Use of heteroterpene I in the preparation of a drug for treating heart failure

Abstract

The application discloses application of a heteroterpene compound I in preparation of a heart failure resisting drug. The heteroterpene compound I is obtained by separation and purification from a marine fungus Aspergillus terreus GZU-311, and is used to treat a mouse heart failure model induced by adriamycin or left anterior descending coronary artery ligation, and it is found that the heteroterpene compound I can improve the heart function of the mouse, reduce myocardial cell damage, inhibit myocardial connective tissue thickening, improve myocardial cell arrangement disorder, reduce inflammatory cell infiltration, and has an effect of resisting heart failure. Therefore, the application provides application of the heteroterpene compound I in preparation of a heart failure resisting drug. The application enriches drug source molecules that can be used for treating heart failure, and is helpful to development of an anti-heart failure drug and clinical treatment.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of biological medicine, and particularly relates to application of a heteroterpene compound I in preparation of an anti-heart failure drug. BACKGROUND

[0002] Heart failure, in short, heart failure, is a pathophysiological state and clinical syndrome in which the heart pump function is reduced and the blood returned from the veins cannot be fully discharged to meet the metabolic needs of the whole body. It has the characteristics of high re-hospitalization rate, high disability rate and high mortality rate.

[0003] At present, the commonly used anti-heart failure drugs in the clinic mainly include renin-angiotensin system inhibitors, anti-aldosterone drugs, diuretics, beta-blockers and cardiac glycosides. Although the above drugs have certain effects on anti-heart failure in the clinic, long-term use of these drugs can produce drug resistance and a series of side effects and adverse reactions, such as postural hypotension, depression, causing blood lipid elevation, hypoglycemia, peripheral circulation disorder, fatigue and bronchial spasm, inhibiting myocardial contractility and causing conduction block. Therefore, it is urgent to find new drug molecules to replace the existing clinical drugs to solve the patient's tolerance to the existing anti-heart failure drugs and the adverse reactions caused by the existing anti-heart failure drugs.

[0004] The secondary metabolites of marine fungi are an important part of natural products, and have the characteristics of sustainability, environmental friendliness, rich diversity of metabolites, and small side effects, and are an important source for screening of natural drugs. At the same time, the secondary metabolites of marine fungi have a wide range of physiological activities, such as antibacterial, antitumor, anti-fibrosis, anti-Alzheimer's disease, anti-heart failure, anti-heart failure and enzyme inhibition, which injects new impetus into the innovation of modern drugs and the research and development of innovative drugs. At present, finding new drug molecules from marine fungi has become a hot research topic at home and abroad.

[0005] Although the development of cardiovascular disease is closely related to inflammation and myocardial fibrosis, not all compounds with anti-inflammatory or anti-fibrosis effects can be used to treat heart failure. For example, drugs prepared from thiazolidinediones can inhibit inflammation in the kidney, inhibit kidney cell fibrosis, and improve kidney microcirculation (DOI: 10.3969 / j.issn.1672-6170.2009.01.044.). However, this kind of drug can cause water and sodium retention, excess body fluid, and induce or aggravate heart failure, increasing the risk of heart failure or cardiovascular disease death. Although the secondary metabolites of marine fungi are rich, it is not easy to obtain compounds with anti-heart failure effects from them. SUMMARY

[0006] The present application provides a heteroterpene compound which can be used for preparing an anti-heart failure drug, i.e. the heteroterpene compound I.

[0007] A first object of the present application is to provide the use of the heteroterpene compound I in the preparation of an anti-heart failure drug.

[0008] A second object of the present application is to provide an anti-heart failure drug.

[0009] The above objects of the present application are achieved by the following technical solutions.

[0010] The heteroterpene compound I isolated from the fermentation culture of the marine fungus Aspergillus terreus GZU-311 is used to treat a mouse heart failure model induced by doxorubicin or ligation of the left anterior descending coronary artery, respectively, and it is found that the heteroterpene compound I has an anti-heart failure effect. Therefore, the present application claims the use of the heteroterpene compound I in the preparation of an anti-heart failure drug.

[0011] Specifically, the structural formula of the heteroterpene compound I is shown in formula (I):

[0012]

[0013] Specifically, the heteroterpene compound I can improve heart function.

[0014] Specifically, the improvement of heart function means that the heteroterpene compound I can improve the cardiac ejection fraction and the short-axis shortening rate.

