Myocardial infarction induces atrial inflammation that can be prevented by C1-esterase inhibitor

Begieneman, Mark P.V.; Emmens, Reindert W.; Rijvers, Liza; Woudstra, Linde; Paulus, Walter J.; Kubat, Bela; Vonk, Alexander B.A.; Rossum, Albert C. van; Wouters, Diana; Ham, Marieke van; Schalkwijk, Casper G.; Niessen, Hans W.M.; Krijnen, Paul A.J.

doi:10.1136/jclinpath-2016-203639

Cited by 12 publications

(14 citation statements)

References 32 publications

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“…More recently, IC1 treatment has also been postulated to counteract myocardial infarction-induced inflammation in a rat model. 36 These data are consistent with our findings of increased IC1 levels among CS survivors. In another line of evidence, it has been reported that patients with more severe forms of septic shock could exhibit a relative deficiency of IC1, 37 also in agreement with our findings in patients with CS.…”

Section: Discussionsupporting

confidence: 93%

“…Overall, these four proteins reflect multiorgan dysfunction, as well as systemic inflammation and immune activation. [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] During the early hours of CS, changes in the expression of these proteins may precede overt multiorgan failure and identify patients at a higher mortality risk. These data highlight the relevance of systemic involvement in CS, beyond primary pump failure.…”

Section: Discussionmentioning

confidence: 99%

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Protein-based cardiogenic shock patient classifier

Rueda

Borràs

García-García

et al. 2019

European Heart Journal

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Aims Cardiogenic shock (CS) is associated with high short-term mortality and a precise CS risk stratification could guide interventions to improve patient outcome. Here, we developed a circulating protein-based score to predict short-term mortality risk among patients with CS. Methods and results Mass spectrometry analysis of 2654 proteins was used for screening in the Barcelona discovery cohort (n = 48). Targeted quantitative proteomics analyses (n = 51 proteins) were used in the independent CardShock cohort (n = 97) to derive and cross-validate the protein classifier. The combination of four circulating proteins (Cardiogenic Shock 4 proteins—CS4P), discriminated patients with low and high 90-day risk of mortality. CS4P comprises the abundances of liver-type fatty acid-binding protein, beta-2-microglobulin, fructose-bisphosphate aldolase B, and SerpinG1. Within the CardShock cohort used for internal validation, the C-statistic was 0.78 for the CardShock risk score, 0.83 for the CS4P model, and 0.84 (P = 0.033 vs. CardShock risk score) for the combination of CardShock risk score with the CS4P model. The CardShock risk score with the CS4P model showed a marked benefit in patient reclassification, with a net reclassification improvement (NRI) of 0.49 (P = 0.020) compared with CardShock risk score. Similar reclassification metrics were observed in the IABP-SHOCK II risk score combined with CS4P (NRI =0.57; P = 0.032). The CS4P patient classification power was confirmed by enzyme-linked immunosorbent assay (ELISA). Conclusion A new protein-based CS patient classifier, the CS4P, was developed for short-term mortality risk stratification. CS4P improved predictive metrics in combination with contemporary risk scores, which may guide clinicians in selecting patients for advanced therapies.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Protein-based cardiogenic shock patient classifier

Rueda

Borràs

García-García

et al. 2019

European Heart Journal

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“…In animal model, prolonged P-wave duration was related to abnormal inter-atrial conduction, independent of the left atrium size, mediated by dysregulation of connexin proteins expression (CX 40 and CX 43) and fibrosis[ 12 ]. In patients with acute coronary syndromes, it has been found an increased number of inflammatory cells infiltrate the atria, coming from the adipose tissue, suggesting that the left ventricular infarction induces atrial inflammation [ 22 ]. By inference, it is possible that the prolonged P-wave represents an early sign of chronic or acute inflammatory stimuli on atrial tissue.…”

