Abundance, localization, and functional correlates of the advanced glycation end-product carboxymethyl lysine in human myocardium

Martin M. LeWinter, Douglas Taatjes, Takamaru Ashikaga, Bradley Palmer, Nicole Bishop, Peter VanBuren, Stephen Bell, Cameron Donaldson, Markus Meyer, Kenneth B. Margulies, Margaret Redfield, David A. Bull, Michael Zile

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7 Scopus citations


Advanced glycation end-products (AGEs) play a role in the pathophysiology of diabetes mellitus (DM) and possibly hypertension (HTN). In experimental DM, AGEs accumulate in myocardium. Little is known about AGEs in human myocardium. We quantified abundance, localization, and functional correlates of the AGE carboxymethyl lysine (CML) in left ventricular (LV) myocardium from patients undergoing coronary bypass grafting (CBG). Immunoelectron microscopy was used to quantify CML in epicardial biopsies from 98 patients (71 M, 27 F) with HTN, HTN + DM or neither (controls), all with normal LV ejection fraction. Myofilament contraction-relaxation function was measured in demembranated myocardial strips. Echocardiography was used to quantify LV structure and function. We found that CML was abundant within cardiomyocytes, but minimally associated with extracellular collagen. CML counts/μm2 were 14.7% higher in mitochondria than the rest of the cytoplasm (P < 0.001). There were no significant sex or diagnostic group differences in CML counts [controls 45.6 ± 3.6/μm2 (±SEM), HTN 45.8 ± 3.6/μm2, HTN + DM 49.3 ± 6.2/μm2; P = 0.85] and no significant correlations between CML counts and age, HgbA1c or myofilament function indexes. However, left atrial volume was significantly correlated with CML counts (r = 0.41, P = 0.004). We conclude that in CBG patients CML is abundant within cardiomyocytes but minimally associated with collagen, suggesting that AGEs do not directly modify the stiffness of myocardial collagen. Coexistent HTN or HTN + DM do not significantly influence CML abundance. The correlation of CML counts with LAV suggests an influence on diastolic function independent of HTN, DM or sex whose mechanism remains to be determined.

Original languageEnglish (US)
Article numbere13462
JournalPhysiological Reports
Issue number20
StatePublished - Nov 2017
Externally publishedYes

Bibliographical note

Funding Information:
NIH grants RO1HL089944 and U10 HL110342 (Dr. LeWinter), R56HL123478 and 1R01HL123478 (Dr. Zile), RO1HL105993 and U10HL110338 (Dr. Margulies), and the NHLBI Heart Failure Research Network. Dr. Zile is also supported by the Research Service of the Department of Veterans Affairs (5101CX000415 and 5101BX000487). In addition to the NHLBI Heart Failure Research Network and the Research Service of the Department of Veterans Affairs, the research was also supported by individual NHLBI RO1 and R56 grants held by Drs. LeWinter, Margulies and Zile, as specified on page 1 of the proofs.

Publisher Copyright:
© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society


  • Advanced glycation end-products
  • carboxymethyl lysine
  • diabetes mellitus
  • hypertension
  • myocardium


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