Thromb Haemost 2017; 117(05): 911-922
DOI: 10.1160/TH16-10-0744
Cellular Haemostasis and Platelets
Schattauer GmbH

Novel role of platelet reactivity in adverse left ventricular remodelling after ST-segment elevation myocardial infarction: The REMODELING Trial

Yongwhi Park
1   Department of Internal Medicine, Gyeongsang National University School of Medicine and Cardiovascular Center, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea
,
Udaya S. Tantry
2   Inova Center for Thrombosis Research and Drug Development, Inova Heart and Vascular Institute, Fairfax, Virginia, USA
,
Jin-Sin Koh
3   Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Republic of Korea
,
Jong-Hwa Ahn
1   Department of Internal Medicine, Gyeongsang National University School of Medicine and Cardiovascular Center, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea
,
Min Gyu Kang
3   Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Republic of Korea
,
Kye Hwan Kim
3   Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Republic of Korea
,
Jeong Yoon Jang
1   Department of Internal Medicine, Gyeongsang National University School of Medicine and Cardiovascular Center, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea
,
Hyun Woong Park
3   Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Republic of Korea
,
Jeong-Rang Park
3   Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Republic of Korea
,
Seok-Jae Hwang
3   Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Republic of Korea
,
Ki-Soo Park
4   Department of Preventive Medicine, Gyeongsang National University School of Medicine, Jinju, Republic of Korea
,
Choong Hwan Kwak
1   Department of Internal Medicine, Gyeongsang National University School of Medicine and Cardiovascular Center, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea
,
Jin-Yong Hwang
3   Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Republic of Korea
,
Paul A. Gurbel
2   Inova Center for Thrombosis Research and Drug Development, Inova Heart and Vascular Institute, Fairfax, Virginia, USA
,
Young-Hoon Jeong
1   Department of Internal Medicine, Gyeongsang National University School of Medicine and Cardiovascular Center, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea
5   Institute of the Health Sciences, Gyeongsang National University, Jinju, Republic of Korea
› Author Affiliations
Financial support: This study was partly supported by research grants from the Yuhan Corporation, and the Basic Science Research Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Science, ICT and Future Planning (NRF-2015R1A5A2008833).
Further Information

Publication History

Received: 01 October 2016

Accepted after major revision: 31 February 2016

Publication Date:
28 November 2017 (online)

Summary

The role of platelet-leukocyte interaction in the infarct myocardium still remains unveiled. We aimed to determine the linkage of platelet activation to post-infarct left ventricular remodelling (LVR) process. REMODELING was a prospective, observational, cohort trial including patients (n = 150) with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. Patients were given aspirin plus clopidogrel therapy (600 mg loading and 75 mg daily). Platelet reactivity (PRU: P2Y12 Reaction Units) was assessed with VerifyNow P2Y12 assay on admission. Transthoracic echocardiography was performed on admission and at one-month follow-up. The primary endpoint was the incidence of LVR according to PRU-based quartile distribution. LVR was defined as a relative ≥ 20 % increase in LV end-diastolic volume (LVEDV) between measurements. Adverse LVR was observed in 36 patients (24.0 %). According to PRU quartile, LVR rate was 10.8 % in the first, 23.1 % in the second, 27.0 % in the third, and 35.1 % in the fourth (p = 0.015): the optimal cut-off of PRU was ≥ 248 (area under curve: 0.643; 95 % confidence interval: 0.543 to 0.744; p = 0.010). LVR rate also increased proportionally according to the level of high sensitivity-C reactive protein (hs-CRP) (p = 0.012). In multivariate analysis, the combination of PRU (≥ 248) and hs-CRP (≥ 1.4 mg/l) significantly increased the predictive value for LVR occurrence by about 21-fold. In conclusion, enhanced levels of platelet activation and inflammation determined the incidence of adverse LVR after STEMI. Combining the measurements of these risk factors increased risk discrimination of LVR. The role of intensified antiplatelet or anti-inflammatory therapy in post-infarct LVR process deserves further study.

