Facts

  • Cardiomyocyte apoptosis plays a key role in the pathogenesis of diabetic cardiomyopathy.

  • Targeting hyperglycemia reduces cytotoxicity in cardiomyocytes.

  • Some new and old small-molecule chemical drugs are in ongoing clinical trials for the treatment of DCM.

  • Traditional Chinese medicine and some natural products can exert protective effects against diabetic cardiomyopathy.

Open questions

  • How do novel biomarkers identify early diabetic cardiomyopathy?

  • What is the mechanism by which hyperglycemia leads to cardiomyocyte apoptosis?

  • How is hyperglycemia involved in the progression of cardiac fibroblast activation?

  • Can some emerging treatment strategies for diabetic cardiomyopathy be used in clinical practice?

Introduction

With the growth of the economy, changes in lifestyles and diets, and the aging of the population, the number of diabetic patients and disease incidence are increasing at an alarming rate. According to statistics from the International Diabetes Federation, as of 2021, there were ~537 million people aged 20–79 with diabetes worldwide, and it is expected that this number will reach 784 million by 2045. Diabetic cardiomyopathy (DCM), which was first introduced by Rullber in 1972, is a common and severe complication of diabetes that can lead to the development of heart failure. DCM, which is the dominant cause of heart failure in patients with diabetes, is caused by abnormal glucose metabolism, resulting in structural heart defects and dysfunction without other cardiac risk factors, such as coronary artery disease, hypertension, and severe valvular diseases [1]. At present, although there are therapeutic strategies available to treat DCM, treatment is mainly focused on controlling blood glucose and blood lipids, and there is a lack of effective drugs or strategies targeting damaged myocardial tissue. Therefore, understanding the clinical symptoms, identifying early and highly sensitive diagnostic biomarkers, elucidating the underlying pathogenetic mechanisms, and develo** new targeted interventions for DCM, are critical for improving the prognosis of patients and preventing the occurrence and development of the disease.

Clinical symptoms and diagnosis of DCM

DCM was initially described as a diabetes mellitus (DM)-induced pathophysiological condition in which cardiac dysfunction and heart failure occurred in the absence of coronary artery disease, hypertension, and other valvular heart disease. The initial symptoms of DCM are mild left ventricular stiffness, slightly decreased compliance, and diastolic dysfunction, which are easily ignored by patients, thus missing the best opportunity for diagnosis and treatment. The subsequent clinical manifestations of DCM are arrhythmia, angina pectoris, and eventually the development of congestive heart failure, which is life-threatening in some severe cases. At present, many noninvasive techniques, including electrocardiography, echocardiography, chest radiography, pulsed-wave Doppler tissue imaging, computed tomography, magnetic resonance imaging, and endocardial biopsy, have been used to detect changes in cardiac architecture and function [2]. Endocardial biopsy, which is the gold standard for the clinical diagnosis of DCM, can detect cardiac hypertrophy, necrosis, myocardial fibrosis, and other pathological changes, but this method cannot show the abnormal diastolic function of the heart in the early subclinical stage and is associated with a certain degree of trauma [3]. Given the rare clinical symptoms in the early stage of DCM, routine noninvasive examinations are almost ineffective. Therefore, researchers have focused on investigating feasible methods for the early diagnosis of DCM.

Evidence has shown that the serum glycosylated hemoglobin (HbA1c) and cardiac troponin I (cTnI) levels in the DCM group were significantly higher than those in the diabetes mellitus alone group, suggesting that serum HbA1c and cTnI levels were closely related to DCM and could serve as promising diagnostic markers for DCM [96]. β-receptor antagonists can reduce cardiomyocyte uptake of glucose, increase the levels of oxidative stress factors (SOD1 and SOD2), and inhibit the production of oxidative stress products in DCM to modulate cardiac metabolism and improve cardiac function [97, 98]. Ca2+ channel antagonists can directly act on L-type Ca2+ channels to reduce intracellular Ca2+ concentrations, thereby alleviating cardiac damage in patients with DCM [99]. Long-term verapamil treatment can effectively improve myocardial hypertrophy and fibrosis by regulating of the intracellular and extracellular Ca2+ balance (Fig. 3) [100, 101].

