Diabetes induced right ventricular remodeling and dysfunction before left ventricular changes, occurring via a distinct CD36-independent fatty acid uptake pathway.
In diabetic cardiomyopathy, right ventricular remodeling and dysfunction precede left ventricular changes and are driven by a distinct fatty acid uptake mechanism involving FATP6 rather than CD36.
Absolute Event Rate: 31% vs 37%
p-value: p=0.0002
Diabetes is a major public health concern, with both type 1 (T1D) and type 2 diabetes (T2D) resulting in diabetic cardiomyopathy (DCM). The hallmark of DCM is metabolic inflexibility, characterized by excess uptake of fatty acids (FA). Elevated FA uptake results in an imbalance between uptake and utilization of FA, leading to lipotoxicity, lipid accumulation associated with DCM. Although DCM is defined by left ventricular (LV) dysfunction, recent work has demonstrated that the right ventricle (RV) also remodels in diabetes but through poorly understood mechanisms. The temporal development of LV versus RV dysfunction is unclear, alongside the metabolic mechanisms that underlie ventricular-specific remodeling. Therefore, we set out to quantify the temporal dynamics of RV and LV remodeling in DCM as well as to identify the mechanisms by which the RV uptakes FA. We utilized several mouse models of T2D as well as a large-animal pig model of T1D to gain mechanistic insight into RV remodeling. In two models of T2D, we show that RV remodeling begins early in disease pathogenesis, before changes in LV structure or function. We quantified FA uptake across models of T1D and T2D, performed lipidomics and found that the LV and RV accumulate different lipid species and that the mechanism of uptake of FA is distinct between the ventricles. Unlike the diabetic LV in which the primary FA transporter CD36 is robustly upregulated, CD36 does not appear to be involved in diabetic RV myopathy. Together, we show that the RV remodels before and independently of the LV via distinct FA metabolic mechanisms. Ventricle-specific targeting for DCM therapies is warranted.
Satyanarayana et al. (Mon,) conducted a other in Diabetic cardiomyopathy. Diabetes (T1D and T2D models) vs. Non-diabetic controls (Wild type/Lean) was evaluated on Right ventricular fractional area change (RV FAC) in db/db mice (p=0.0002). Diabetes induced right ventricular remodeling and dysfunction before left ventricular changes, occurring via a distinct CD36-independent fatty acid uptake pathway.