Abstract 337: Cardiac Inflammation Contributes to Heart Failure With Preserved Ejection Fraction (HFpEF) in Diabetic Mice With Low Aldehyde Dehydrogenase 2 (aldh2) Activity

Abstract

Heart failure with preserved ejection fraction (HFpEF) is the prevalent form of cardiac complication in type 2 diabetes, which is associated with higher mortality. Inflammation plays a central role in the development of HFpEF, although the mechanism is unclear. Aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme, detoxifies oxidative-stress mediated 4-hydroxy-2-nonenal (4HNE) and thereby confers cardioprotective in diabetes. ALDH2*2 is the most common genetic mutation which causes a low ALDH2 activity. We hypothesize that low ALDH2 activity increases cardiac inflammation and consequentially aggravates HFpEF in diabetic mice. We bred a diabetic mouse model which carries mutant leptin receptor (same as db/db mice) and mutant ALDH2*2 (AL mice). The mice with double mutations are termed as ALDH2*2-fat (AF) mice. The ejection fraction (EF) is preserved in db/db (65.9±2.2%) and AF (67.2±3.9%) diabetic mice compared to db/m (68.5±4.6%, p>0.05 vs db/db) and AL (68.6±4.8%, p>0.05 vs AF) non-diabetic mice at 20 weeks. The running stress by treadmill decreased EF in AF mice (56.3±5.0%) compared to db/db (65.0±3.3%; p<0.05), db/m (70.5±2.8%; p<0.01) and AL (66.4±4.1%; p<0.05). The maximum running distance was significantly decreased in AF (128.7±28.8m) mice compared to db/db (193.2±14.2m; p<0.05), AL (305.2±21.5m; p<0.01) and db/m (371.3±16.6m; p<0.01) mice. In heart sections, the CD64+ macrophages in AF mice (88.64±22.12 /mm 2 ) were significantly increased, compared to db/db (53.24±12.55 /mm 2 , p<0.05), db/m (12.57±2.56 /mm 2 , p<0.01) and AL mice (47.89±13.97/mm 2 , p<0.05). In conclusion, the low ALDH2 activity contributes to cardiac inflammation and thus HFpEF in diabetic mice.