Section: Discussionmentioning

confidence: 99%

P-wave duration is a predictor for long-term mortality in post-CABG patients

et al. 2018

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Risk stratification in secondary prevention has emerged as an unmet clinical need in order to mitigate the Number-Needed-to-Treat and make expensive therapies both clinically relevant and cost-effective. P wave indices reflect atrial conduction, which is a sensitive marker for inflammatory, metabolic, and pressure overload myocardial cell remodeling; the three stimuli are traditional mechanisms for adverse clinical evolution. Accordingly, we sought to investigate the predictive role of P-wave indices to estimate residual risk in patients with chronic coronary artery disease (CAD). The cohort included 520 post-Coronary Artery Bypass Grafting patients with a median age of 60 years who were followed for a median period of 1025 days. The primary endpoint was long-term all-cause death. Cubic spline model demonstrated a linear association between P-wave duration and incidence rate of long-term all-cause death (p = 0.023). P-wave >110ms was a marker for an average of 425 days shorter survival as compared with P-wave under 80ms (Logrank p = 0.020). The Cox stepwise regression models retained P-wave duration as independent marker (HR:1.37; 95%CI:1.05–1.79,p = 0.023). In conclusion, the present study suggests that P-wave measurement may constitute a simple, inexpensive and accessible prognostic tool to be added in the bedside risk estimation in CAD patients.

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“…Moreover, C1-INH exhibited therapeutic effects in other diseases and clinical situations [25,24] and may have therapeutic potential in numerous diseases, where the tightly cross-linked complement and contact system are concurrently activated [2]. Due to their C1-INH potentiating effect, sulfated glycans may offer an option to improve either the efficacy of therapeutically applied C1-INH or the activity of endogenous C1-INH.…”

Section: Discussionmentioning

confidence: 99%

“…These may also be obstacles to the application of C1-INH in further indications, although clinical studies showed beneficial effects of C1-INH also in other disease states like sepsis, gram-negative endotoxic shock, vascular leak syndrome, transplant rejection, ischemia-reperfusion injury, myocardial infarction, and emergency coronary artery bypass surgery [24,25]. …”

Section: Introductionmentioning

confidence: 99%

Regulation of Complement and Contact System Activation via C1 Inhibitor Potentiation and Factor XIIa Activity Modulation by Sulfated Glycans – Structure-Activity Relationships

2016

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The serpin C1 inhibitor (C1-INH) is the only regulator of classical complement activation as well as the major regulator of the contact system. Its importance is demonstrated by hereditary angioedema (HAE), a severe disease with potentially life-threatening attacks due to deficiency or dysfunction of C1-INH. C1-INH replacement is the therapy of choice in HAE. In addition, C1-INH showed to have beneficial effects in other diseases characterized by inappropriate complement and contact system activation. Due to some limitations of its clinical application, there is a need for improving the efficacy of therapeutically applied C1-INH or to enhance the activity of endogenous C1-INH. Given the known potentiating effect of heparin on C1-INH, sulfated glycans (SG) may be such candidates. The aim of this study was to characterize suitable SG by evaluating structure-activity relationships. For this, more than 40 structurally distinct SG were examined for their effects on C1-INH, C1s and FXIIa. The SG turned out to potentiate the C1s inhibition by C1-INH without any direct influence on C1s. Their potentiating activity proved to depend on their degree of sulfation, molecular mass as well as glycan structure. In contrast, the SG had no effect on the FXIIa inhibition by C1-INH, but structure-dependently modulated the activity of FXIIa. Among the tested SG, β-1,3-glucan sulfates with a Mr ≤ 10 000 were identified as most promising lead candidates for the development of a glycan-based C1-INH amplifier. In conclusion, the obtained information on structural characteristics of SG favoring C1-INH potentiation represent an useful elementary basis for the development of compounds improving the potency of C1-INH in diseases and clinical situations characterized by inappropriate activation of complement and contact system.

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Myocardial infarction induces atrial inflammation that can be prevented by C1-esterase inhibitor

Abstract: MI induces atrial inflammation in patients and in rats. C1inh treatment could counteract this MI-induced atrial inflammation in rats.

Cited by 12 publications

References 32 publications

Protein-based cardiogenic shock patient classifier

Protein-based cardiogenic shock patient classifier

P-wave duration is a predictor for long-term mortality in post-CABG patients

Regulation of Complement and Contact System Activation via C1 Inhibitor Potentiation and Factor XIIa Activity Modulation by Sulfated Glycans – Structure-Activity Relationships

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