[0015] Specifically, the heteroterpene compound I can reduce myocardial cell damage.

[0016] Specifically, the heteroterpene compound I can inhibit myocardial connective tissue thickening.

[0017] Specifically, the heteroterpene compound I can improve myocardial cell arrangement disorder.

[0018] Specifically, the heteroterpene compound I can reduce inflammatory cell infiltration.

[0019] Specifically, the heart failure is chronic heart failure or ischemic heart failure.

[0020] Specifically, the heart failure is doxorubicin-induced heart failure.

[0021] Specifically, the heteroterpene compound I is isolated and purified from the fermentation culture of the marine fungus Aspergillus terreus GZU-311.

[0022] Specifically, the culture medium used for fermentation is a solid corn culture medium prepared by corn and seawater.

[0023] Specifically, the preparation method of the heteroterpene compound I comprises the following steps:

[0024] S1. preparing a seed liquid of a marine fungus Aspergillus terreus GZU-311;

[0025] S2. inoculating the seed liquid prepared in S1 into a solid corn culture medium to culture to obtain a fermentation culture;

[0026] S3. extracting the fermentation culture obtained in S2 with methanol for 2-5 times, concentrating the extract, and extracting the obtained concentrated extract with ethyl acetate to obtain an ethyl acetate crude extract;

[0027] S4. separating the ethyl acetate crude extract obtained in S3 by normal phase silica gel chromatography, and then gradient eluting with petroleum ether / ethyl acetate mixed solutions with volume fractions of 10%, 20%, 30%, 40%, 50%, 60%, and 70% of petroleum ether, respectively, collecting the 40% petroleum ether / ethyl acetate eluent part, and then separating and purifying by silica gel, gel, and C-18 reverse phase column chromatography to obtain the heteroterpene compound I.

[0028] Specifically, the marine fungus Aspergillus terreus GZU-311 strain in S1 was preserved in the Guangdong Microbial Culture Collection Center on December 17, 2019, and the preservation number was GDMCC No: 60789.

[0029] Specifically, the preparation method of the seed liquid in S1 is as follows: inoculating the marine fungus Aspergillus terreus GZU-311 into a slant culture medium to culture, and then inoculating into a liquid culture medium to culture to obtain a seed liquid; the culture temperature is 28-35°C, and the culture time is 4-10 days.

[0030] More specifically, the culture temperature is 30°C, and the culture time is 6 days.

[0031] Specifically, S2 is inoculating the seed liquid prepared in S1 into a solid corn culture medium to culture to obtain a fermentation culture; the culture temperature is 28-35°C, and the culture time is 30-60 days.

[0032] More specifically, the culture temperature is 30°C, and the culture time is 60 days.

[0033] Specifically, the formula of the slant culture medium in S1 is as follows: glucose 0.3%, yeast extract 0.1%, peptone 0.1%-0.5%, agar 1.5%-2.5%, sodium chloride 1.5%-4%, and water to make up to 100%.

[0034] More specifically, the formula of the slant medium S1 is as follows: glucose 0.3%, yeast extract 0.1%, peptone 0.5%, agar 2.5%, sodium chloride 3%, and water to make up 100%.

[0035] Specifically, the formula of the solid corn medium S2 is as follows: corn: sea water = 1:1-2 (by mass ratio).

[0036] More specifically, the formula of the solid corn medium S2 is as follows: corn: sea water = 1:1 (by mass ratio).

[0037] Specifically, the number of times of methanol extraction S3 is 3.

[0038] The present application provides a medicine for treating heart failure, which contains the heteroterpene compound I or a pharmaceutically acceptable salt thereof.

[0039] Specifically, the medicine further comprises the heteroterpene compound I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0040] Specifically, the heteroterpene compound I can be administered alone or in the form of a pharmaceutical composition. The pharmaceutical composition can be formulated into various suitable pharmaceutical preparations according to the administration route.

[0041] Alternatively, the pharmaceutical preparation is an oral preparation, an injection preparation or a transdermal preparation for external use.

[0042] Specifically, the oral preparation can be formulated into any orally acceptable preparation form, including but not limited to tablets, capsules, aqueous solutions or aqueous suspensions. The carriers used in the tablets generally include lactose and corn starch, and lubricants such as magnesium stearate can also be added. The diluents used in the capsule preparations generally include lactose and dry corn starch. The aqueous suspensions generally use the active ingredient in combination with suitable emulsifying agents and suspending agents.

