title: Insulin resistance, endothelial function, angiogenic factors and clinical outcome in non-diabetic patients with chest pain without myocardial perfusion defects.
abstract: BACKGROUND
  Patients with angina-like symptoms without myocardial perfusion scintigram (MPS)-verified abnormality may still be at risk for cardiovascular events. We hypothesized that insulin resistance could play a role in this population even without diagnosed diabetes. We further explored physiological and blood biomarkers, as well as global gene expression patterns that could be closely related to impaired glucose homeostasis to deepen our mechanistic understanding.
  
  
  METHODS
  A total of 365 non-diabetic patients with suspected myocardial ischemia referred to MPS were enrolled and followed up regarding event-free survival with a median time of 5.1 years. All patients underwent endothelial function assessment by reactive hyperemic index (RHI) using EndoPAT and extensive biomarker analysis. Whole blood global gene expression pathway analysis was performed in a subset of patients.
  
  
  RESULTS
  Homeostasis model assessment of insulin resistance (HOMA-IR) added independent prognostic value in patients without myocardial perfusion defects. In a multivariable analysis, HOMA-IR was inversely associated with low RHI. Furthermore, elevated HOMA-IR was associated with decreased levels of vascular endothelial growth factor D, stem cell factor and endocan as well as to increased level of interleukin-6. Global gene expression pathway analysis of whole blood cells showed that high HOMA-IR and impaired endothelial function were associated with upregulated pro-inflammatory pathways and down-regulated eukaryotic initiation factor-2 pathway.
  
  
  CONCLUSIONS
  Insulin resistance measured by HOMA-IR is associated with endothelial dysfunction and confers independent prognostic information in non-diabetic patients with chest pain without myocardial perfusion defects. Increased systemic pro-inflammatory state and decreased levels of pro-angiogenic vascular growth factors may be important underlying molecular mechanisms.
authors.affiliation: Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. helena.westergren@gu.se.
authors.forename: Helena U
authors.initials: HU
authors.lastname: Westergren
authors.affiliation: Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. Sara.svedlund@gu.se.|Department of Clinical Physiology, Sahlgrenska University Hospital, Gothenburg, Sweden. Sara.svedlund@gu.se.
authors.forename: Sara
authors.initials: S
authors.lastname: Svedlund
authors.affiliation: AstraZeneca R&D, Gothenburg, Sweden. Remi.momo@astrazeneca.com.
authors.forename: Remi A
authors.initials: RA
authors.lastname: Momo
authors.affiliation: Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. Juuso.blomster@gmail.com.|AstraZeneca R&D, Gothenburg, Sweden. Juuso.blomster@gmail.com.
authors.forename: Juuso I
authors.initials: JI
authors.lastname: Blomster
authors.affiliation: AstraZeneca R&D, Gothenburg, Sweden. karin.fc.wahlander@telia.com.
authors.forename: Karin
authors.initials: K
authors.lastname: Wåhlander
authors.affiliation: AstraZeneca R&D, Gothenburg, Sweden. Erika.Rehnstrom@astrazeneca.com.
authors.forename: Erika
authors.initials: E
authors.lastname: Rehnström
authors.affiliation: AstraZeneca R&D, Gothenburg, Sweden. Peter.Greasley@astrazeneca.com.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Greasley
authors.affiliation: AstraZeneca R&D, Gothenburg, Sweden. Regina.Fritsche-Danielson@astrazeneca.com.
authors.forename: Regina
authors.initials: R
authors.lastname: Fritsche-Danielson
authors.affiliation: AstraZeneca R&D, Gothenburg, Sweden. Jan.oscarsson@astrazeneca.com.
authors.forename: Jan
authors.initials: J
authors.lastname: Oscarsson
authors.affiliation: Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. li-ming.gan@gu.se.|Department of Clinical Physiology, Sahlgrenska University Hospital, Gothenburg, Sweden. li-ming.gan@gu.se.|AstraZeneca R&D, Gothenburg, Sweden. li-ming.gan@gu.se.
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Gan
mesh_terms: D000368:Aged; D000787:Angina Pectoris / Q000097:blood / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D042501:Angiogenic Proteins / Q000097:blood* / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D016009:Chi-Square Distribution; D003324:Coronary Artery Disease / Q000097:blood / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D018572:Disease-Free Survival; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006940:Hyperemia / Q000503:physiopathology; D018836:Inflammation Mediators / Q000097:blood; D007333:Insulin Resistance; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011236:Prediabetic State / Q000097:blood / Q000150:complications* / Q000175:diagnosis / Q000503:physiopathology; D016016:Proportional Hazards Models; D012307:Risk Factors; D013997:Time Factors; D014664:Vasodilation
chemical_list: D042501:Angiogenic Proteins; D015415:Biomarkers; D018836:Inflammation Mediators