 
  • References

  • 1 Heart Disease and Stroke Statistics--2013 Update: A Report From the American Heart Association. Circulation 2013; 127: e6-e245.
  • 2 Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Steg PG, James SK, Atar D. et al. ESC Guidellines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012; 33: 2569-2619.
  • 3 Chen J, Hsieh AF, Dharmarajan K, Masoudi FA, Krumholz HM. National trends in heart failure hospitalisation after acute myocardial infarction for Medicare beneficiaries: 1998-2010. Circulation 2013; 128: 2577-2584.
  • 4 Westman PC, Lipinski MJ, Luger D. et al. Inflammation as a Driver of Adverse Left Ventricular Remodelling After Acute Myocardial Infarction. J Am Coll Cardiol 2016; 67: 2050-2060.
  • 5 Burchfield JS, Xie M, Hill JA. Pathological ventricular remodelling: mechanisms: part 1 of 2. Circulation 2013; 128: 388-400.
  • 6 Fraccarollo D, Galuppo P, Bauersachs J. Novel therapeutic approaches to post-infarction remodelling. Cardiovasc Res 2012; 94: 293-303.
  • 7 Xie M, Burchfield JS, Hill JA. Pathological ventricular remodelling: therapies: part 2 of 2. Circulation 2013; 128: 1021-1030.
  • 8 Anzai T. Post-infarction inflammation and left ventricular remodelling: a double-edged sword. Circ J 2013; 77: 580-587.
  • 9 Erkol A, Oduncu V, Pala S. et al. Plasma osteoprotegerin level on admission is associated with no-reflow phenomenon after primary angioplasty and subsequent left ventricular remodelling in patients with acute ST-segment elevation myocardial infarction. Atherosclerosis 2012; 221: 254-259.
  • 10 Sim DS, Ahn Y, Kim YH. et al. The Relationship among N-Terminal Pro-B-Type Natriuretic Peptide, High-Sensitivity C-Reactive Protein and Infarct Size in Patients with Acute ST-Elevation Myocardial Infarction. Korean Circ J 2015; 45: 285-293.
  • 11 Swiatkiewicz I, Kozinski M, Magielski P. et al. Value of C-reactive protein in predicting left ventricular remodelling in patients with a first ST-segment elevation myocardial infarction. Mediators Inflamm 2012; 2012: 250867.
  • 12 Takahashi T, Anzai T, Kaneko H. et al. Increased C-reactive protein expression exacerbates left ventricular dysfunction and remodelling after myocardial infarction. Am J Physiol Heart Circ Physiol 2010; 299: H1795-1804.
  • 13 Urbano-Moral JA, Lopez-Haldon JE, Fernandez M. et al. Prognostic value of different serum biomarkers for left ventricular remodelling after ST-elevation myocardial infarction treated with primary percutaneous coronary intervention. Heart 2012; 98: 1153-1159.
  • 14 Gurbel PA, Jeong YH, Navarese EP, Tantry US. Platelet-Mediated Thrombosis: From Bench to Bedside. Circ Res 2016; 118: 1380-1391.
  • 15 von Hundelshausen P, Weber C. Platelets as immune cells: bridging inflammation and cardiovascular disease. Circ Res 2007; 100: 27-40.
  • 16 Zarbock A, Polanowska-Grabowska RK, Ley K. Platelet-neutrophil interactions: linking hemostasis and inflammation. Blood Rev 2007; 21: 99-111.
  • 17 Du XJ, Shan L, Gao XM. et al. Role of intramural platelet thrombus in the pathogenesis of wall rupture and intra-ventricular thrombosis following acute myocardial infarction. Thromb Haemost 2011; 105: 356-364.
  • 18 Liu Y, Gao XM, Fang L. et al. Novel role of platelets in mediating inflammatory responses and ventricular rupture or remodelling following myocardial infarction. Arterioscler Thromb Vasc Biol 2011; 31: 834-841.
  • 19 Nanhwan MK, Ling S, Kodakandla M, Nylander S, Ye Y, Birnbaum Y. Chronic treatment with ticagrelor limits myocardial infarct size: an adenosine and cyclooxygenase-2-dependent effect. Arterioscler Thromb Vasc Biol 2014; 34: 2078-2085.
  • 20 Ye Y, Birnbaum GD, Perez-Polo JR, Nanhwan MK, Nylander S, Birnbaum Y. Ticagrelor protects the heart against reperfusion injury and improves remodelling after myocardial infarction. Arterioscler Thromb Vasc Biol 2015; 35: 1805-1814.
  • 21 World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. J Am Med Assoc 2013; 310: 2191-2194.
  • 22 Mahaffey KW, Granger CB, Nicolau JC. et al. COMPLY Investigators. Effect of pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to fibrinolysis in acute myocardial infarction: the COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) trial. Circulation 2003; 108: 1176-1183.
