Microalbuminuria predicts silent myocardial ischaemia in type 2 diabetes patients

  • Giampiero Giovacchini
  • Mario Cappagli
  • Stefano Carro
  • Sandro Borrini
  • Antonella Montepagani
  • Rossella Leoncini
  • Gianfranco Mazzotta
  • Gianmario Sambuceti
  • Giuliano Mariani
  • Duccio Volterrani
  • Michael J. Zellweger
  • Andrea Ciarmiello
Original Article

Abstract

Purpose

Myocardial ischaemia is frequently silent in patients with type 2 diabetes. Although it has been proposed as a potential screening tool, the role of myocardial perfusion single photon emission computed tomography (MPS) has recently been questioned, due to the low prevalence of positive scans and the low rate of cardiac events. The aim of this study was to assess if pretest clinical variables can identify a subgroup of asymptomatic patients with type 2 diabetes at risk of silent myocardial ischaemia and a subsequent poor outcome

Methods

This prospective study included 77 patients (50 men, mean age 63 ± 9 years) with type 2 diabetes and no known coronary artery disease (CAD) or angina pectoris who underwent gated MPS to screen for CAD between March 2006 and October 2008. MPS images were interpreted using a semiquantitative visual 20-segment model to define summed stress, rest and difference scores. Ischaemia was defined as a sum difference score (SDS) ≥2. Patients were followed-up (median 4.1 years, range 0.8 – 6.1 years) and cardiac hard events (cardiac death or nonfatal myocardial infarction) were recorded.

Results

Silent ischaemia was detected in 25 of the 77 patients (32 %). Specifically, 10 patients (13 %) had mild ischaemia (SDS 2 to ≤4) and 15 patients (19 %) had severe ischaemia (SDS >4). In univariate binary logistic analysis, microalbuminuria was the only significant predictor of silent ischaemia on MPS (odds ratio 4.42, 95 % CI 1.27 – 15.40; P = 0.019). The overall accuracy of microalbuminuria for predicting silent ischaemia was 71.4 % and was 89.6 % for predicting severe ischaemia. Kaplan-Meier curves showed no significant group differences in 5-year cardiac event-free survival between patients with and those without microalbuminuria, or between patients with SDS ≥2 and those with SDS <2. In contrast, 5-year event-free survival was significantly lower in patients with SDS >4 than in patients with SDS ≤4: 55.6 % (95 % CI 39.0 – 72.2 %) vs. 94.5 % (95 % CI: 91.4 – 97.6 %), respectively (Breslow test, chi-square 20.9, P < 0.001). Median cardiac event-free survival was not observed in the whole group, while the 25th percentile of cardiac event-free survival was reached only in patients with SDS >4 (2.3 years). In univariate Cox regression analysis, SDS >4 predicted cardiac event-free survival (hazard ratio 12.87, 95 % CI 2.86 – 27.98; P = 0.001), while SDS ≥2 did not (hazard ratio 2.78, 95 % CI 0.62 – 12.46, P = 0.16).

Conclusion

In this group of patients with type 2 diabetes, microalbuminuria was the only predictor of silent ischaemia on MPS. Assessment of microalbuminuria should be routinely considered among the first risk stratification steps for CAD in patients with type 2 diabetes, even though severe ischaemia on MPS is a major predictor of cardiac event-free survival.

Keywords

Microalbuminuria Type 2 diabetes Silent ischaemia Myocardial perfusion SPECT Cardiac event-free survival 

