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. 2022 Sep 6;14(1):112.
doi: 10.1186/s13148-022-01331-6.

Serum level of total histone 3, H3K4me3, and H3K27ac after non-emergent cardiac surgery suggests the persistence of smoldering inflammation at 3 months in an adult population

Krzysztof Laudanski  1   2   3 , Da Liu  4 , Jihane Hajj  5 , Danyal Ghani  6 , Wilson Y Szeto  7
Affiliations

Serum level of total histone 3, H3K4me3, and H3K27ac after non-emergent cardiac surgery suggests the persistence of smoldering inflammation at 3 months in an adult population

Krzysztof Laudanski et al. Clin Epigenetics. .

Abstract

Background: Despite clinical relevance of immunological activation due to histone leakage into the serum following cardiac surgery, long-term data describing their longitudinal dynamic are lacking. Therefore, this study examines the serum levels of histone 3 (tH3) and its modifications (H3K4me3 and H3K27ac) alongside immune system activation during the acute and convalescence phases of cardiac surgery.

Methods: Blood samples from fifty-nine individuals were collected before non-emergent cardiac surgery (tpre-op) and 24 h (t24hr), seven days (t7d), and three months (t3m) post-procedure to examine serum levels of tH3, H3K4me3, and H3K27ac. Serum heat shock protein-60 (HSP-60) was a surrogate of the cellular damage marker. Serum C-reactive protein (CRP) and interleukin 6 (IL-6) assessed smoldering inflammation. TNFα and IL-6 production by whole blood in response to lipopolysaccharide (LPS) evaluated immunological activation. Electronic medical records provided demographic, peri-operative, and clinical information. Paired longitudinal analyses were employed with data expressed as mean and standard deviation (X ± SD) or median and interquartile range (Me[IQ25; 75%].

Results: Compared to pre-operative levels (tH3Pre-op = 1.6[0.33;2.4]), post-operative serum tH3 significantly (p > 0.0001) increased after heart surgery (tH324hr = 2.2[0.3;28]), remained elevated at 7 days (tH37d = 2.4[0.37;5.3]), and at 3 months (tH33m = 2.0[0.31;2.9]). Serum H3K27ac was elevated at 24 h (H3K27ac24hr = 0.66 ± 0.51; p = 0.025) and seven days (H3K27ac7d = 0.94 ± 0.95; p = 0.032) as compared to baseline hours (H3K27acPre-op = 0.55 ± 0.54). Serum H3K4me3 was significantly diminished at three months (H3K4me3Pre-op = 0.94 ± 0.54 vs. H3K27ac3m = 0.59 ± 0.89; p = 0.008). tH3 correlated significantly with the duration of anesthesia (r2 = 0.38). In contrast, HSP-60 normalized seven days after surgery. Peri-operative intake of acetaminophen, but no acetylsalicylic acid (ASA), acid, ketorolac or steroids, resulted in the significant depression of serum H3K4me3 at 24 h (H3K4me3acetom- = 1.26[0.71; 3.21] vs H3K4me3acetom+ = 0.54[0.07;1.01]; W[50] = 2.26; p = 0.021). CRP, but not IL-6, remained elevated at 3 months compared to pre-surgical levels and correlated with tH324hrs (r2 = 0.43), tH37d (r2 = 0.71; p < 0.05), H3K4me37d (r2 = 0.53), and H3K27ac7d (r2 = 0.49). Production of TNFα by whole blood in response to LPS was associated with serum tH324hrs (r2 = 0.67). Diminished H3K4me324hrs, H3K27ac24hrs, and H3K27ac3m, accompanied the emergence of liver failure.

Conclusions: We demonstrated a prolonged elevation in serum histone 3 three months after cardiac surgery. Furthermore, histone 3 modifications had a discrete time evolution indicating differential immune activation.

Keywords: Acetaminophen; Cardiac surgery; H3K427ac; H3K4me3; Histone 3; Long-term outcome; Smoldering inflammation.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Histone levels pre- and post-cardiac surgery. A Serum tH3 levels before surgery (Pre-op), and 24 h (t24h), 7 days (t7d), and 3 months (t3m) after surgery; Histone modifications H3K4me3 (stripes) B and H3K27ac (dots) C at Pre-op, t24h, t7d, and t3m; and changes in %tH modifications over time before and post cardiac surgery (C). *two-sided p < 0.05; #one sided p < 0.05
Fig. 2
Fig. 2
tH3 serum level and peri-operative events. There was significant correlation between tH3 and duration of anesthesia A as well as other measures of the burden of surgical intervention B with only significant (p < 0.05) presented on figure B
Fig. 3
Fig. 3
General inflammatory markers pre- and post-cardiac surgery. Serum CRP (dark scales) and IL-6 (dark bubbles) levels before surgery (tPre-op), and 24 h (t24h), 7 days (t7d), and 3 months (t3m) after surgery. *p < 0.05 as compared to tpre-op
Fig. 4
Fig. 4
General inflammatory markers pre- and post-cardiac surgery. A Correlation between tH324h and CRP at 24 h (A) and 7 days (B). Cluster analysis of patients grouped the individuals at 24 h into clusters #1, 2, and 3 (C). At long term follow-up only two clusters were seen, one with persistent inflammation containing patients (D). Levels of IL-6 (red), CRP (yellow), and tH3 (black line) are indicated
Fig. 5
Fig. 5
Correlation between leukocyte activation and serum H3K27ac. A significant correlation is seen between TNFα production in response to LPS by whole blood and serum H3K27ac levels at 24 h post-surgery
Fig. 6
Fig. 6
Histone levels in patients with and without liver failure. Levels of H3K27ac were elevated at 24 hours, 7 days amd 3 months post-surgery in patients with liver failure [Lf( +)] as compared to those and without liver failure [Lf(-)]. In contrast, H3Kme4 was significantly different only at 24 h. *p < 0.05 for two-sided hypothesize, #p < 0.05 for one-sided hypothesize
Fig. 7
Fig. 7
Changes in tH3 level between older (over 60 years old) and younger. Younger subjects demonstrated elevated levels of circulating histone 3 before the surgery, 24 h and 7 days but not three months. *denotes p < 0.05 when comparing both age populations
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References

    1. Day JR, Taylor KM. The systemic inflammatory response syndrome and cardiopulmonary bypass. Int J Surg. 2005;3:129–140. - PubMed
    1. Giacinto O, Satriano U, Nenna A, Spadaccio C, Lusini M, Mastroianni C, Nappi F, Chello M. Inflammatory response and endothelial dysfunction following cardiopulmonary bypass: pathophysiology and pharmacological targets. Recent Pat Inflamm Allergy Drug Discov. 2019;13:158–173. - PubMed
    1. Ruifrok WT, Westenbrink BD, de Boer RA, den Hamer IJ, Erasmus ME, Mungroop HE, Epema AH, Voors AA, van Veldhuisen DJ, van Gilst WH. Apoptosis during CABG surgery with the use of cardiopulmonary bypass is prominent in ventricular but not in atrial myocardium. Neth Heart J. 2010;18:236–242. - PMC - PubMed
    1. Squiccimarro E, Stasi A, Lorusso R, Paparella D: Narrative review of the systemic inflammatory reaction to cardiac surgery and cardiopulmonary bypass. Artif Organs; n/a - PMC - PubMed
    1. Wen Z, Lei Z, Yao L, Jiang P, Gu T, Ren F, Liu Y, Gou C, Li X, Wen T. Circulating histones are major mediators of systemic inflammation and cellular injury in patients with acute liver failure. Cell Death Dis. 2016;7:e2391–e2391. - PMC - PubMed

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