ALDH2 Enzyme Deficiency in Diabetic Cardiomyopathy

Abstract

Diabetic cardiomyopathy (DCM) is a significant complication of diabetes, particularly affecting East Asian populations with a high prevalence of the ALDH2*2 (Glu504Lys) genetic variant. This variant impairs aldehyde detoxification, leading to increased oxidative stress, mitochondrial dysfunction, and chronic inflammation, exacerbating cardiac damage and fibrosis. This review aimed to systematically delineate the pathological role of ALDH2 enzyme deficiency in DCM by integrating clinical observations with mechanistic insights from experimental models and evaluating emerging therapies for genetically susceptible populations. In vitro and in vivo studies demonstrate that ALDH2*2 amplifies oxidative stress and disrupts mitochondrial homeostasis under hyperglycemic conditions, leading to enhanced cardiac fibrosis and functional decline. Additionally, ALDH2*2 carriers show heightened susceptibility to metabolic stress, further aggravating DCM. Given the high prevalence of ALDH2*2 in East Asian populations, targeted therapeutic strategies are urgently needed. Promising approaches include ALDH2 activators (e.g., Alda-1) that enhance detoxification of reactive aldehydes, and SGLT2 inhibitors (e.g., empagliflozin) that improve mitochondrial function and reduce oxidative damage. These therapies can mitigate oxidative stress and preserve cardiac function in ALDH2*2 carriers, thereby potentially reducing DCM burden, especially in high-risk East Asian populations. Further clinical investigations are warranted to validate these therapeutic approaches and optimize management for ALDH2-deficient individuals.

Keywords: ALDH2 activators; ALDH2 enzyme deficiency; ALDH2*2 carriers; East Asian populations; SGLT2 inhibitors; diabetic cardiomyopathy.

Figure 1

Progression of diabetic cardiomyopathy mediated by the ALDH2*2 variant and the potentiality of the SGLT2 inhibitor in alleviating relevant harmful factors in the Asian diabetic population. The diagram illustrates the progression of diabetic cardiomyopathy (DCM) mediated by the ALDH2*2 variant. Impaired detoxification due to ALDH2*2 leads to increased oxidative stress and mitochondrial dysfunction. Oxidative stress promotes fibrosis and inflammation, contributing to the restrictive phenotype with increased LV wall thickness and LA volume. Mitochondrial dysfunction causes energy deficiency and cardiac remodeling, leading to reduced contractile function and the dilated phenotype characterized by ventricular enlargement and heart failure. This pathway demonstrates how ALDH2*2 accelerates DCM progression and how implementing the SGLT2 inhibitor may be helpful, highlighting potential therapeutic targets for mitigating cardiac remodeling.