Of note, there are some new and old small-molecule chemical drugs in completed and ongoing clinical trials for the treatment of DCM (Table 1). Among them, AT-001 (Caficrestat) and Ninerafaxstat (IMB-1018972) are newly-developed small-molecule chemical drugs for the treatment of DCM. AT-001 is a novel and potent oral aldose reductase inhibitor targeting AKR1B1 that is in phase 3 clinical development for the treatment of DCM (https://synapse.zhihuiya.com/clinical-progress-detail/0a5aea2aa5058d22852a258dea9d44aa). A clinical trial (NCT04365699) on the role of COVID-19 with and without treatment with AT-001 on cardiac structure and function in patients hospitalized for the management of COVID-19 infection was completed and revealed a reduction in the mortality of the AT-001 treatment group (https://synapse.zhihuiya.com/clinical-progress-detail/ed5e59202eae554e9d29a40542aea820). A clinical study evaluating the effects of Ninerafaxstat on myocardial energetics, metabolism, and functions in T2DM and obesity with HFpEF is still underway. Trimetazidine, an inhibitor of ACAA2, can improve DCM by inhibiting Nox2/TRPC3-induced oxidative stress [102], reducing the deposition of fatty acids [103], preventing fibrosis, reducing apoptosis, and enhancing autophagy [104]. The effects of trimetazidine on left ventricular function and inflammatory markers in type 2 diabetic patients were tested in a phase 2 clinical trial (https://synapse.zhihuiya.com/clinical-progress-detail/55d254aea55e524d82a2e2534e5e282e). Alpha-lipoic acid, which is a small molecule with antioxidant properties, was reported to alleviate cardiac remodeling in the diabetic heart [105], and a clinical study of the effects of alpha-lipoic acid on DCM is ongoing (https://synapse.zhihuiya.com/clinical-progress-detail/08490325eaa4e895d5a0e53324e54822). Empagliflozin and dapagliflozin, which are the initial drugs targeting SGLT2, were shown to protect cardiac function in diabetic models [106,107,

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Acknowledgements

This work was funded by the China Postdoctoral Science Foundation (No. 2022M722892 and No. 2022M722901), the Key R&D and promotion Special Project of Henan Province (No. 232102311171), the National Natural Science Foundation of China Young Scientists Project (No. 82200796), and the Henan Province Medical Science and Technology Research Plan Joint Project (No. LHGJ20220289 and No. LHGJ20200364).

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  1. These authors contributed equally: **-Ling Huo, Qi Feng.

Authors and Affiliations

  1. Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China

    **-Ling Huo, Qi Feng, Shaokang Pan, Wen-Jia Fu & Zhangsuo Liu

  2. Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, P. R. China

    **-Ling Huo, Qi Feng, Shaokang Pan, Wen-Jia Fu & Zhangsuo Liu

  3. Henan Province Research Center For Kidney Disease, Zhengzhou, 450052, P. R. China

    **-Ling Huo, Qi Feng, Shaokang Pan, Wen-Jia Fu & Zhangsuo Liu

  4. Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P. R. China

    **-Ling Huo, Qi Feng, Shaokang Pan, Wen-Jia Fu & Zhangsuo Liu

  5. Department of Chinese Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China

    Zhenzhen Liu

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**-Ling Huo and Qi Feng conceptualized the ideas and drafted and wrote the original manuscript. Wenjia Fu, Shaokang Pan, Zhangsuo Liu and Zhenzhen Liu revised the manuscript. All authors reviewed the manuscript and approved the final version of the manuscript for submission.

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Huo, JL., Feng, Q., Pan, S. et al. Diabetic cardiomyopathy: Early diagnostic biomarkers, pathogenetic mechanisms, and therapeutic interventions. Cell Death Discov. 9, 256 (2023). https://doi.org/10.1038/s41420-023-01553-4

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