References

  1. 1.
    Bonow RO, Bohannon N, Hazzard W. Risk stratification in coronary artery disease and special populations. Am J Med. 1996;101:4A17S–22S.PubMedGoogle Scholar
  2. 2.
    Bax JJ, Inzucchi SE, Bonow RO, Schuijf JD, Freeman MR, Barrett EJ. Cardiac imaging for risk stratification in diabetes. Diabetes Care. 2007;30:1295–304.PubMedCrossRefGoogle Scholar
  3. 3.
    Kang X, Berman DS, Lewin H, Miranda R, Erel J, Friedman JD, et al. Comparative ability of myocardial perfusion single-photon emission computed tomography to detect coronary artery disease in patients with and without diabetes mellitus. Am Heart J. 1999;137:949–57.PubMedCrossRefGoogle Scholar
  4. 4.
    BARI Investigators. Influence of diabetes on 5-year mortality and morbidity in a randomized trial comparing CABG and PTCA in patients with multivessel disease: the Bypass Angioplasty Revascularization Investigation (BARI). Circulation. 1997;96:1761–9.CrossRefGoogle Scholar
  5. 5.
    Wackers FJ, Young LH, Inzucchi SE, Chyun DA, Davey JA, Barrett EJ, et al. Detection of silent myocardial ischemia in asymptomatic diabetic subjects: the DIAD study. Diabetes Care. 2004;27:1954–61.PubMedCrossRefGoogle Scholar
  6. 6.
    Miller TD, Redberg RF, Wackers FJ. Screening asymptomatic diabetic patients for coronary artery disease: why not? J Am Coll Cardiol. 2006;48:761–4.PubMedCrossRefGoogle Scholar
  7. 7.
    Bax JJ, Young LH, Frye RL, Bonow RO, Steinberg HO, Barrett EJ. Screening for coronary artery disease in patients with diabetes. Diabetes Care. 2007;30:2729–36.PubMedCrossRefGoogle Scholar
  8. 8.
    Young LH, Wackers FJ, Chyun DA, Davey JA, Barrett EJ, Taillefer R, et al. Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes: the DIAD study: a randomized controlled trial. JAMA. 2009;301:1547–55.PubMedCrossRefGoogle Scholar
  9. 9.
    American Diabetes Association. Consensus development conference on the diagnosis of coronary heart disease in people with diabetes: 10–11 February 1998, Miami, Florida. Diabetes Care. 1998;21:1551–9.CrossRefGoogle Scholar
  10. 10.
    Zellweger MJ, Hachamovitch R, Kang X, Hayes SW, Friedman JD, Germano G, et al. Threshold, incidence, and predictors of prognostically high-risk silent ischemia in asymptomatic patients without prior diagnosis of coronary artery disease. J Nucl Cardiol. 2009;16:193–200.PubMedCrossRefGoogle Scholar
  11. 11.
    Bax JJ, Bonow RO, Tschope D, Inzucchi SE, Barrett E. The potential of myocardial perfusion scintigraphy for risk stratification of asymptomatic patients with type 2 diabetes. J Am Coll Cardiol. 2006;48:754–60.PubMedCrossRefGoogle Scholar
  12. 12.
    Wackers FJ, Chyun DA, Young LH, Heller GV, Iskandrian AE, Davey JA, et al. Resolution of asymptomatic myocardial ischemia in patients with type 2 diabetes in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study. Diabetes Care. 2007;30:2892–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Ewing DJ, Martyn CN, Young RJ, Clarke BF. The value of cardiovascular autonomic function tests: 10 years experience in diabetes. Diabetes Care. 1985;8:491–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Berman DS, Hachamovitch R, Kiat H, Cohen I, Cabico JA, Wang FP, et al. Incremental value of prognostic testing in patients with known or suspected ischemic heart disease: a basis for optimal utilization of exercise technetium-99m sestamibi myocardial perfusion single-photon emission computed tomography. J Am Coll Cardiol. 1995;26:639–47.PubMedCrossRefGoogle Scholar
