Cardiomyopathy Treatment in Rodent Models – ADA 2018
At ADA 2018, we shared the latest data on our next generation type 2 diabetes (T2D) and obesity rodent models. This included our latest ZDSD rat studies, examining possible therapeutic approaches for cardiomyopathy with the presence of metabolic syndrome.
- initial cardiac hypertrophy
- followed by thinning of the cardiac walls with declines in both systolic and diastolic functions
- leading to heart failure.
No conventional rodent models fully capture DC phenotypes – but the ZDSD rat model arguably comes closest.
ZDSD Next Generation T2D Rat Model
The ZDSD rat, a new generation of T2D rodent model with intact leptin signaling, features slow onset of diabetes, obesity, and dyslipidemia. This closely mimics the development of T2D in patients(1,2).
Studying Cardiomyopathy in ZDSD Rat Models
The ZDSD rat develops multiple dysmetabolic phenotypes. They are spontaneously hypertensive with reduction in LV function and cardiac reserve, which resembles ultrasonic symptoms of diabetic cardiomyopathy patients. Therefore, the ZDSD rat may serve as a suitable preclinical model to study potential therapeutic approaches to treat cardiomyopathy with the presence of metabolic syndrome.
ADA Poster 421-P: Next Generation of Spontaneous Diabetic Model of ZDSD Rats with Intact Leptin Signaling Develop Cardiac Dysfunction and Compromised Cardiac Reserve
ZDSD rats develop hypertension from at eighteen weeks, with both systolic and diastolic blood pressure significantly higher than controls. Their left ventricular (LV) functions are compromised, along with changes in cardiac morphology.
Systolic Dysfunction at Resting Condition
At resting state, ZDSD rats showed LV hypertrophy from the age of eighteen to twenty-two weeks. Following this, cardiac walls became thinner with larger LV volume. Concomitantly, both ejection fraction (EF) and trans-mitral E/A ratio of LV declined at thirty-four weeks old.
Compromised LV Contractility
Upon treatment with dobutamine for five minutes, SD rats reached almost 98% EF and 80% fractional shortening (FS), while the values for ZDSD were 91% and 60%, respectively, after thirty weeks old. This suggests a loss of contractility and cardiac reserve in ZDSD rats.
More ADA 2018
Don’t miss the rest of our ADA recap posts, examining the underlying mechanisms of inflammation in metabolic disease and the therapeutic potential of FTY720 in T2D.
Further Reading on the ZDSD Rat:
- Peterson et al. Characterization of the ZDSD Rat: A Translational Model for the Study of Metabolic Syndrome and Type 2 Diabetes. J Diabetes Res 2015; 2015:487816.
- Davis et al. Age-Related Differences in Response to High-Fat Feeding on Adipose Tissue and Metabolic Profile in ZDSD Rats. ISRN Obes 2013; 2013:584547.