Cell-free DNA as a new indicator of cellular ischemia in isolated coronary artery ectasia

   Background: Coronary artery ectasia (CAE) is the diffuse or localized enlargement of the epicardial coronary arteries without any particular symptoms. Cell-free DNA (cfDNA) is defined as the DNA originating from nucleated cells which circulates freely in circulatory system. In our study, we aimed to measure the cfDNA levels, an indicator of ischemia at cellular level, which is shown to be elevated in non-invasive exercise tests and perfusion scintigraphies.
   Methods: 41 patients with isolated CAE and 39 patients with normal coronary angiograms (NCA) were included in the study. Coronary angiography was performed in case of typical angina or a positive exercise test. The amount of cfDNA was determined by centrifugation of peripheral blood samples from both groups.
   Results: Plasma cfDNA levels were 5.86 ± 4.41 ng/µl in isolated CAE patients and 2.36 ± 1.32 ng/µl in NCA group (p=0.000). When angiographic types were evaluated based on Markis Classification, cfDNA levels were found as follows: type I (n=7) 10.15±5.25, type II (n=5) 6.42±3.91, type III (n=4) 5.15±3.74 and type IV (n=25) 4.66±3.78. The level of cfDNA was found significantly higher in type I CAE group when compared to other groups based on the Markis Classification (p=0.028).
   Conclusion: High levels of cfDNA in patients with CAE suggest that impaired myocardial perfusion and the resulting ischemia cause myocardial cell lysis or rapid apoptosis that leads to earlier programmed cell death. High levels in cfDNA in these patients might be used as a marker of increased cardiovascular risk.

1. Yetkin E.., Waltenberger J. Novel insights into an old controversy: is coronary artery ectasia a variant of coronary atherosclerosis? Clin Res Cardiol 2007; 96 [6]: 331 – 9.

2. Markis J. E., Joffe C. D., Cohn P. F., Feen D. J., Herman M. V., Gorlin R. Clinical significance of coronary arterial ectasia. Am J Cardiol 1976; 37 [2]: 217 – 22.

3. Yolcu M., Ipek E., Turkmen S., Ozen Y., Yildirim E., Sertcelik A., et al. The relationship between elevated magnesium levels and coronary artery ectasia. CVJ Africa 2016; 27 [5]: 294 – 8.

4. Giannoglou G. D., Antoniadis A. P., Chatzizisis Y. S., Damvopoulou E., Parcharidis G. E., Louridas G. E. Prevalence of ectasia in human coronary arteries in patients in northern Greece referred for coronary angiography. Am J Cardiol 2006; 98 [3]: 314 – 8.

5. Krüger D., Stierle U., Herrmann G., Simon R., Sheikhzadeh A. Exercise - induced myocardial ischemia in isolated coronary artery ectasias and aneurysms [‘dilated coronopathy’]. J Am Coll Cardiol 1999; 34: 1461 – 70.

6. Befeler B., Aranda M.J., Embi A., Mullin F. L., El-Sherif N., Lazzara R. Coronary artery aneurysms: study of their etiology, clinical course a defect on left ventricular function and prognosis. Am J Med 1977; 62: 597 – 607.

7. Rath S., Har-Zahav Y., Battler A., Agranat O., Rotstein Z., Rabinowitz B., et al. Fate of nonobstructive aneurysmatic coronary artery disease: angiographic and clinical follow-up report. Am Heart J 1985; 109: 785 – 791.

8. Doi T., Kataoka Y., Noguchi T., Shibata T., Nakashima T., Kawakami S., et al. Coronary Artery Ectasia Predicts Future Cardiac Events in Patients with Acute Myocardial Infarction. Arterioscler Thromb Vasc Biol. 2017; 37 [12]: 2350 – 2355.

9. Lo Y. M. D., Tein M. S. C., Lau T. K., Haines C. J., Leung T. N., Poon Pm., et al. Quantitative analysis of fetal DNA in maternal plasma and serum: implications for noninvasive prenatal diagnosis. Am J Hum Genet1998; 62: 768 – 775.

10. Lo Y. M., Rainer T. H., Chan L. Y., Hjelm N. M., Cocks R. A. Plasma DNA as a prognostic marker in trauma patients. Clin Chem 2000; 46:319 - 323.

11. Song H., Nan Y., Cheng X. W. Circulating cf - DNA: A promising, noninvasive tool for assessment of early cardiometabolic risk. Atherosclerosis 2014; 233: 307 - 9.

12. Mandel P., Metais P. C R Seances Soc Biol Fil 1948; 142: 241 – 3.

13. Pathak A. K., Bhutani M., Kumar S., Mohan A., Guleria R. Circulating cell-free DNA in plasma / serum of lung cancer patients as a potential screening and prognostic tool.Clin Chem. 2006 Oct; 52 [10]: 1833 - 42.

14. Bendich A., Wilczok T., Borenfreund E. Circulating DNA as a possible factor in oncogenesis. Science 1965; 148: 374 – 6.

15. Tan E. M., Schur P. H., Carr R. I., Kunkel H. G. Deoxybonucleic acid [DNA] and antibodies to DNA in the serum of patients with systemic lupus erythematosus. J Clin Invest 1966; 45: 1732 – 40.

16. Koffler D., Agnello V., Winchester R., Kunkel H. G. The occurrence of single-stranded DNA in the serum of patients with systemic lupus erythematosus and other diseases. J Clin Invest 1973; 52: 198 – 204.

17. Leon S. A., Shapiro B., Sklaroff D. M., Yaros M. J. FreeDNA in the serum of cancer patients and the effect of therapy. Cancer Res 1977; 37: 646 – 50.