  • 23 Jeong YH, Bliden KP, Antonino MJ, Park KS, Tantry US, Gurbel PA. Usefulness of the VerifyNow P2Y12 assay to evaluate the antiplatelet effects of ticagrelor and clopidogrel therapies. Am Heart J 2012; 164: 35-42.
  • 24 Lang RM, Bierig M, Devereux RB. et al. Chamber Quantification Writing Group; American Society of Echocardiographys Guidellines and Standards Committee; European Association of Echocardiography. Recommendations for chamber quantification: a report from the American Society of Echocardiographys Guidellines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005; 18: 1440-1463
  • 25 Bolognese L, Neskovic AN, Parodi G. et al. Left ventricular remodelling after primary coronary angioplasty: patterns of left ventricular dilation and long-term prognostic implications. Circulation 2002; 106: 2351-2357.
  • 26 Gawaz M, Vogel S. Platelets in tissue repair: control of apoptosis and interactions with regenerative cells. Blood 2013; 122: 2550-2554.
  • 27 Gawaz M. Role of platelets in coronary thrombosis and reperfusion of ischemic myocardium. Cardiovasc Res 2004; 61: 498-511.
  • 28 Kirtane AJ, Parikh PB, Stuckey TD. et al. Is There an Ideal Level of Platelet P2Y12-Receptor Inhibition in Patients Undergoing Percutaneous Coronary Intervention?: Window Analysis From the ADAPT-DES Study (Assessment of Dual AntiPlatelet Therapy With Drug-Eluting Stents). JACC Cardiovasc Interv 2015; 08: 1978-1987.
  • 29 Wu E, Ortiz JT, Tejedor P. et al. Infarct size by contrast enhanced cardiac magnetic resonance is a stronger predictor of outcomes than left ventricular ejection fraction or end-systolic volume index: prospective cohort study. Heart 2008; 94: 730-736.
  • 30 Giannuzzi P, Temporelli PL, Bosimini E. et al. Heterogeneity of left ventricular remodelling after acute myocardial infarction: results of the Gruppo Italiano per lo Studio della Sopravvivenza nellInfarto Miocardico-3 Echo Substudy. Am Heart J 2001; 141: 131-138.
  • 31 Vogel S, Chatterjee M, Metzger K. et al. Activated platelets interfere with recruitment of mesenchymal stem cells to apoptotic cardiac cells via high mobility group box 1/Toll-like receptor 4-mediated down-regulation of hepatocyte growth factor receptor MET. J Biol Chem 2014; 289: 11068-11082.
  • 32 Gao XM, Xu Q, Kiriazis H. et al. Mouse model of postinfarct ventricular rupture: time course, strain- and gender-dependency, tensile strength, and histopathology. Cardiovasc Res 2005; 65: 469-477.
  • 33 Tapp LD, Shantsila E, Wrigley BJ. et al. The CD14++CD16+ monocyte subset and monocyte-platelet interactions in patients with ST-elevation myocardial infarction. J Thromb Haemost 2012; 10: 1231-1241.
  • 34 Stone GW, Maehara A, Witzenbichler B. et al. INFUSE-AMI Investigators. Intracoronary abciximab and aspiration thrombectomy in patients with large anterior myocardial infarction: the INFUSE-AMI randomized trial. JAMA 2012; 307: 1817-1826
  • 35 Brener SJ, Oldroyd KG, Maehara A. et al. Outcomes in patients with ST-segment elevation acute myocardial infarction treated with clopidogrel versus prasugrel (from the INFUSE-AMI trial). Am J Cardiol 2014; 113: 1457-1460.
  • 36 High PlatElet Inhibition With TicAgrelor to Improve Left Ventricular RemodellinG in Patients With ST-segment ElevAtion Myocardial Infarction: the HEALING-AMI Trial. Available from: https://clinicaltrials.gov/ct2/show/NCT02224534?term=HEALING-AMI&rank=1 Accessed October 1, 2016
  • 37 Lee K, Yoo SY, Suh J. et al. Efficacy of cilostazol on inhibition of platelet aggregation, inflammation and myonecrosis in acute coronary syndrome patients undergoing percutaneous coronary intervention: The ACCEL-LOADING-ACS (ACCELerated Inhibition of Platelet Aggregation, Inflammation and Myonecrosis by Adjunctive Cilostazol Loading in Patients With Acute Coronary Syndrome) study. Int J Cardiol 2015; 190: 370-375.
  • 38 Gibbons RJ, Valeti US, Araoz PA, Jaffe AS. The quantification of infarct size. J Am Coll Cardiol 2004; 44: 1533-1542.
  • 39 Sjblom J, Muhrbeck J, Witt N. et al. Evolution of left ventricular ejection fraction after acute myocardial infarction: implications for implantable cardioverter-defibrillator eligibility. Circulation 2014; 130: 743-748.