Abstract 3754: Fibrosis, AGEs or Stiff Cardiomyocytes: Which One to Blame for the High Diastolic Stiffness of the Diabetic Heart?
High diastolic LV stiffness is recognized as an important manifestation of diabetes mellitus (DM)-induced LV dysfunction. High diastolic LV stiffness is usually attributed to myocardial fibrosis and to myocardial deposition of advanced glycation endproducts (AGEs). A high cardiomyocyte (CM) resting tension (RT) can also affect diastolic LV stiffness in DM, as DM induces hypertrophy and as hypertrophied CM have elevated RT. Both structural and functional myocardial determinants of LV diastolic stiffness were therefore compared in endomyocardial biopsies of heart failure (HF) patients with DM (DM+) (n=27) and without DM (DM-) (n=31). All patients had been admitted for worsening HF, were free of coronary artery disease and were subdivided into patients with either systolic HF (SHF), if LVEF < 45%, or diastolic HF (DHF). Collagen volume fraction (CVF) and CM diameter (D) were assessed by histomorphometry. Myocardial AGEs deposition was quantified by a carboxymethyllysine immunofluorescence score. Single CM were isolated from the biopsies and attached to a force transducer to measure RT at a sarcomere length of 2.2 μm. AGEs were higher in LV myocardium of DM+ (17.2±2.4 score/cm2) than of DM- (8.3±1.9 score/cm2; P<0.01). DM affected AGEs deposition similarly in SHF and DHF (Table⇓). CVF was higher in SHF (17.0±1.0 %) than in DHF (11.7±0.8 %; P<0.001). DM further increased CVF in SHF (Table⇓). CM-D was larger in DM+ (20.2±0.3 μm) than in DM- (17.1±0.3 μm; P<0.0001) and larger in DHF (21.2±0.3 μm) than in SHF (16.7±0.3 μm; P<0.0001). RT of single CM was also higher in DHF (7.8±0.7 kN/m2) than in SHF (4.8±0.2 kN/m2; P<0.0001). DM caused further elevation of RT in DHF (Table⇓).
Conclusion: Apart from myocardial AGEs deposition, mechanisms of DM-induced myocardial stiffening differ in SHF and DHF: myocardial fibrosis is prominent in DM with SHF and RT of CM is highest in DM with DHF. DM therefore accentuates the structural and functional differences between LV myocardium in SHF and DHF.