  15. 15.
    Zellweger MJ, Weinbacher M, Zutter AW, Jeger RV, Mueller-Brand J, Kaiser C, et al. Long-term outcome of patients with silent versus symptomatic ischemia six months after percutaneous coronary intervention and stenting. J Am Coll Cardiol. 2003;42:33–40.PubMedCrossRefGoogle Scholar
  16. 16.
    Hachamovitch R, Berman DS, Kiat H, Cohen I, Cabico JA, Friedman J, et al. Exercise myocardial perfusion SPECT in patients without known coronary artery disease: incremental prognostic value and use in risk stratification. Circulation. 1996;93:905–14.PubMedCrossRefGoogle Scholar
  17. 17.
    Berman DS, Abidov A, Kang X, Hayes SW, Friedman JD, Sciammarella MG, et al. Prognostic validation of a 17-segment score derived from a 20-segment score for myocardial perfusion SPECT interpretation. J Nucl Cardiol. 2004;11:414–23.PubMedCrossRefGoogle Scholar
  18. 18.
    Nakajima K, Kusuoka H, Nishimura S, Yamashina A, Nishimura T. Prognostic value of myocardial perfusion and ventricular function in a Japanese multicenter cohort study (J-ACCESS): the first-year total events and hard events. Ann Nucl Med. 2009;23:373–81.PubMedCrossRefGoogle Scholar
  19. 19.
    Nakajima K, Yamasaki Y, Kusuoka H, Izumi T, Kashiwagi A, Kawamori R, et al. Cardiovascular events in Japanese asymptomatic patients with type 2 diabetes: a 1-year interim report of a J-ACCESS 2 investigation using myocardial perfusion imaging. Eur J Nucl Med Mol Imaging. 2009;36:2049–57.PubMedCrossRefGoogle Scholar
  20. 20.
    Djaberi R, Roodt J, Schuijf JD, Rabelink TJ, de Koning EJ, Pereira AM, et al. Endothelial dysfunction in diabetic patients with abnormal myocardial perfusion in the absence of epicardial obstructive coronary artery disease. J Nucl Med. 2009;50:1980–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Schuijf JD, Shaw LJ, Wijns W, Lamb HJ, Poldermans D, de Roos A, et al. Cardiac imaging in coronary artery disease: differing modalities. Heart. 2005;91:1110–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Milan Study on Atherosclerosis and Diabetes (MiSAD) Group. Prevalence of unrecognized silent myocardial ischemia and its association with atherosclerotic risk factors in noninsulin-dependent diabetes mellitus. Am J Cardiol. 1997;79:134–9.CrossRefGoogle Scholar
  23. 23.
    Gazzaruso C, Garzaniti A, Giordanetti S, Falcone C, De Amici E, Geroldi D, et al. Assessment of asymptomatic coronary artery disease in apparently uncomplicated type 2 diabetic patients: a role for lipoprotein(a) and apolipoprotein(a) polymorphism. Diabetes Care. 2002;25:1418–24.PubMedCrossRefGoogle Scholar
  24. 24.
    De Lorenzo A, Lima RS, Siqueira-Filho AG, Pantoja MR. Prevalence and prognostic value of perfusion defects detected by stress technetium-99m sestamibi myocardial perfusion single-photon emission computed tomography in asymptomatic patients with diabetes mellitus and no known coronary artery disease. Am J Cardiol. 2002;90:827–32.PubMedCrossRefGoogle Scholar
  25. 25.
    Berman DS, Kang X, Hayes SW, Friedman JD, Cohen I, Abidov A, et al. Adenosine myocardial perfusion single-photon emission computed tomography in women compared with men. Impact of diabetes mellitus on incremental prognostic value and effect on patient management. J Am Coll Cardiol. 2003;41:1125–33.PubMedCrossRefGoogle Scholar
  26. 26.
