Inflammatory immune response in recipients of transcatheter aortic valves

Abstract

Objective: Transcatheter aortic valve implantation (TAVI) is rapidly replacing cardiac surgery due to its minimal invasiveness and practicality. Midterm immunological studies on the biocompatibility of galactose-alpha-1,3-galactose (α-Gal)-carrying bioprosthetic heart valves for TAVI are not available. In this study we investigated whether bioprosthetic heart valves employed for TAVI augment an α-Gal-specific antibody-dependent and antibody-independent immune response 3 months after TAVI implantation.

Methods: This prospective observational study included 27 patients with severe aortic valve stenosis undergoing TAVI and 10 patients with severe mitral valve regurgitation treated with a transcatheter MitraClip (Abbott Laboratories, Abbott Park, Ill) procedure. Blood samples were drawn before and 90 days after treatment at a routine checkup. Serum samples were analyzed using enzyme-linked immunosorbent assay. Serum concentrations of α-Gal-specific immunoglobulin (Ig) G, IgG subclasses and IgE, complement factor 3a, NETosis-specific citrullinated H3, and the systemic inflammation markers soluble suppression of tumorigenicity and interleukin 33 were evaluated.

Results: Three months after TAVI, we found significantly increased serum concentrations of α-Gal-specific IgG3, complement factor complement factor 3a, citrullinated H3 levels, and soluble suppression of tumorigenicity (P = .002, P = .001, P = .025, and P = .039, respectively). Sensitization of α-Gal-specific IgE antibodies occurred in 55% of all patients after TAVI.

Conclusions: Our results indicate that TAVI elicits a midterm, specific humoral immune response against α-Gal and causes an unspecific humoral inflammation compared with patients undergoing MitraClip implantation. This observation will lead to a better understanding of postintervention morbidity and the long-term durability of bioprostheses and indicates that caution is appropriate when designing implantation strategies for younger patients.

Keywords: BHV, bioprosthetic heart valve; C3a, complement factor 3a; CitH3, citrullinated H3; DAPI, 4′,6-diamidino-2-phenylindole; ELISA, enzyme-linked immunosorbent assay; IL, interleukin; Ig, immunoglobulin; MitraClip; NET, neutrophil extracellular traps; NETosis; NT-proBNP, N-terminal pro-brain natriuretic peptide; ST2; TAVI; TAVI, transcatheter aortic valve implantation; alpha Gal; bioprosthetic heart valves; complement activation; mAb, monoclonal antibody; sST2, soluble suppression of tumorigenicity-2; α-Gal, galactose-alpha-1,3-galactose.

Graphical abstract

Significant immune response after transcatheter aortic valve implantation (TAVI) and MitraClip (Abbott Laboratories, Abbott Park, Ill). Three months after TAVI we found significantly increased serum concentrations of galactose-alpha-1,3-galactose (α-Gal-specific IgG3), complement factor 3a (C3a), citrullinated H3 (citH3), and soluble suppression of tumorigenicity (sST2) levels compared with baseline levels (P = .002, P = .001, P = .025, and P = .039). Three months after MitraClip implant, citH3 levels were significantly elevated compared with baseline levels (P = .03).

Figure 1

Inflammatory immune response in transcatheter aortic valve implantation (TAVI) and MitraClip (Abbott Laboratories, Abbott Park, Ill) recipients. Hypothesis: Biological medical devices for TAVI induce an galactose-alpha-1,3-galactose (α-Gal)–specific antibody dependent and antibody-independent immune response 3 months after implantation. Methods: Serum samples were drawn before and 90 days after TAVI and MitraClip and analyzed for α-Gal-specific immunoglobulin (Ig) G, IgG subclasses, IgE, complement factor 3a (C3a), citrullinated H3 (CitH3), soluble suppression of tumorigenicity-2 (sST2), and interleukin (IL)-33 using the enzyme-linked immunosorbent assay technique. Results: Significant immune responses were observed after TAVI in C3a, α-Gal-specific IgG3, citH3, and sST2 and MitraClip in citH3. – indicates no significance; + indicates significance.

Figure 2

Significantly increased serum concentration of complement factor 3a (C3a), citrullinated H3 (CitH3), and soluble suppression of tumorigenicity-2 (sST2) 3 months after transcatheter aortic valve implantation (TAVI) compared with baseline levels. A, Three months after TAVI, C3a serum concentrations were significantly elevated compared to baseline levels. B, C3a serum concentrations did not increase 3 months after MitraClip (Abbott Laboratories, Abbott Park, Ill). C and D, Three months after TAVI and MitraClip, CitH3 serum concentrations were significantly upregulated compared with baseline levels. E and F, In TAVI patients, but not MitraClip patients, sST2 serum concentrations were significantly higher 3 months after intervention. For statistical analyses of serum concentrations between baseline levels and 3 months after TAVI or MitraClip the Wilcoxon matched-pairs signed-rank test was used.