Emerging Therapy for Diabetic Cardiomyopathy: From Molecular Mechanism to Clinical Practice

Abstract

Diabetic cardiomyopathy is characterized by abnormal myocardial structure or performance in the absence of coronary artery disease or significant valvular heart disease in patients with diabetes mellitus. The spectrum of diabetic cardiomyopathy ranges from subtle myocardial changes to myocardial fibrosis and diastolic function and finally to symptomatic heart failure. Except for sodium-glucose transport protein 2 inhibitors and possibly bariatric and metabolic surgery, there is currently no specific treatment for this distinct disease entity in patients with diabetes. The molecular mechanism of diabetic cardiomyopathy includes impaired nutrient-sensing signaling, dysregulated autophagy, impaired mitochondrial energetics, altered fuel utilization, oxidative stress and lipid peroxidation, advanced glycation end-products, inflammation, impaired calcium homeostasis, abnormal endothelial function and nitric oxide production, aberrant epidermal growth factor receptor signaling, the activation of the renin-angiotensin-aldosterone system and sympathetic hyperactivity, and extracellular matrix accumulation and fibrosis. Here, we summarize several important emerging treatments for diabetic cardiomyopathy targeting specific molecular mechanisms, with evidence from preclinical studies and clinical trials.

Keywords: diabetic cardiomyopathy; emerging therapy; mechanism.

Figure 1

Impaired nutrient-sensing signaling, dysregulated autophagy, impaired mitochondrial energetics, and altered fuel utilization in the pathogenesis of diabetic cardiomyopathy. AMPK:5’ adenosine monophosphate-activated protein kinase; mTORC1: mammalian target of rapamycin complex 1; ULK1: unc-51-like autophagy activating kinase 1; PGC-1á: peroxisome proliferator-activated receptor-gamma coactivator 1-alpha; FFA: fatty acid, DCM: diabetic cardiomyopathy.

Figure 2

Oxidative stress, inflammation, impaired calcium homeostasis, abnormal endothelial function and nitric oxide production, aberrant epidermal growth factor receptor singling, and activation of the renin–angiotensin–aldosterone and sympathetic systemsin the pathogenesis of diabetic cardiomyopathy. MG: methylglyoxal, AGE: advanced glycation end-products, AR: aldose reductase, PKC: protein kinase C; ROS: reactive oxygen species; RAGE: receptor for advanced glycation end-products; TRL4: toll-like receptor 4; TNFR: tumor necrosis factor receptor; NF-κB: nuclear factor kappa-B; TNF-α: tumor necrosis factor-α; GC: guanylate cyclase; eNOS: constitutive nitric oxide synthase; ErbB2/4 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2); NOX: NADPH oxidase; ACE2: angiotensin-converting enzyme 2; SERCA2a: sarcoplasmic reticulum Ca²⁺-ATPase 2a; NO: nitric oxide; ATP: adenosine triphosphate, IKK: IκB kinase; SR: sarcoplasmic reticulum.

Figure 3

The pathogenesis of extracellular matrix (ECM) accumulation and fibrosis in diabetic cardiomyopathy.PI3Kã:phosphoinositide 3-kinaseã; ROS: reactive oxygen species; JNK: c-Jun N-terminal kinase, PKC: protein kinase C; p38 MAPK: p38 mitogen-activated protein kinase; GC: guanylate cyclase; cGMP: cyclic guanosine monophosphate; PKG: protein kinase G; ERK1/2: extracellular signal-regulated protein kinase 1/2;TGF-β: transforming growth factor-beta; GIP: gastric inhibitory polypeptide; GIP R: gastric inhibitory polypeptide receptor; IRS-1: insulin receptor substrate 1; O-GlcNAcylation (O-linked-N-acetylglucosaminylation); EMT: epithelial–mesenchymal transition; OCT: O-linked N-acetylglucosamine transferase; SGLT2i: sodium–glucose cotransporter 2inhibitors: NOX: NADPH oxidase; PUFA: polyunsaturated fatty acid; ECM: extracellular matrix.

Figure 4

Proposed algorithm for diagnosis of diabetic cardiomyopathy. LVH: left ventricular hypertrophy; MRI: magnetic resonance imaging; STE: speckle-tracking echocardiography; TDI; tissue Doppler imaging.