    Zellweger MJ, Hachamovitch R, Kang X, Hayes SW, Friedman JD, Germano G, et al. Prognostic relevance of symptoms versus objective evidence of coronary artery disease in diabetic patients. Eur Heart J. 2004;25:543–50.PubMedCrossRefGoogle Scholar
  27. 27.
    Rajagopalan N, Miller TD, Hodge DO, Frye RL, Gibbons RJ. Identifying high-risk asymptomatic diabetic patients who are candidates for screening stress single-photon emission computed tomography imaging. J Am Coll Cardiol. 2005;45:43–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Moralidis E, Didangelos T, Arsos G, Athyros V, Mikhailidis DP. Myocardial perfusion scintigraphy in asymptomatic diabetic patients: a critical review. Diabetes Metab Res Rev. 2010;26:336–47.PubMedCrossRefGoogle Scholar
  29. 29.
    Petretta M, Acampa W, Evangelista L, Daniele S, Ferro A, Cuocolo A. Impact of inducible ischemia by stress SPECT in cardiac risk assessment in diabetic patients: rationale and design of a prospective, multicenter trial. J Nucl Cardiol. 2008;15:100–4.PubMedCrossRefGoogle Scholar
  30. 30.
    Acampa W, Petretta M, Evangelista L, Daniele S, Xhoxhi E, De Rimini ML, et al. Myocardial perfusion imaging and risk classification for coronary heart disease in diabetic patients. The IDIS study: a prospective, multicentre trial. Eur J Nucl Med Mol Imaging. 2012;39:387–95.PubMedCrossRefGoogle Scholar
  31. 31.
    Vanzetto G, Halimi S, Hammoud T, Fagret D, Benhamou PY, Cordonnier D, et al. Prediction of cardiovascular events in clinically selected high-risk NIDDM patients. Prognostic value of exercise stress test and thallium-201 single-photon emission computed tomography. Diabetes Care. 1999;22:19–26.PubMedCrossRefGoogle Scholar
  32. 32.
    Miller TD, Rajagopalan N, Hodge DO, Frye RL, Gibbons RJ. Yield of stress single-photon emission computed tomography in asymptomatic patients with diabetes. Am Heart J. 2004;147:890–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Scholte AJ, Schuijf JD, Kharagjitsingh AV, Dibbets-Schneider P, Stokkel MP, van der Wall EE, et al. Prevalence and predictors of an abnormal stress myocardial perfusion study in asymptomatic patients with type 2 diabetes mellitus. Eur J Nucl Med Mol Imaging. 2009;36:567–75.PubMedCrossRefGoogle Scholar
  34. 34.
    Nishimura T, Nakajima K, Kusuoka H, Yamashina A, Nishimura S. Prognostic study of risk stratification among Japanese patients with ischemic heart disease using gated myocardial perfusion SPECT: J-ACCESS study. Eur J Nucl Med Mol Imaging. 2008;35:319–28.PubMedCrossRefGoogle Scholar
  35. 35.
    Giugliano D, Acampora R, De Rosa N, Quatraro A, De Angelis L, Ceriello A, et al. Coronary artery disease in type-2 diabetes mellitus: a scintigraphic study. Diabete Metab. 1993;19:463–6.PubMedGoogle Scholar
  36. 36.
    Rutter MK, McComb JM, Brady S, Marshall SM. Silent myocardial ischemia and microalbuminuria in asymptomatic subjects with non-insulin-dependent diabetes mellitus. Am J Cardiol. 1999;83:27–31.PubMedCrossRefGoogle Scholar
  37. 37.
    Nasr G, Sliem H. Silent myocardial ischemia in prediabetics in relation to insulin resistance. J Cardiovasc Dis Res. 2010;1:116–21.PubMedCrossRefGoogle Scholar
  38. 38.
    Nasr G, Sliem H. Silent ischemia in relation to insulin resistance in normotensive prediabetic adults: early detection by single photon emission computed tomography (SPECT). Int J Cardiovasc Imaging. 2011;27:335–41.PubMedCrossRefGoogle Scholar
