of variation between 1.06 and 4.46 percent.

A crucial methodological obstacle occurred during interleukin-6 measurement, where thirty-one of the sixty-two specimens registered mean optical density values below 0.034, corresponding to the assay’s lowest-concentration calibration standard. Because numerous samples fell near background signal limits, calculating interpolated concentrations would have introduced substantial quantitative error. Researchers therefore categorized interleukin-6 status using raw mean optical density measurements rather than interpolated concentrations. For primary comparisons, patients were stratified into low and high biomarker groups using rank-based tertiles, where the lower two tertiles constituted the low group and the upper tertile represented the high group. In contrast, all soluble interleukin-6 receptor measurements fell cleanly within quantifiable dynamic ranges, permitting direct evaluation of calculated circulating concentrations. Sensitivity evaluations tested alternative classification thresholds, including a median split and an upper-quartile division, to verify the consistency of the findings.

The substudy focused on two primary endpoints: the incidence of major adverse cardiac and cerebrovascular events within twelve months after transcatheter implantation, and overall survival across extended follow-up. The composite adverse event endpoint comprised all-cause mortality, myocardial infarction, stroke, transient ischemic attack, heart failure worsening requiring intensified diuretics or hospitalization, valve reintervention, and prosthetic valve thrombosis. Diagnostics using scaled Schoenfeld residuals confirmed that the proportional hazards assumption held across all primary models. Patients completing twelve months without an adverse event were censored at 365 days or their last clinical visit. Secondary endpoints comprised individual adverse event components reported descriptively.

During twelve-month follow-up, major adverse cardiac and cerebrovascular complications occurred in eleven patients overall, affecting five of forty-two individuals (11.9 percent) in the low interleukin-6 group versus six of twenty (30.0 percent) in the high group. In unadjusted Kaplan-Meier analysis, the between-group difference showed a borderline trend without achieving statistical significance (log-rank P = 0.07). However, after adjusting for age and sex using Firth penalized Cox regression, high baseline interleukin-6 was significantly associated with increased twelve-month event risk, yielding a hazard ratio of 3.31 (95% confidence interval, 1.02 to 11.04; P = 0.0458). The median observed time to first complication or censoring across the entire study population was 264.5 days. Worsening heart failure represented the most frequent individual adverse event, followed by all-cause mortality, though individual secondary complications were evaluated descriptively without between-group hypothesis testing.

Despite the observed correlation with twelve-month complications, baseline interleukin-6 did not predict long-term overall mortality across an average follow-up of 2.8 ± 1.3 years. Death from any cause occurred in ten of forty-two patients (23.8 percent) in the low interleukin-6 group and seven of twenty (35.0 percent) in the high group (log-rank P = 0.26; adjusted hazard ratio, 2.38; 95% CI, 0.86 to 6.34; P = 0.09). Continuous, log-transformed and standardized optical density analysis likewise showed no significant association with twelve-month events (hazard ratio per 1-SD increase, 1.52; 95% CI, 0.86 to 2.46; P = 0.13). Optical density displayed moderate positive correlation with C-reactive protein (Spearman rho = 0.49; P < 0.001). Exploratory adjustment for atrial fibrillation attenuated the twelve-month event relationship so it no longer reached statistical significance.

In contrast to interleukin-6, soluble interleukin-6 receptor concentrations showed no significant associations with primary clinical outcomes. Twelve-month adverse events occurred in seven of forty-two patients (16.7 percent) with low soluble receptor concentrations compared with four of twenty (20.0 percent) in the high group (log-rank P = 0.68; adjusted hazard ratio, 1.22; 95% CI, 0.34 to 3.94; P = 0.74). Long-term mortality occurred in twelve patients (28.6 percent) in the low group and five (25.0 percent) in the high group (log-rank P = 0.76; adjusted hazard ratio, 0.75; 95% CI, 0.25 to 2.02; P = 0.58). A subgroup interaction for mortality emerged by chronic kidney disease status (P = 0.03; hazard ratio 3.44 with kidney disease versus 0.43 without), though investigators emphasized this pattern remained exploratory.

Sensitivity analyses highlighted the sensitivity of the primary interleukin-6 findings to threshold selection. While a 30-day landmark analysis showed significant separation in event-free survival (log-rank P = 0.03), associations became non-significant when using median cutoffs (P = 0.15) or upper-quartile splits (P = 0.25). Authors highlighted several methodological limitations, including the small cohort of sixty-two patients, sparse event rates, potential selection bias from available stored plasma, prolonged sample freezing, unmeasured soluble glycoprotein 130, reliance on optical density rather than quantified concentrations, and incomplete twelve-month follow-up in twenty-nine censored patients. Administrative follow-up concluded on November 12, 2023, leaving definitive clinical evaluation to future investigations.

Subject of Research: Inflammatory biomarkers and clinical outcomes following transcatheter aortic valve implantation

Article Title: Interleukin-6, soluble interleukin-6 receptor, and outcomes after transcatheter aortic valve implantation: an exploratory biomarker substudy of a prospective multicenter cohort

Article References: Procyk, G., Tyrna, P., Młynarczuk-Biały, I., Budzianowski, J., Olasińska-Wiśniewska, A., Kochman, J., & Gąsecka, A. (2026). Interleukin-6, soluble interleukin-6 receptor, and outcomes after transcatheter aortic valve implantation: an exploratory biomarker substudy of a prospective multicenter cohort. Molecular Biology Reports, 53(1), Article 1941. https://doi.org/10.1007/s11033-026-13152-4

Image Credits: AI Generated

DOI: 10.1007/s11033-026-13152-4

Keywords: transcatheter aortic valve implantation, interleukin-6, soluble interleukin-6 receptor, aortic stenosis, major adverse cardiac and cerebrovascular events, biomarkers, cardiovascular outcomes, C-reactive protein, Firth penalized Cox regression, heart failure worsening, systemic inflammation, calcific aortic valve disease, atrial fibrillation, chronic kidney disease, optical density, enzyme-linked immunosorbent assay, overall survival