title: Diabetes mellitus worsens diastolic left ventricular dysfunction in aortic stenosis through altered myocardial structure and cardiomyocyte stiffness.
abstract: BACKGROUND
  Aortic stenosis (AS) and diabetes mellitus (DM) are frequent comorbidities in aging populations. In heart failure, DM worsens diastolic left ventricular (LV) dysfunction, thereby adversely affecting symptoms and prognosis. Effects of DM on diastolic LV function were therefore assessed in aortic stenosis, and underlying myocardial mechanisms were identified.
  
  
  RESULTS
  Patients referred for aortic valve replacement were subdivided into patients with AS and no DM (AS; n=46) and patients with AS and DM (AS-DM; n=16). Preoperative Doppler echocardiography and hemodynamics were implemented with perioperative LV biopsies. Histomorphometry and immunohistochemistry quantified myocardial collagen volume fraction and myocardial advanced glycation end product deposition. Isolated cardiomyocytes were stretched to 2.2-μm sarcomere length to measure resting tension (F(passive)). Expression and phosphorylation of titin isoforms were analyzed with gel electrophoresis with ProQ Diamond and SYPRO Ruby stains. Reduced LV end-diastolic distensibility in AS-DM was evident from higher LV end-diastolic pressure (21±1 mm Hg for AS versus 28±4 mm Hg for AS-DM; P=0.04) at comparable LV end-diastolic volume index and attributed to higher myocardial collagen volume fraction (AS, 12.9±1.1% versus AS-DM, 18.2±2.6%; P<0.001), more advanced glycation end product deposition in arterioles, venules, and capillaries (AS, 14.4±2.1 score per 1 mm(2) versus AS-DM, 31.4±6.1 score per 1 mm2; P=0.03), and higher F(passive) (AS, 3.5±1.7 kN/m2 versus AS-DM, 5.1±0.7 kN/m2; P=0.04). Significant hypophosphorylation of the stiff N2B titin isoform in AS-DM explained the higher F(passive) and normalization of F(passive) after in vitro treatment with protein kinase A.
  
  
  CONCLUSIONS
  Worse diastolic LV dysfunction in AS-DM predisposes to heart failure and results from more myocardial fibrosis, more intramyocardial vascular advanced glycation end product deposition, and higher cardiomyocyte F(passive), which was related to hypophosphorylation of the N2B titin isoform.
authors.affiliation: Department of Physiology, VU University Medical Center Amsterdam, Van der Boechorststraat 7,1081BT Amsterdam, The Netherlands.
authors.forename: Inês
authors.initials: I
authors.lastname: Falcão-Pires
authors.forename: Nazha
authors.initials: N
authors.lastname: Hamdani
authors.forename: Attila
authors.initials: A
authors.lastname: Borbély
authors.forename: Cristina
authors.initials: C
authors.lastname: Gavina
authors.forename: Casper G
authors.initials: CG
authors.lastname: Schalkwijk
authors.forename: Jolanda
authors.initials: J
authors.lastname: van der Velden
authors.forename: Loek
authors.initials: L
authors.lastname: van Heerebeek
authors.forename: Ger J M
authors.initials: GJ
authors.lastname: Stienen
authors.forename: Hans W M
authors.initials: HW
authors.lastname: Niessen
authors.forename: Adelino F
authors.initials: AF
authors.lastname: Leite-Moreira
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Paulus
mesh_terms: D000368:Aged; D001024:Aortic Valve Stenosis / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology*; D001706:Biopsy; D003094:Collagen / Q000378:metabolism; D064211:Connectin; D003326:Coronary Circulation / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology*; D015150:Echocardiography, Doppler; D005260:Female; D005355:Fibrosis; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006339:Heart Rate / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D012518:Sarcomeres / Q000378:metabolism / Q000473:pathology; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D064211:Connectin; D017127:Glycation End Products, Advanced; D009124:Muscle Proteins; C577285:TTN protein, human; D003094:Collagen; D011494:Protein Kinases