  39. 39.
    Nishimura M, Tsukamoto K, Tamaki N, Kikuchi K, Iwamoto N, Ono T. Risk stratification for cardiac death in hemodialysis patients without obstructive coronary artery disease. Kidney Int. 2011;79:363–71.PubMedCrossRefGoogle Scholar
  40. 40.
    Kawamori R. Insulin resistance seen in non-insulin dependent diabetes mellitus and hypertension. Hypertens Res. 1996;19 Suppl 1:S61–4.PubMedCrossRefGoogle Scholar
  41. 41.
    Kaptoge S, Di Angelantonio E, Pennells L, Wood AM, White IR, Gao P, et al. C-reactive protein, fibrinogen, and cardiovascular disease prediction. N Engl J Med. 2012;367:1310–20.PubMedCrossRefGoogle Scholar
  42. 42.
    Pfutzner A, Schondorf T, Hanefeld M, Forst T. High-sensitivity C-reactive protein predicts cardiovascular risk in diabetic and nondiabetic patients: effects of insulin-sensitizing treatment with pioglitazone. J Diabetes Sci Technol. 2010;4:706–16.PubMedGoogle Scholar
  43. 43.
    Hsieh MC, Tien KJ, Chang SJ, Perng DS, Hsiao JY, Chen YW, et al. High-sensitivity C-reactive protein and silent myocardial ischemia in Chinese with type 2 diabetes mellitus. Metabolism. 2008;57:1533–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Lombardi F, Tundo F, Terranova P, Battezzati PM, Ramella M, Bestetti A, et al. Prognostic value of C-reactive protein in patients with stress induced myocardial ischemia. Int J Cardiol. 2005;98:313–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Scholte AJ, Schuijf JD, Kharagjitsingh AV, Dibbets-Schneider P, Stokkel MP, Jukema JW, et al. Different manifestations of coronary artery disease by stress SPECT myocardial perfusion imaging, coronary calcium scoring, and multislice CT coronary angiography in asymptomatic patients with type 2 diabetes mellitus. J Nucl Cardiol. 2008;15:503–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, Jensen T, Kofoed-Enevoldsen A. Albuminuria reflects widespread vascular damage. The Steno hypothesis. Diabetologia. 1989;32:219–26.PubMedCrossRefGoogle Scholar
  47. 47.
    Stehouwer CD, Smulders YM. Microalbuminuria and risk for cardiovascular disease: analysis of potential mechanisms. J Am Soc Nephrol. 2006;17:2106–11.PubMedCrossRefGoogle Scholar
  48. 48.
    Weiner DA, Ryan TJ, Parsons L, Fisher LD, Chaitman BR, Sheffield LT, et al. Significance of silent myocardial ischemia during exercise testing in patients with diabetes mellitus: a report from the Coronary Artery Surgery Study (CASS) Registry. Am J Cardiol. 1991;68:729–34.PubMedCrossRefGoogle Scholar
  49. 49.
    Hachamovitch R, Berman DS, Shaw LJ, Kiat H, Cohen I, Cabico JA, et al. Incremental prognostic value of myocardial perfusion single photon emission computed tomography for the prediction of cardiac death: differential stratification for risk of cardiac death and myocardial infarction. Circulation. 1998;97:535–43.PubMedCrossRefGoogle Scholar
  50. 50.
    Jackson CE, Solomon SD, Gerstein HC, Zetterstrand S, Olofsson B, Michelson EL, et al. Albuminuria in chronic heart failure: prevalence and prognostic importance. Lancet. 2009;374:543–50.PubMedCrossRefGoogle Scholar
  51. 51.
    Gerstein HC, Mann JF, Pogue J, Dinneen SF, Halle JP, Hoogwerf B, et al. Prevalence and determinants of microalbuminuria in high-risk diabetic and nondiabetic patients in the Heart Outcomes Prevention Evaluation Study. The HOPE Study Investigators. Diabetes Care. 2000;23 Suppl 2:B35–9.PubMedGoogle Scholar
