Diabetes mellitus is a common clinical chronic disease, and epidemiological and clinical studies have shown that the incidence of myocardial infarction in diabetic patients is significantly higher than that in non-diabetic patients.
Macrovascular, microvascular, myocardial and autonomic nerve disorders of the heart on the basis of metabolic disorders such as sugar and fat in diabetic patients, including diabetic coronary heart disease, diabetic cardiomyopathy, diabetic autonomic disorders, etc., the clinical manifestations can range from asymptomatic to severe arrhythmia, acute myocardial infarction, heart failure and even sudden death.
Diabetic heart disease is one of the most common complications of diabetes, with a high disability mortality rate, atherosclerosis accounts for 80% of diabetes mortality, and 75% of hospitalized patients with diabetes have cardiovascular disease.
Diabetic heart disease
There are mainly the following types of diabetic heart disease:
1. Diabetic coronary heart disease
Can be manifested as chest tightness, shortness of breath after activity, angina, severe cases can have heart failure, myocardial infarction, arrhythmia and even sudden death, its symptoms are often atypical, often manifested as asymptomatic myocardial ischemia, the incidence of painless myocardial infarction is as high as 35.5%, and the incidence of non-diabetic patients is 17.6%.
Diabetic patients with coronary heart disease have an early onset time, high incidence, rapid progression, easy to occur painless myocardial infarction or even sudden death, and the frequency of heart failure, shock, heart rupture and recurrent myocardial infarction after myocardial infarction is high.
2. Diabetic cardiomyopathy
Most diabetic cardiomyopathy is relatively insidious and often has no obvious symptoms in the early stage, and the systemic symptoms are mainly fatigue, weakness, palpitations, and shortness of breath; Cardiac symptoms often include the following:
(1) Palpitation, shortness of breath, chest tightness, which occurs after exertion, nervousness or emotional agitation, and in the late stage, there may be serosal effusion, edema, cardiac insufficiency and other manifestations;
(2) Occasional chest pain, the degree of pain onset is lighter than that of non-diabetic patients, which may be caused by pain nerve dullness or numbness;
(3) Complex arrhythmias.
3. Diabetic cardiac autonomic neuropathy
Diabetic cardiac autonomic dysfunction, which used to be thought to occur only in the late stages of diabetes, is now believed to have existed at the time of diagnosis of diabetes, and its high incidence but hidden clinical manifestations can cause painless myocardial infarction and sudden death of diabetes, which is a major cause of increased diabetes mortality.
Typical clinical features include orthostatic hypotension, tachycardia at rest, decreased tolerance to activity and certain medications, myocardial ischemia or myocardial infarction lacking typical symptoms, prolonged QT interval on ECG, and low heart rate variability. Among the above typical manifestations, painless myocardial infarction can induce malignant arrhythmias, heart failure and even sudden death, and the consequences are the most serious.
Research on hydrogen protecting the heart of diabetics
As early as 2013, mainland scholar Professor Tan Yongxing (Guilin Medical College) wrote that experiments found that inhalation of gas containing 2% hydrogen can improve myocardial depression, and inhalation of gas containing 4% hydrogen can significantly reduce the area of myocardial infarction.
Hydrogen and carbon monoxide were used together to treat cold ischemia 6 or 18 hours after rat homologous ectopic heart transplantation, and the effect was to significantly reduce the I/R injury of the graft (ischemia-reperfusion injury), reduce the infarct area and reduce serum troponin I and creatine phosphokinase (CPK), and the hydrogen treatment group reduced the MDA content and serum high-mobility group protein B (HMGB1) protein levels, and reduced apoptosis in the transplanted heart compared with the air treatment group.
Therefore, hydrogen has a protective effect on the donor heart by reducing myocardial oxidative damage during the preservation of the donor heart and reducing the production of inflammatory cytokines.
Professor Tan Yongxing
In 2022, experts from the Department of Cardiology and Laboratory Medicine of the Fourth Affiliated Hospital of Harbin Medical University in mainland China published a study on the cardioprotective effect of hydrogen combined with metformin in Free Radical Biology and Medicine.
Research published by mainland scholars
In this study, mainland scholars found for the first time that hydrogen improved the cardiac dysfunction and abnormal morphological structure of streptozotocin (STZ)-induced diabetic mice, and confirmed that hydrogen reduced cardiac pyrosis through the AMPK/mTOR/NLRP3 signaling pathway and improved cardiac fibrosis through the TGF-β1/Smad signaling pathway. In addition, the findings suggest that the combination of hydrogen and metformin has a stronger cardioprotective effect than hydrogen or metformin alone.
Study results
Results 1: Inhalation of hydrogen can improve cardiac dysfunction and abnormal morphological structure in diabetic mice
As shown in the figure above, after hydrogen treatment (DM+H2), the left ventricular ejection fraction (EF%), left ventricular short axis shortening rate (FS%), end-diastolic left ventricular diameter (LVIDd) and end-systolic left ventricular diameter (LVIDs) have been significantly improved.
Results 2: Inhalation of hydrogen decreased the expression of cellular pyrozoprotein mediated by NLRP3 in diabetic mice.
To determine the efficacy of hydrogen on cytopyrosis in diabetic mice, the researchers looked at levels of proteins associated with cell pyroptosis, including NLRP3, cl-Caspase-1, ASC, IL-18, IL-1β, and GSDMD-N.
As shown in the figure above, after hydrogen treatment, the levels of proteins associated with pyroptosis in the hydrogen treatment group (blue) and cell pyrosis decreased significantly compared to the control group (gray).
Results 3: Inhalation of hydrogen decreased the expression of TGF-β1-mediated fibrotic protein in diabetic mice.
Excessive myocardial fibrosis in diabetic patients is another important feature of dilated cardiomyopathy and makes treatment difficult. The TGF-β1/SMAD signaling pathway plays a crucial role in the process of myocardial fibrosis. To determine the efficacy of hydrogen on myocardial fibrosis in diabetic mice, the researchers looked at levels of fibrosis-related proteins, including TGF-β1, p-smad3, p-smad2, COL-I, COL-III, and α-SMA.
As shown in the figure above, after hydrogen treatment, there was a significant decrease in the levels of protein associated with fibrosis in the hydrogen treatment group (blue) compared to the control group (gray).
Results 4: Metformin combined with hydrogen inhibited the histopathological changes of mice caused by diabetes.
Although metformin is a first-line treatment for diabetes, high-dose use in patients with hepatic and renal insufficiency has historically been contraindicated due to concerns about the increased risk of side effects. Hydrogen, on the other hand, is a physiologically inert gas that does not react with any active compounds, is easy to use, and does not require configuration.
As shown in the figure above, metformin (DM+Met) and hydrogen therapy (DM+H2) both improved the survival rate of mice, while metformin + hydrogen combination therapy showed a more significant protective effect (+Met+H2).
Outcome five, metformin and hydrogen combined therapy reduced cell pyrosis and fibrosis in diabetic mice.
Hydrogen can inhibit cell pyrozis and fibrosis in diabetic mice, and metformin also has anti-cell pyrosis and anti-fibrosis effects.
As shown in the figure above, metformin (DM+Met) and hydrogen (DM+H2) both reduced the expression of NLRP3, cl-Caspase-1, and IL-1β, while combination therapy (+Met+H2) significantly reduced protein expression levels.
Outcome 6: Metformin and hydrogen combined therapy reduced cell damage.
As shown in the figure above, metformin (DM+Met, purple) and hydrogen (DM+H2, blue) treatment can increase the activity of cardiomyocytes; The combination of metformin and hydrogen (+Met+H2, light green) provided better protection than treatment alone.
Result 7: Metformin and hydrogen combined therapy further alleviated fibrosis.
As shown in the figure above, the combination therapy of metformin and hydrogen (+Met+H2, light green) can reduce the expression of fibrosis-related proteins more than monotherapy, including TGF-β1, p-smad3, p-smad2, COL-I, COL-III, α-SMA,
Conclusion of the study
Due to aging, obesity and diabetes, the incidence of heart failure and its associated morbidity and mortality is increasing at an alarming rate. In terms of heart failure, the clinical manifestations are more severe in diabetic patients than in non-diabetic patients. Complications of diabetes, such as dilated cardiomyopathy, diabetic nephropathy and diabetic retinopathy, are the most harmful to humans.
The study of mainland scholars showed for the first time that inhalation of hydrogen can effectively reduce heart damage in diabetic mice by inhibiting cell pyrosis and fibrosis. Experimental evidence suggests that hydrogen reduces pyroptosis by reducing the AMPK/mTOR/NLRP3 signaling pathway and mitigating fibrosis by inhibiting the TGF-β1/Smad signaling pathway. On the other hand, metformin and hydrogen combined therapy had a better protective effect than treatment alone, suggesting that hydrogen can be used in combination with metformin to reduce heart damage caused by diabetes.
Resources
WU Shuxin, YANG Xiaohui. Diagnosis and management of diabetic heart disease[J]. Chinese Journal of General Practice, 2017, 15(5):2.
Wei Ran (review), Tan Yongxing (reviser). Effect of diabetes mellitus on myocardial ischemia-reperfusion injury and research progress in hydrogen-related treatment[J]. Journal of Anhui Medical University, 2013, 48(11):4.
Zou R, Nie C, Pan S, et al. Co-administration of hydrogen and metformin exerts cardioprotective effects by inhibiting pyroptosis and fibrosis in diabetic cardiomyopathy[J]. Free Radical Biology and Medicine, 2022, 183: 35-50.