Correction: Type-2 diabetic aldehyde dehydrogenase 2 mutant mice (ALDH 2*2) exhibiting heart failure with preserved ejection fraction phenotype can be determined by exercise stress echocardiography

4-hydroxy-2-nonenal (4HNE), a cellular reactive aldehyde which is significantly increased in diabetic hearts due to decrease in the activity of its metabolizing enzyme, aldehyde dehydrogenase (ALDH)2, contributes to diabetes mellitus (DM)-mediated cardiotoxicity. Therefore, we hypothesize that lowering 4HNE ameliorates heart failure with preserved ejection fraction (HFpEF) in DM. To ameliorate DM mediated HFpEF, we will lower diabetes-mediated oxidative stress-induced 4HNE accumulation as well as augment 4HNE detoxification by activating ALDH2, via pharmacological agents. We induced type-2 DM by feeding high-fat diet (HFD) in ALDH2*2 mutant mice which have intrinsically low ALDH2 activity and thus having increased cardiac 4HNE levels. After 4 months of DM, the mice exhibited features of HFpEF and we treated the diabetic ALDH2*2 mice with vehicle (Veh), empagliflozin (EMP) (3mg/kg/d), a sodium-glucose cotransporter (SGLT) 2 inhibitor to reduce hyperglycemia and Alda-1 (10mg/kg/d), an ALDH2 activator to enhance ALDH2 activity as well as combination of EMP + Alda-1 (E + A), via subcutaneous osmatic pumps. After treating for 2 months, cardiac function was assessed by conscious echocardiography before and after exercise stress. EMP + Alda-1 improved running distance (RD, 231 ± 53 m), ejection fraction after running (EF, 69 ± 5 %), and decreased left atrial area (LA, 3.0 ± 0.2 mm 2 ), cardiomyocyte cross-section area (CA, 251 ± 32 μm 2 ) and myocardial fibrotic area (FA 1.0 ± 0.3 %) in ALDH2*2 mice with diabetic HFpEF compared to EMP (RD 142 ± 53 m; EF 62 ± 5 %; LA 3.5 ± 0.3 mm 2 ; CA 303 ± 55 μm 2 ; and FA 3.2 ± 1.8 %), Alda-1 (RD 183 ± 73 m; EF 68 ± 3 %; LA 3.2 ± 0.2 mm 2 ; CA 288 ± 34 μm 2 ; and FA 2.5 ± 1.2 %) and Veh (RD 52 ± 66 m; EF 55 ± 5.0 %; LA 4.7 ± 0.4 mm 2 ; CA 448 ± 65 μm 2 ; and FA 11 ± 3.5 %). This improvement was exerted by decreasing 4HNE levels as well as attenuating 4HNE-mediated decrease in cardiac liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. In conclusion, our data implicate that ALDH2 activation along with the treatment of hypoglycemic agents may be important strategy to alleviate diabetic HFpEF.

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

Circulation Research ◽

10.1161/res.127.suppl_1.337 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Guodong Pan ◽

Suresh S Palaniyandi

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Aldehyde Dehydrogenase ◽

Leptin Receptor ◽

Diabetic Mouse ◽

Genetic Mutation ◽

Preserved Ejection Fraction ◽

Diabetic Mice ◽

Aldehyde Dehydrogenase 2 ◽

Cardiac Inflammation

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.

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