  52. 52.
    Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S, Schroll M, Jensen JS. Urinary albumin excretion. An independent predictor of ischemic heart disease. Arterioscler Thromb Vasc Biol. 1999;19:1992–7.PubMedCrossRefGoogle Scholar
  53. 53.
    Beijers HJ, Ferreira I, Bravenboer B, Dekker JM, Nijpels G, Heine RJ, et al. Microalbuminuria and cardiovascular autonomic dysfunction are independently associated with cardiovascular mortality: evidence for distinct pathways: the Hoorn Study. Diabetes Care. 2009;32:1698–703.PubMedCrossRefGoogle Scholar
  54. 54.
    Rutter MK, Wahid ST, McComb JM, Marshall SM. Significance of silent ischemia and microalbuminuria in predicting coronary events in asymptomatic patients with type 2 diabetes. J Am Coll Cardiol. 2002;40:56–61.PubMedCrossRefGoogle Scholar
  55. 55.
    Schmitz A. Microalbuminuria, blood pressure, metabolic control, and renal involvement: longitudinal studies in white non-insulin-dependent diabetic patients. Am J Hypertens. 1997;10:189S–97S.PubMedCrossRefGoogle Scholar
  56. 56.
    Rein P, Vonbank A, Saely CH, Beer S, Jankovic V, Boehnel C, et al. Relation of albuminuria to angiographically determined coronary arterial narrowing in patients with and without type 2 diabetes mellitus and stable or suspected coronary artery disease. Am J Cardiol. 2011;107:1144–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Deveci OS, Kabakci G, Tulumen E, Okutucu S, Aksoy H, Kaya EB, et al. The relationship between microalbuminuria and the presence and extent of coronary atherosclerosis. Angiology. 2010;61:184–91.PubMedCrossRefGoogle Scholar
  58. 58.
    Elhendy A, Tsutsui JM, O'Leary EL, Xie F, McGrain AC, Porter TR. Noninvasive diagnosis of coronary artery disease in patients with diabetes by dobutamine stress real-time myocardial contrast perfusion imaging. Diabetes Care. 2005;28:1662–7.PubMedCrossRefGoogle Scholar
  59. 59.
    Janand-Delenne B, Savin B, Habib G, Bory M, Vague P, Lassmann-Vague V. Silent myocardial ischemia in patients with diabetes: who to screen. Diabetes Care. 1999;22:1396–400.PubMedCrossRefGoogle Scholar
  60. 60.
    Gimelli A, Rossi G, Landi P, Marzullo P, Iervasi G, L'Abbate A, et al. Stress/rest myocardial perfusion abnormalities by gated SPECT: still the best predictor of cardiac events in stable ischemic heart disease. J Nucl Med. 2009;50:546–53.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Giampiero Giovacchini
    • 1
    • 2
    • 3
  • Mario Cappagli
    • 1
  • Stefano Carro
    • 4
  • Sandro Borrini
    • 5
  • Antonella Montepagani
    • 1
  • Rossella Leoncini
    • 1
  • Gianfranco Mazzotta
    • 5
  • Gianmario Sambuceti
    • 6
  • Giuliano Mariani
    • 7
  • Duccio Volterrani
    • 7
  • Michael J. Zellweger
    • 8
  • Andrea Ciarmiello
    • 1
  1. 1.Nuclear Medicine DepartmentS. Andrea HospitalLa SpeziaItaly
  2. 2.Department of RadiologyStadtspital TriemliZurichSwitzerland
  3. 3.Department of Radiology and Nuclear MedicineStadtspital WaidZurichSwitzerland
  4. 4.Diabetes CenterS. Andrea HospitalLa SpeziaItaly
  5. 5.Cardiology DepartmentS. Andrea HospitalLa SpeziaItaly
  6. 6.Department of Internal Medicine, Nuclear Medicine UnitUniversity of Genoa Medical SchoolGenoaItaly
  7. 7.Regional Center of Nuclear MedicineUniversity of Pisa Medical SchoolPisaItaly
  8. 8.Department of CardiologyUniversity Hospital BaselBaselSwitzerland

Personalised recommendations