18. Ponti G., Maccaferri M., Manfredini M., Kaleci S., Mandrioli M., Pellacani G., et al. The value of fluorimetry [Qubit] and spectrophotometry [NanoDrop] in the quantification of cell-free DNA [cfDNA] in malignant melanoma and prostate cancer patients.Clinica Chimica Acta 2018; 479: 14 – 19.

19. Francaviglia I., Magliacane G., Grassini G., et al. Identification and monitoring of somatic mutations in circulating cell-free DNA by next-generation sequencing in patients with lung adenocarcinoma. Cancer Research 2018; 78 [13 Supplement]: 5580.

20. Lin C. T., Chen C. W., Lin T. W., Lin C. L. Coronary artery ectasia. Tzu Chi Med 2008; 20 [14]: 270 – 4.

21. Yilmaz H., Sayar N., Yilmaz M., Tangurek B., Cakmak N., Gurkan U., et al. Coronary artery ectasia clinical and angiographical evaluation. Turk Kardiyol Dern Ars 2008; 36 [8]: 530 – 5.

22. Ismail A. M., Rayan M., Adel A., Demerdash S., Atef M., Abdallah M., et al. Prevalence and pattern of abnormal myocardial perfusion in patients with isolated coronary artery ectasia: study by 99mTc-sestamibi radionuclide scintigraphy. Int J Cardiovasc Imaging 2014: 30: 425 – 430.

23. Tambe A. A., Demany M. A., Zimmerman Mascarenhas E. Angina pectoris and slow flow velocity of dye in coronary arteries: a new angiographic finding. Am Heart J 1972; 84: 66 –71.

24. Papadakis M. C., Manginas A., Cotileas P., Demopoulus V., Voudris V., Pavlides G., et al. Documentation of slow coronary flow by the TIMI frame count in patients with corona ry ectasia. Am J Cardiol 2001; 88: 1030 – 1032.

25. Gibson C. M., Cannon C. P., Daley W. L., Dodge J. T. Jr, Alexander B. Jr, Marble S. J., et al. TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation 1996; 93: 879 – 88.

26. Huang W. H., Luo J. F., Zhou H. L., Chen J. Y. Exercise-induced myocardial ischemia in patients with coronary artery ectasia without significant coronary stenosis. Di Yi Jun Yi Da Xue Xue Bao. 2005; 25 [7]: 899 - 900.

27. Abdel Dayem T. M., El-Mawardy R., Abdel-Dayem M. K., Rayan M., El-Mahmoudy A., Shawky G., et al. Assessment of coronary flow parameters by transesophageal echocardiography in patients with isolated coronary artery ectasia: effect of intravenous nitroglycerin. Echocardiography 2010; 27 [8]: 1004 – 10.

28. Akyürek O., Berkalp B., Sayin T., Kumbasar D., Kervancioglu C., Oral D. Altered coronary flow properties in diffuse coronary artery ectasia. Am Heart J 2003; 145: 66 – 72.

29. Krüger D., ElMokhtari N. E., Wieckhorst A., Simon-Herrmann G., Simon R. Intravascular ultrasound study and evidence of pathological coronary flow reserve in patients with isolated coronary artery aneurysms. Clin Res Cardiol 2010; 99: 157 – 64.

30. Gulec S., Atmaca Y., Kilickap M., Akyurek O., Aras O., Oral D. Angiographic assessment of myocardial perfusion in patients with isolated coronary artery ectasia. Am J Cardiol 2003; 91: 996 – 9.

31. Lou X., Hou Y., Liang D., Peng L., Chen H., Ma S., et al. A novel Alu-basedreal-time PCR method for the quantitative detection of plasma circulating cell free DNA: sensitivity and pecificity for the diagnosis of myocardial infarction. Int J Mol Med. 2015; 35 [1]: 72 - 80.

32. Jung K., Fleischlacker M. and Rabien A. Cell-free DNA in the blood as a solid tumor biomarker-a critical appraisal of the literature. Clin Chim Acta 2010; 411: 1611 – 24.

33. Chang C. P., Chia R. H., Wu T. L., Tsao K. C., Sun C. F., Wu J. T. Elevated cell-free serum DNA detected in patients with myocardial infarction. Clin Chim Acta 2003; 327: 95-101.

34. Jing R. R., Wang H. M., Cui M., Fang M. K., Qui X. J., Wu X. H., et al. A sensitive method to quantify human cell-free circulating DNA in blood: relevance to myocardial infarction screening. Clin Biochem 2011; 44: 1074 – 79.

35. Destouni A., Vrettou C., Antonatos D., Chouliaras G., Traeger-Synodinos J., Patsilinakos S., et al. Cell-free DNA levels in acute myocardial infarction patients during hospitalization. Acta Cardiol 2009; 64: 51 - 7.

36. Cui M., Fan M., Jing R., Wang H., Qin J., Sheng H., et al. Cell-free circulating DNA: a new biomarker for the acute coronary syndrome. Cardiology 2013; 124: 76 - 84.

37. Baman T. S., Cole J. H., Devireddy C. M., Sperling L. S. Risk factors and outcomes in patients with coronary artery aneurysms. Am J Cardiol. 2004; 93: 1549 - 51.

38. Yolcu M., Dogan A., Kurtoglu N., Hancer V. S., Gürbüzel M. New indicator of cellular ischemia in coronary slow-flow phenomenon: Cell-free DNA. Turk Kardiyol Dern Ars. 2020 Sep; 48 (6): 558-565. doi: 10.5543/tkda.2020.45605. PMID: 32955030.