title: Left ventricular diastolic dysfunction in nonhuman primate model of dysmetabolism and diabetes.
abstract: BACKGROUND
  Diabetes is one of the major risk factors for cardiomyopathy and heart failure with reduced ejection fraction (EF) and highly associated with left ventricular (LV) dysfunction in human. This study aimed 1) to noninvasively assess cardiac function using echocardiography; 2) to test the hypothesis that like diabetic human, cardiac function may also be compromised; in spontaneously developed obese, dysmetabolic and diabetic nonhuman primates (NHPs).
  
  
  METHODS
  Cardiovascular functions were measured by noninvasive echocardiography in 28 control, 20 dysmetabolic/pre-diabetic and 41 diabetic cynomolgus monkeys based on fasting blood glucose and other metabolic status.
  
  
  RESULTS
  The LV end-systolic volume (ESV) was higher while end-diastolic volume (EDV, 12 ± 5.7 mL) and EF (63 ± 12.8 %) significantly lower in the diabetic compared to control (14 ± 7 mL and 68 ± 9.8 %) group, respectively. The E/A ratio of LV trans-mitral peak flow rate during early (E) over late (A) diastole was significantly lower in the diabetic (1.19 ± 0.45) than control (1.44 ± 0.48) group. E-wave deceleration time (E DT) was prolonged in the diabetic (89 ± 41 ms) compared to control (78 ± 26 ms) group. Left atrial (LA) maximal dimension (LADmax) was significantly greater in the diabetic (1.3 ± 0.17 cm) than control (1.1 ± 0.16 cm) group. Biochemical tests showed that total cholesterol and LDL were significant higher in the diabetic (167 ± 63 and 69 ± 37 mg/dL) than both pre-diabetic (113 ± 37 and 41 ± 23 mg/dL) and control (120 ± 28 and 41 ± 17 mg/dL) groups, respectively. Multivariable logistic regression analysis demonstrated that LV systolic (reduced EF) and diastolic (abnormal E/A ratio) dysfunctions are significantly correlated with aging and hyperglycemia. Histopathology examination of the necropsy heart revealed inflammatory infiltration, cardiomyocyte hypertrophy and fragmentation, indicating the myocardial ischemia and remodeling which is consistent with the LV dysfunction phenotype.
  
  
  CONCLUSIONS
  Using noninvasive echocardiography, the present study demonstrated for the first time that dysmetabolic and diabetic NHPs are associated with LV systolic (increased ESV, decreased EF, etc.) and diastolic (decreased EDV and E/A ratio, prolonged E DT, etc.) dysfunctions, accompanied by LA hypertrophic remodeling (increased LADmax), the phenotypes similarly to those found in diabetic patients. Thus, spontaneously developed dysmetabolic and diabetic NHPs is a highly translatable model to human diseases not only in the pathogenic mechanisms but also can be used for testing novel therapies for cardiometabolic disorders.
authors.affiliation: Crown Bioscience, Inc. at David H. Murdoch Research Institute, 150 N Research Campus drive, Kannapolis, NC, USA. guhaihua@crownbio.com.
authors.forename: Haihua
authors.initials: H
authors.lastname: Gu
authors.affiliation: Cardiovascular and metabolic diseases division, Crown Bioscience, Inc., 6 West Beijing road, Taicang, Jiangsu, China. liuyongqiong@crownbio.com.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Crown Bioscience, Inc. at David H. Murdoch Research Institute, 150 N Research Campus drive, Kannapolis, NC, USA. meishuang@crownbio.com.
authors.forename: Shuang
authors.initials: S
authors.lastname: Mei
authors.affiliation: Cardiovascular and metabolic diseases division, Crown Bioscience, Inc., 6 West Beijing road, Taicang, Jiangsu, China. wangbingdi@crownbio.com.
authors.forename: Bingdi
authors.initials: B
authors.lastname: Wang
authors.affiliation: Cardiovascular and metabolic diseases division, Crown Bioscience, Inc., 6 West Beijing road, Taicang, Jiangsu, China. sunguofeng@crownbio.com.
authors.forename: Guofeng
authors.initials: G
authors.lastname: Sun
authors.affiliation: Cardiovascular and metabolic diseases division, Crown Bioscience, Inc., 6 West Beijing road, Taicang, Jiangsu, China. wangxiaoli@crownbio.com.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wang
authors.affiliation: Cardiovascular and metabolic diseases division, Crown Bioscience, Inc., 6 West Beijing road, Taicang, Jiangsu, China. xiaoyongfu@crownbio.com.
authors.forename: Yongfu
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Cardiovascular and metabolic diseases division, Crown Bioscience, Inc., 6 West Beijing road, Taicang, Jiangsu, China. staupmichael@crownbio.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Staup
authors.affiliation: Crown Bioscience, Inc. at David H. Murdoch Research Institute, 150 N Research Campus drive, Kannapolis, NC, USA. gregoireFM@crownbio.com.
authors.forename: Francine M
authors.initials: FM
authors.lastname: Gregoire
authors.affiliation: Crown Bioscience, Inc. at David H. Murdoch Research Institute, 150 N Research Campus drive, Kannapolis, NC, USA. chngkeefe@crownbio.com.
authors.forename: Keefe
authors.initials: K
authors.lastname: Chng
authors.affiliation: Cardiovascular and metabolic diseases division, Crown Bioscience, Inc., 6 West Beijing road, Taicang, Jiangsu, China. yxwang@crownbio.com.|Crown Bioscience, Inc. at David H. Murdoch Research Institute, 150 N Research Campus drive, Kannapolis, NC, USA. yxwang@crownbio.com.
authors.forename: Yixin Jim
authors.initials: YJ
authors.lastname: Wang
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D003920:Diabetes Mellitus / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000150:complications / Q000000981:diagnostic imaging / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D006943:Hyperglycemia / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000627:therapeutic use; D008252:Macaca fascicularis; D008297:Male; D009206:Myocardium / Q000473:pathology; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000150:complications / Q000000981:diagnostic imaging / Q000503:physiopathology*
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin