Medicine for chronic heart failure complicated with abnormal electrocardio

Abstract

The invention discloses a medicine for chronic heart failure complicated with electrocardio abnormality, belongs to the technical field of biomedicine, and relates to cardiovascular diseases. The invention discloses a medicine for treating chronic heart failure and sudden cardiac death. The medicine is a small molecule Sal B. The Sal B can be used for inhibiting chronic heart failure and sudden cardiac death; the heart function of chronic heart failure is recovered; ventricular thinning and tissue remodeling combined with chronic heart failure are inhibited; eCG disorder combined with chronic heart failure is inhibited, and the heart rate is stabilized; the ventricular premature beat combined with chronic heart failure is eliminated, and the ventricular fibrillation risk is reduced.

Description

Technical Field

[0001] The present invention belongs to the field of biomedical technologies, relates to cardiovascular diseases, and particularly relates to a drug for chronic heart failure complicated with electrocardiogram abnormalities. Background Art

[0002] Chronic heart failure (CHF) is a major disease recognized worldwide. Clinically, CHF often complicates ventricular arrhythmia and cardiac output disorder in patients, and the cause of ventricular arrhythmia is disordered cardiac electrical signal output. Premature ventricular contractions, ventricular tachycardia and ventricular fibrillation complications are the main outcome events induced from chronic heart failure to heart failure deterioration. Particularly seriously, arrhythmia after pathological ventricular remodeling complicated with chronic heart failure ultimately leads to poor or complete failure of the heart's blood transport function, and even serious consequences such as sudden cardiac death of patients. It is estimated that more than 30 - 40% of patients have major adverse cardiovascular events within 5 years, and the all-cause mortality rates of patients at 30 days, 1 year, and 3 years after discharge are 2.4%, 13.7%, and 28.2% respectively, while the composite endpoint of cardiovascular death accounts for as high as 71.5% of the total number of all-cause deaths, and the 5-year survival rate of patients with chronic heart failure is no more than 5%.

[0003] For heart failure with reduced ejection fraction (HFrEF, ≤ 40%), heart failure with mildly reduced ejection fraction (HFmrEF, 41% - 49%), and heart failure with preserved ejection fraction (HFpEF, ≥ 50%) in the heart failure classification of grades Ⅰ - Ⅳ, HFmrEF and HFrEF are respectively treated according to the gold standard of "quadruple therapy" (angiotensin-converting enzyme inhibitor + β-blocker + aldosterone receptor antagonist + renin-angiotensin system inhibitor), and HFpEF is treated by additionally combining a soluble guanylate cyclase stimulator on the basis of "quadruple therapy". Although the survival rate of 50% of patients can be extended from 5 years to 10 years, in terms of core indicators such as how to further improve the survival rate of patients and extend the survival time of heart failure patients, drug treatment of chronic heart failure generally still faces huge clinical challenges.

[0004] For single organic arrhythmia, the commonly used drugs for treating premature ventricular contractions, ventricular tachycardia, and ventricular fibrillation are amiodarone, lidocaine, ivabradine, ranolazine, finerenone, and spironolactone. However, these drugs have the following disadvantages: Some patients are intolerant, inducing acute pulmonary toxicity and thyroid function abnormalities (amiodarone), may cause pulmonary and renal system fibrosis (amiodarone, ranolazine), progression of chronic kidney disease and cardiovascular damage (finerenone), hypotension or bradycardia (such as amiodarone, ivabradine), and neurotoxicity (such as lidocaine), etc., with many adverse reactions. However, for ventricular systolic dysfunction and ventricular bradycardia caused by pathological tissue remodeling, only positive inotropic cardiac drugs can be used to achieve the purpose of quickly relieving symptoms. As the main outcome event of chronic heart failure, domestic and foreign treatment guidelines have not yet formulated drug recommendation criteria for heart failure exacerbation.

[0005] Chronic heart failure complicated with electrocardiogram abnormalities is mostly seen in heart failure types III-IV. Its pathological basis is extremely complex and is generally considered to be regulated by mechanisms such as hypoxia-induced oxidative stress, over-activated inflammatory response, fibrosis, and myocardial metabolic disorders. For a long time, the effect of drug treatment for chronic heart failure complicated with electrocardiogram abnormalities has been unsatisfactory. Based on the detection of specific indicators of serum markers, histopathology, electrocardiogram, and echocardiogram, as well as evidence-based medical research, it has been continuously revealed that the unsatisfactory efficacy caused by drug-drug interactions, the blockade of multi-organ signal axis transmission caused by inappropriate drug combinations, and the complexity of clinical drug combination regimens. Therefore, it is urgent to develop highly effective drugs with multi-functional effects from the perspective of systematic intervention and based on the recently confirmed and dominant pathological mechanisms, which is not only beneficial to solving the complex combination regimens faced in current clinical medication, effectively avoiding the adverse reactions of drug-drug interactions, but also will highly inhibit this highly lethal heart disease of chronic heart failure complicated with ventricular electrocardiogram abnormalities.

[0006] To solve the above problems existing in the prior art, a drug for chronic heart failure has been developed. Summary of the Invention

[0007] The purpose of the present invention is to provide a drug for treating chronic heart failure complicated with electrocardiogram abnormalities.

[0008] The present invention is achieved through the following technical solutions: A drug for treating chronic heart failure and sudden cardiac death, the drug being small molecule Sal B (salvianolic acid B with a phenolic acid structure).

[0009] A drug for restoring the cardiac function of chronic heart failure, the drug being small molecule Sal B.

[0010] A drug for inhibiting ventricular thinning and tissue remodeling complicated with chronic heart failure, the drug being small molecule Sal B.

[0011] A drug for inhibiting electrocardiographic disturbances associated with chronic heart failure and stabilizing heart rate, wherein the drug is a small molecule SalB.

[0012] A drug for eliminating premature ventricular beats associated with chronic heart failure and reducing the risk of ventricular fibrillation, wherein the drug is the small molecule Sal B.

[0013] Chronic heart failure with ventricular ECG abnormalities is characterized by pathological features such as infarct-induced myocardial remodeling, leading to ECG abnormalities, cardiac systolic / diastolic rhythm disorders, and poor hemodynamics, which in turn lead to a decline in the function of the patient's important organs and a high risk of death. Sal B (salvianolic acid B) is derived from the components of the traditional Chinese medicine Salvia miltiorrhiza, and is generally used to treat ischemic stroke caused by blood stasis blocking the meridians, including cerebral stroke and the nerve damage caused by it. Based on its multiple pathways of anti-oxidation, anti-inflammatory, anti-fibrosis, and promotion of myocardial metabolism, the present invention uses Sal B to achieve efficient inhibition of chronic heart failure with ventricular ECG abnormalities.

[0014] Compared with the prior art, the present invention has the following advantages: (1) Sal B improves the survival rate of mice with chronic heart failure: Figure 1 The figure shows the survival rate of mice with chronic heart failure induced by ligation of the left anterior descending coronary artery and the experimental results of the therapeutic effects of captopril, metoprolol and sal B. The survival rate of mice with chronic heart failure was 50% after 10 weeks without drug intervention; Figure 1 The results showed that Sal B increased the survival rate of mice with chronic heart failure in a dose-dependent manner. At a dose of 20 mg / kg, the level of improvement in the survival rate of mice with chronic heart failure by Sal B was comparable to that of captopril, but the effect of 40 mg / kg Sal B on the survival rate of mice with chronic heart failure was higher than that of captopril. The efficacy of metoprolol was lower than that of Sal B.

[0015] (2) Sal B protects cardiac function and inhibits pathological remodeling of ventricular tissue in mice with chronic heart failure: Figure 2 The results of echocardiographic monitoring of captopril, metoprolol and sal b in the treatment of chronic heart failure in mice. The statistical results of CO, EF, FS and SV are shown in Figure 2. Figure 2As shown, it can be seen from the figure that Sal B promotes the recovery of these cardiac indexes in a dose-dependent manner. The efficacy of 20 mg / kg Sal B is comparable to that of captopril and metoprolol, but the treatment result of 40 mg / kg Sal B is more significant than that of captopril and metoprolol. For ventricular tissue remodeling, chronic heart failure causes the thickness of the left ventricular anterior wall at the end of systole and diastole to be adjusted from 1.45 ± 0.16 mm and 2.50 ± 0.41 mm in normal mice to 1.21 ± 0.16 mm and 3.19 ± 0.52 mm respectively, indicating that both left ventricular systole and diastole are damaged. After treating chronic heart failure mice with captopril and metoprolol respectively, the above results are adjusted to 1.18 ± 0.15 mm, 2.83 ± 0.77 mm, and 1.13 ± 0.19 mm, 2.67 ± 0.76 mm respectively, which is basically ineffective in restoring ventricular systole but beneficial in restoring ventricular diastole. When treating chronic heart failure mice with 10 mg / kg, 20 mg / kg, and 40 mg / kg Sal B respectively, the thickness of the left ventricular anterior wall is adjusted to 0.80 ± 0.37 mm and 2.90 ± 0.53 mm, 1.09 ± 0.20 mm and 2.89 ± 0.22 mm, and 1.37 ± 0.10 mm and 2.77 ± 0.17 mm respectively. Sal B not only restores ventricular diastole in a dose-dependent manner, but also the ventricular systolic function basically returns to the normal level after treating chronic heart failure mice with a 40 mg / kg dose.

[0016] 3. Sal B inhibits electrocardiogram abnormalities associated with chronic heart failure: The heart rate of mice with chronic heart failure combined with electrocardiogram abnormalities slows down significantly, the ST-segment of myocardial infarction electrocardiogram markers rises significantly, the QRS wave delay increases, and the pulse pressure and systolic blood pressure decrease significantly (compared with the results of sham-operated mice). Figure 3For the Captopril, Metoprolol, and Sal B treatment groups in mice with chronic heart failure: A: Electrocardiogram (monitoring time: 600 - 600.2 s, n = 8); B: Statistical results of heart rate (Cardiac rate beat); C: Statistical results of ST-segment; D: Statistical results of QRS duration; E: Statistical results of pulse pressure; F: Statistical results of diastolic pressure; Note: **, ***: Compared with Sham, P < 0.01 and P < 0.001 respectively. #, ##, : Compared with HF, P < 0.05, P < 0.01, and P < 0.001 respectively (one-way ANOVA). It can be seen from the figure that both Captopril and Metoprolol significantly reversed these changes and restored the electrocardiogram indices to near normal, while Sal B dose-dependently restored the electrocardiogram index changes in mice with chronic heart failure. The degree of restoration of heart rate, ST-band, QRS duration, pulse pressure, and systolic pressure changes by 40 mg / kg Sal B was more significant than that of Captopril and Metoprolol, and the electrocardiogram indices of the mice after restoration were closer to the normal range.

[0017] 4. Sal B inhibits premature ventricular contractions and paroxysmal ventricular fibrillation in mice with chronic heart failure complicated by heart failure: The electrocardiogram results of the Captopril, Metoprolol, and Sal B treatment groups of mice are as Figure 4 (n = 6) and Figure 5 (n = 3) shown; Figure 4 It shows that during the electrocardiogram monitoring from 200 to 200.2 s, the electrocardiogram signal output by mice with chronic heart failure (HF) twists up and down around the baseline and shows non-continuous wavy patterns. Paroxysmal ventricular fibrillation occurred in the hearts of mice in the HF group (at about 3.33 minutes); while Figure 5 It shows that during the electrocardiogram monitoring from 160 to 160.2 s, the hearts of mice in the HF group showed paroxysmal pathological Q waves, inverted T waves, and the presence of R waves (at about 2.67 minutes). After treating HF mice with 40 mg / kg Sal B, the wavy electrical signals disappeared at 3.33 minutes of electrocardiogram monitoring and then turned into normal electrocardiogram waves. After 2.67 minutes of electrocardiogram monitoring, the Q waves and R waves were normal and the T waves were upright. Sal B inhibited premature ventricular contractions complicated by chronic heart failure and eliminated the risk of ventricular fibrillation. By comprehensively analyzing the characteristics of each electrocardiogram waveform, the effect of Sal B was significantly better than that of Captopril and Metoprolol.

[0018] Compared with the prior art, Salvianolic acid B (Sal B) of the present invention can be used to inhibit chronic heart failure and sudden cardiac death; restore the cardiac function of chronic heart failure; inhibit ventricular thinning and tissue remodeling associated with chronic heart failure; inhibit electrocardiogram disorders associated with chronic heart failure and stabilize heart rate; eliminate premature ventricular contractions associated with chronic heart failure and reduce the risk of ventricular fibrillation. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 Survival rate of mice with chronic heart failure induced by left anterior descending coronary artery ligation and the therapeutic effects of Captopril, Metoprolol, and Sal B.

[0020] Figure 2 Echocardiogram monitoring results of mice with chronic heart failure and its treatment groups with Captopril, Metoprolol, and Salvianolic acid B (Sal B) (n = 6). Wherein A: echocardiogram; B: statistical analysis of cardiac output (CO); C: statistical analysis of ejection fraction (EF); D: statistical analysis of left ventricular fractional shortening (FS); E: statistical analysis results of stroke volume (SV).

[0021] Figure 3 Electrocardiogram results of mice with chronic heart failure and its treatment groups with Captopril, Metoprolol, and Salvianolic acid B (Sal B). A): electrocardiogram (monitoring time: 600 - 600.2 seconds, n = 8); B): statistical results of heart rate (Cardiac rate beat); C): statistical results of ST-segment; D): statistical results of QRS duration; E): statistical results of pulse pressure; F): statistical results of diastolic pressure.

[0022] Figure 4 Electrocardiogram results of mice with chronic heart failure and its treatment groups with Captopril, Metoprolol, and Salvianolic acid B (Sal B) (monitoring time: 200 - 200.2 seconds, n = 6).

[0023] Figure 5ECG results of mice with chronic heart failure and those treated with Captopril, Metoprolol, and Salvianolic acid B (Sal B) (monitoring time: 160 - 160.2 s, n = 3). Detailed implementation mode

[0024] The present invention will be further described below in conjunction with the drawings and embodiments.

[0025] Sal B inhibits chronic heart failure and sudden cardiac death Male C57BL / 6J mice aged 6 - 8 weeks with a body weight of 20 - 23 g were ordered. They were fed normal feed and provided with drinking water, and adapted for 1 week. They were randomly divided into a sham operation group (Sham, only intraperitoneally injected with normal saline), a surgically induced chronic heart failure group (HF), a Captopril (20 mg / kg) treatment group, a Metoprolol (20 mg / kg) treatment group, and Sal B treatment groups of 10 mg / kg, 20 mg / kg, and 40 mg / kg, with 6 mice in each group. Chronic heart failure was induced by ligation of the left anterior descending coronary artery for 4 weeks, and blood was taken to detect the elevated level of the N-terminal pro-brain natriuretic peptide (NT-proBNP) marker to ensure the induction of chronic heart failure. Then, the positive drugs Captopril, Metoprolol, and Sal B were dissolved in normal saline, and the drugs were intraperitoneally injected once a day for 1 week. Subsequently, electrocardiogram and echocardiogram were monitored. By comparing the results between the Sham group and the chronic heart failure group, and between the chronic heart failure group and the Sal B treatment groups, and by comparing the changes in the survival rate of mice, it was determined that Sal B could inhibit chronic heart failure and sudden cardiac death, and the dosage of 40 mg / kg Sal B had a significant effect.

[0026] Sal B restores cardiac function in chronic heart failure Mice with chronic heart failure were treated with Sal B for 1 week, and echocardiogram was monitored. The changes in cardiac output (CO), ejection fraction (EF), left ventricular fractional shortening (FS), and stroke volume (SV) were statistically analyzed to determine that Sal B has a role in restoring cardiac function in chronic heart failure.

[0027] Sal B inhibits ventricular thinning and tissue remodeling associated with chronic heart failure The basal region of the inferior wall of the left ventricle was monitored by echocardiogram. The changes in the systolic and diastolic amplitudes of the basal segment of the inferior wall of the left ventricle in chronic heart failure mice and Sal B-treated mice were observed respectively, and the changes in the thickness of the left ventricular wall at the end of ventricular systole and diastole were compared. According to the observation results, it was determined that Sal B had an inhibitory effect on chronic heart failure complicated with ventricular thinning.

[0028] Sal B inhibits the electrocardiogram disorder associated with chronic heart failure and stabilizes the heart rate After the stable period (about 10 minutes) of the electrocardiogram signal, the changes in the heart rate (Cardiac rate beat), ST-segment elevation, QRS duration, pulse pressure, and systolic pressure of chronic heart failure mice and Sal B-treated heart failure mice were compared respectively through electrocardiogram monitoring. It was determined that Sal B had the effect of inhibiting the electrocardiogram disorder associated with chronic heart failure and stabilizing the heart rate.

[0029] Sal B reduces the premature ventricular contractions associated with chronic heart failure and eliminates the risk of ventricular fibrillation In the early stage of electrocardiogram monitoring, whether the chronic heart failure mice and Sal B-treated heart failure mice output electrocardiogram signals that twist up and down around the baseline, are non-persistent wavy (about 3.33 minutes), and whether pathological Q waves, T wave inversions, and the presence of R waves are formed (about 2.67 minutes) were observed respectively. According to the changes in electrocardiogram output at these two time points, it was determined that Sal B had the effect of reducing the paroxysmal premature ventricular contractions associated with chronic heart failure and eliminating the risk of ventricular fibrillation.

Claims

1. A drug for inhibiting chronic heart failure and sudden cardiac death, characterized in that: The drug is Sal B with a small molecule phenolic acid structure.

2. A drug for restoring cardiac function in chronic heart failure, characterized in that: The drug is Sal B with a small molecule phenolic acid structure.

3. A drug for inhibiting ventricular thinning and tissue remodeling associated with chronic heart failure, characterized in that: The drug is Sal B with a small molecule phenolic acid structure.

4. A drug for inhibiting electrocardiographic disturbances associated with chronic heart failure and stabilizing heart rate, characterized in that: The drug is Sal B with a small molecule phenolic acid structure.

5. A drug for eliminating premature ventricular beats associated with chronic heart failure and reducing the risk of ventricular fibrillation, characterized in that: The drug is Sal B with a small molecule phenolic acid structure.

Images