Right ventricular dysfunctions in type 1 diabetic mice: A longitudinal study

Abstract

BACKGROUND

Diabetes has become a widespread metabolic disease affecting multiple organs. Among diabetic complications, cardiovascular complications are the main cause of patient morbidity and mortality. Diabetic cardiomyopathy is a diabetes-specific cardiomyopathy in the absence of other cardiovascular disease and occurs more frequently in type 1 diabetes (T1D) than in type 2 diabetes. Previous studies on diabetic cardiomyopathy have predominantly focused on the effects of diabetes on left ventricular (LV) dysfunction, while studies of right ventricular (RV) dysfunction have been sparse but are gaining attention. Although T1D accounts for only 5%-10% of the total diabetic population, diabetic cardiomyopathy is a major cause of morbidity and mortality in children with life-long, long-term complications.

AIM

To evaluate longitudinal RV and LV functional changes in female transgenic OVE26, T1D mice and wild-type FVB mice over a 30-week period.

METHODS

RV and LV structure and function were evaluated by transthoracic echocardiography. RV systolic pressure was measured by a transducer-tipped pressure catheter. Sirius-red staining was used to quantify collagen and fibrosis, wheat germ agglutinin staining was utilized to measure cardiomyocyte size, and quantitative real-time polymerase chain reaction and Western blotting were used to quantify miRNA expression and protein abundance, respectively.

RESULTS

RV systolic function, measured by tricuspid valve annular plane systolic excursion and RV systolic velocity, was similar between control and T1D mice, but LV systolic function decreased in T1D mice at 30 weeks of age. RV diastolic dysfunction in T1D mice significantly increased by 18 weeks and progressed until 30 weeks, while LV diastolic dysfunction trended towards abnormal at 12 weeks, significantly increased by 18 weeks, and continued to progress by 30 weeks. Furthermore, RV diastolic dysfunction was accompanied by RV cardiac fibrosis and hypertrophy in T1D mice, occurring later than that in the LV. Pulmonary arterial hypertension developed in T1D mice, evidenced by increased pulmonary acceleration time to pulmonary ejection time ratio and increased RV peak systolic pressure at 30 weeks. These results suggest the development of early LV diastolic dysfunction followed by LV systolic dysfunction and RV diastolic dysfunction at 30 weeks in T1D mice.

CONCLUSION

RV diastolic dysfunction develops later than LV dysfunction in OVE26 T1D mice. Mild pulmonary arterial hypertension appear at later stages of T1D and could contribute to RV systolic impairment and remodeling.

Keywords: Diabetic cardiomyopathy; Type 1 diabetes; Right ventricle; Left ventricle; Cardiac remodeling; Cardiac dysfunction

Core Tip: Diabetic cardiomyopathy is a diabetes-associated complication. However, the temporal relationship between right ventricle (RV) and left ventricle (LV) systolic/diastolic functions in diabetes has not been explored. Therefore, we examined longitudinal RV and LV function changes in transgenic OVE26 type 1 diabetes (T1D) mice and wild-type FVB mice over a 30-week period. T1D mice developed early LV diastolic dysfunction, followed by LV systolic dysfunction and RV diastolic dysfunction at 30 weeks. Furthermore, T1D mice demonstrated an increase in the pulmonary acceleration time to pulmonary ejection time ratio and RV peak systolic pressure at 30 weeks, suggesting the development of mild pulmonary arterial hypertension.