Amyloid Biomarker Predictive of Mortality in Non-STEMI Heart Attack

MedicalResearch.com 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

MedicalResearch.com: 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.

MedicalResearch.com: 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.

MedicalResearch.com: 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. 

MedicalResearch.com: 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.

MedicalResearch.com: 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.

  1. Ohman EM, Harskamp RE. We need to do better for patients with non-ST-segment elevation acute coronary syndrome who are managed without revascularization. J Am Coll Cardiol. 2014;63(21):2258-60.
  2. Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J. 2016;37(3):267-315.
  3. Wright RS, Anderson JL, Adams CD, Bridges CR, Casey DE, Jr., Ettinger SM, et al. 2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/ Non-ST-Elevation Myocardial Infarction (Updating the 2007 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;123(18):2022-60.
  4. Amsterdam EA, Wenger NK, Brindis RG, Casey DE, Jr., Ganiats TG, Holmes DR, Jr., et al. 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;64(24):e139-228.
  5. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352(16):1685-95.
  6. Stellos K, Gatsiou A, Stamatelopoulos K, Perisic Matic L, John D, Lunella FF, et al. Adenosine-to-inosine RNA editing controls cathepsin S expression in atherosclerosis by enabling HuR-mediated post-transcriptional regulation. Nat Med. 2016;22(10):1140-50.
  7. Fox KA, Dabbous OH, Goldberg RJ, Pieper KS, Eagle KA, Van de Werf F, et al. Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: prospective multinational observational study (GRACE). BMJ. 2006;333(7578):1091.
  8. Abu-Assi E, Ferreira-Gonzalez I, Ribera A, Marsal JR, Cascant P, Heras M, et al. “Do GRACE (Global Registry of Acute Coronary events) risk scores still maintain their performance for predicting mortality in the era of contemporary management of acute coronary syndromes?”. Am Heart J. 2010;160(5):826-34 e1-3.
  9. De Meyer GR, De Cleen DM, Cooper S, Knaapen MW, Jans DM, Martinet W, et al. Platelet phagocytosis and processing of beta-amyloid precursor protein as a mechanism of macrophage activation in atherosclerosis. Circ Res. 2002;90(11):1197-204.
  10. Kitazume S, Yoshihisa A, Yamaki T, Oikawa M, Tachida Y, Ogawa K, et al. Soluble amyloid precursor protein 770 is released from inflamed endothelial cells and activated platelets: a novel biomarker for acute coronary syndrome. J Biol Chem. 2012;287(48):40817-25.
  11. Stamatelopoulos K, Sibbing D, Rallidis LS, Georgiopoulos G, Stakos D, Braun S, et al. Amyloid-Beta (1-40) and the risk of death from cardiovascular causes in patients with coronary heart disease. J Am Coll Cardiol. 2015;65(9):904-16.
  12. Wang J, Ho L, Chen L, Zhao Z, Zhao W, Qian X, et al. Valsartan lowers brain beta-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease. J Clin Invest. 2007;117(11):3393-402.
  13. Abdullah L, Paris D, Luis C, Quadros A, Parrish J, Valdes L, et al. The influence of diagnosis, intra- and inter-person variability on serum and plasma Abeta levels. Neurosci Lett. 2007;428(2-3):53-8.
  14. Tang EW, Wong CK, Herbison P. Global Registry of Acute Coronary Events (GRACE) hospital discharge risk score accurately predicts long-term mortality post acute coronary syndrome. Am Heart J. 2007;153(1):29-35.
  15. Eagle KA, Lim MJ, Dabbous OH, Pieper KS, Goldberg RJ, Van de Werf F, et al. A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry. JAMA. 2004;291(22):2727-33.
  16. Farooq V, Vergouwe Y, Genereux P, Bourantas CV, Palmerini T, Caixeta A, et al. Prediction of 1-year mortality in patients with acute coronary syndromes undergoing percutaneous coronary intervention: validation of the logistic clinical SYNTAX (Synergy Between Percutaneous Coronary Interventions With Taxus and Cardiac Surgery) score. JACC Cardiovasc Interv. 2013;6(7):737-45.
  17. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017;377(12):1119-31.
  18. Fassbender K, Simons M, Bergmann C, Stroick M, Lutjohann D, Keller P, et al. Simvastatin strongly reduces levels of Alzheimer’s disease beta -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci U S A. 2001;98(10):5856-61.
  19. Wang J, Zhao Z, Lin E, Zhao W, Qian X, Freire D, et al. Unintended effects of cardiovascular drugs on the pathogenesis of Alzheimer’s disease. PLoS One. 2013;8(6):e65232.
  20. Hall M, Dondo TB, Yan AT, Goodman SG, Bueno H, Chew DP, et al. Association of Clinical Factors and Therapeutic Strategies With Improvements in Survival Following Non-ST-Elevation Myocardial Infarction, 2003-2013. JAMA. 2016;316(10):1073-82.
  21. Bibl M, Welge V, Esselmann H, Wiltfang J. Stability of amyloid-beta peptides in plasma and serum. Electrophoresis. 2012;33(3):445-50. 

Citation: 

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

 

 

 

 

 

 

The information on MedicalResearch.com is provided for educational purposes only, and is in no way intended to diagnose, cure, or treat any medical or other condition. Always seek the advice of your physician or other qualified health and ask your doctor any questions you may have regarding a medical condition. In addition to all other limitations and disclaimers in this agreement, service provider and its third party providers disclaim any liability or loss in connection with the content provided on this website.

 

Leave a Reply

Your email address will not be published.

This site uses Akismet to reduce spam. Learn how your comment data is processed.