Amyloid Biomarker Predictive of Mortality in Non-STEMI Heart Attack Interview with:

Prof. Dr. med. Konstantinos Stellos,MD, FAHA, FESC Cardiovascular Research Centre, Institute of Genetic Medicine Newcastle upon Tyne United Kingdom

Prof. Stellos

Prof. Dr. med. Konstantinos Stellos,MD, FAHA, FESC
Cardiovascular Research Centre, Institute of Genetic Medicine
Newcastle upon Tyne
United Kingdom What is the background for this study?


Response: Risk stratification of patients with a non-ST-segment elevation acute coronary syndrome (NSTE-ACS) remains a major challenge in clinical cardiology. Risk stratification is important to identify patients at high risk, to whom an early coronary intervention with optimal adjunctive medical therapy shall be applied to reduce that risk. Conversely, it is equally important to identify patients at low risk, to whom a potentially hazardous invasive therapy or a multi-drug administration shall be avoided. Current ACC/AHA and ESC guidelines agree in a standardized approach that uses Global Registry of Acute Coronary Events (GRACE) score, a well validated scoring system, to calculate a patient’s risk and guide triage and management decisions.

Amyloid-β (Aβ) 1-40 and 1-42 peptides (Aβ40 and Aβ42), are proteolytic fragments of a larger protein, the amyloid precursor protein (APP) cleaved by β- and γ-secretases, found in typical brain amyloid deposits in Alzheimer’s disease. Many lines of evidence support a role of Aβ40 in cardiovascular disease as a peptide with pro-inflammatory and pro-thrombotic properties. Most cardiovascular risk factors seem to affect APP metabolism and thus, Aβ production and its soluble circulating APP770 isoform are elevated in patients with ACS_ENREF_15, suggesting a role for Aβ40 in the triggering and outcome of ACS in stable CAD patients. Although vascular inflammation is considered as a hallmark in the pathophysiologic pathways of coronary artery disease (CAD) and novel mechanisms are continuously recognized in its pathogenesis, no inflammatory marker is currently recommended for risk stratification of patients with NSTE-ACS individually or as a component of the GRACE score. This may partly explain the moderate discriminative ability of GRACE score in some studies, especially in older patients and those after early percutaneous coronary intervention (PCI).

In this retrospective study, we used data from two independent prospective cohorts, the Heidelberg study (n=1,145) and the validation multicenter international APACE (Advantageous Predictors of Acute Coronary Syndrome Evaluation, n=734) study and determined the clinical prognostic and reclassification value of baseline circulating Aβ40 levels in the prediction of mortality over the GRACE risk score in patients with NSTE-ACS across a median follow-up of 21.9 ( Heidelberg cohort) and 24.9 months (APACE cohort), respectively. What are the main findings?

Response: In brief, we found that in patients with adjudicated NSTE-ACS, Aβ40 was associated with all-cause mortality after multivariate adjustment for established risk factors (i.e. age, gender, diabetes mellitus, high-sensitivity cardiac Troponin T and C-reactive protein, revascularization and ACS type) or for the GRACE score in both the Heidelberg and the APACE cohort. Most importantly, Aβ40 correctly reclassified risk for death over the GRACE score (net reclassification index=33.4% and 47.1% for the Heidelberg and APACE cohort, respectively). Similar associations of Aβ40 with the secondary endpoint of all-cause mortality and/or non-fatal myocardial infarction were observed in both cohorts. What should readers take away from your report?

Response: The novel finding of this study is that a single measurement of Aβ40 at presentation of an NSTE-ACS confers prognostic value and correctly reclassifies patients for mortality and a composite of death and/or non-fatal MI risk categories over GRACE score, an established score and widely recommended approach by clinical guidelines in current clinical practice for accurate risk stratification of these patients. These results were confirmed in an independent well-characterized multicenter European prospective cohort and therefore support the hypothesis that Aβ40 may be a useful biomarker to improve risk stratification in patients with NSTE-ACS. This is particularly important since models for risk prediction in patients with ACS are continuously changing in the era of intensified indications for early percutaneous coronary intervention_ENREF_42. Potential clinical applications of this peptide in NSTE-ACS should be further explored. What recommendations do you have for future research as a result of this work? 

Response: Atherosclerosis is a systematic low-grade inflammatory disease with the culprit vulnerable plaque often being a non-flow limiting “hidden” lesion and strictly anatomical characteristics derived from coronary angiography at NSTE-ACS presentation may not perform well in terms of prognosis. Accordingly, the GRACE score, which is recommended in routine clinical practice by the ACC/AHA and ESC guidelines, fails to take into consideration biomarkers reflecting inflammation. Notably, recent evidence supports the clinical role of inflammation in the ACS, indicating that targeting interleukin-1β inflammatory pathway with canakinumab in patients with previous myocardial infarction lowers incidence of recurrent adverse cardiovascular events. Along this line, we observed that Aβ40, a pro-inflammatory peptide improves prognostic assessment in patients with NSTE-ACS. Thus, the potential for clinical application of this peptide as a possible novel biomarker and emerging therapeutic implications in the NSTE-ACS should be further explored. To that end, our research group has recently observed that circulating Aβ40 levels are higher in patients with subclinical atherosclerosis and those with stable CAD and predict cardiovascular mortality and major adverse cardiac events. Therefore, Αβ40 may represent a pivotal peptide in the continuum of coronary artery disease from subclinical stages to its chronic and acute clinical phenotypes and it should be further explored whether this peptide is a suitable early therapeutic target during the development of atherosclerosis in order to prevent ACS triggering and improve post ACS outcome. From a clinical point of view, several therapeutic approaches have been developed to prevent Aβ peptide aggregation in Alzheimer’s disease whereas therapeutic interventions, including statin and anti-hypertensive treatment can influence plasma Aβ peptide concentrations. Is there anything else you would like to add?

Response: As already outlined, Αβ40 circulating levels in this study consistently predicted increased mortality over the GRACE score in two independent cohorts of NSTE-ACS patients. However, the authors should like to emphasize that although measurement of circulating Αβ40 in clinical practice is feasible, its concentrations may be affected by the antibody used in each ELISA assay as well as the sample storage and preparation conditions. Given the increasing importance of Aβ40 in human disease, automated commercial methods such as nephelometry are warranted to address these issues. Further prospectively designed research should focus on derivation of reference values for Αβ40 in NSTE-ACS settings. Indisputably, the use of Aβ40 peptide concentrations in any routine application will require standardization of pre-analytical handling and a commercially-available standardized measurement technique, like for instance for hsCRP or hs-cTnT.

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Amyloid-β (1-40) and mortality in patients with non-ST elevation acute coronary syndrome: a cohort study.

Kimon Stamatelopoulos, MD; Matthias Mueller-Hennessen, MD; Georgios Georgiopoulos, MD; Marco Sachse, Jasper Boeddinghaus, MD; Kateryna Sopova, MD; Aikaterini Gatsiou, MSc; Carolin Amrhein|, Moritz Biener, MD; Mehrshad Vafaie, MD; Fani Athanasouli, MD; Dimitrios Stakos, MD; Konstantinos Pateras, MSc; Raphael Twerenbold, MD; Patrick Badertscher, MD; Thomas Nestelberger, MD; Stefanie Dimmeler, PhD; Hugo A. Katus, MD; Andreas M. Zeiher, MD; Christian Mueller, MD; Evangelos Giannitsis, MD; and Konstantinos Stellos, MD
Published: Ann Intern Med. 2018.

DOI: 10.7326/M17-1540





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