[0043] Alternatively, some sweeteners, fragrances or colorants can also be added to the above-mentioned oral preparations.

[0044] Specifically, the injection preparation includes liquid injection, injection powder or injection tablets. The injection preparation can be administered in the form of sterile injection preparations, including sterile injection water or oil suspensions or sterile injection solutions. As the carriers and solvents used in the injection preparations, water, Ringer's solution, isotonic sodium chloride solution and sterilized non-volatile oils such as monoglyceride and diglyceride are included.

[0045] Specifically, the transdermal preparation for external use includes a spray, a gel, an emulsion, an ointment, a lotion, a cream or a gel patch. The carrier of the ointment includes but is not limited to mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water. The carrier of the lotion or cream includes but is not limited to mineral oil, sorbitan monostearate, Tween 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0046] Specifically, the pharmaceutically acceptable excipient includes one or more of a drug carrier, a surfactant, a buffer substance, a disintegrant, a binder, a filler, a lubricant, an excipient, a solubilizer, a flavoring agent and a colorant.

[0047] Specifically, the pharmaceutical preparation can be administered in any of the following ways: oral administration, spray inhalation, rectal administration, nasal administration, topical administration and parenteral administration; wherein the parenteral administration is subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal and / or intracranial injection or infusion, or administration by means of an external implant reservoir.

[0048] Specifically, the pharmaceutical preparation is preferably administered orally, intraperitoneally or intravenously.

[0049] It should be further pointed out that the dosage and method of use of the heteroterpene compound I according to the present application depend on many factors, including the age, weight, sex, natural health status, nutritional status of the patient, the activity intensity of the compound, the time of administration, the metabolic rate, the severity of the condition and the subjective judgment of the treating physician.

[0050] The present application has the following beneficial effects:

[0051] The present application uses the heteroterpene compound I isolated and purified from the marine fungus Aspergillus terreus GZU-311 to treat a mouse heart failure model induced by doxorubicin or ligation of the left anterior descending coronary artery, and it is found that the heteroterpene compound I can improve the heart function of the mouse, reduce the damage to the myocardial cells, inhibit the thickening of the myocardial connective tissue, improve the disordered arrangement of the myocardial cells and reduce the inflammatory cell infiltration. Thus, the present application provides the use of the heteroterpene compound I in the preparation of an anti-heart failure drug. The present application enriches the drug source molecules that can be used to treat heart failure, helps the development of anti-heart failure drugs and their clinical treatment, and has a good clinical application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0052] Figure 1 Figure 2 shows the echocardiogram of the doxorubicin-induced mouse heart failure model and the mouse heart failure model treated with the heteroterpene compound I.

[0053] Figure 2Figure 2 is the heart function detection results of the doxorubicin-induced mouse heart failure model and the mouse heart failure model treated with the heteroterpene compound I; Figure A is the ejection fraction (EF) calculation results, and Figure B is the fractional shortening (FS) calculation results; "#" indicates P<0.05; "*" indicates P<0.05; "**" indicates P<0.01; "***" indicates P<0.001.

[0054] Figure 3 Figure 3 is the heart slice HE staining diagram of the doxorubicin-induced mouse heart failure model and the mouse heart failure model treated with the heteroterpene compound I, with a scale of 100 μm.

[0055] Figure 4 Figure 4 is the heart slice Masson staining diagram of the doxorubicin-induced mouse heart failure model and the mouse heart failure model treated with the heteroterpene compound I, with a scale of 50 μm.

[0056] Figure 5 Figure 5 is the echocardiogram of the left anterior descending coronary artery ligation-induced mouse heart failure model and the mouse heart failure model treated with the heteroterpene compound I.

[0057] Figure 6 Figure 6 is the heart function detection results of the left anterior descending coronary artery ligation-induced mouse heart failure model and the mouse heart failure model treated with the heteroterpene compound I; Figure A is the ejection fraction (EF) calculation results, and Figure B is the fractional shortening (FS) calculation results; "### " indicates P<0.001; "***" indicates P<0.001.

[0058] Figure 7 Figure 7 is the heart slice HE staining diagram of the left anterior descending coronary artery ligation-induced mouse heart failure model and the mouse heart failure model treated with the heteroterpene compound I, with a scale of 50 μm. DETAILED DESCRIPTION

[0059] The present application will be further described below in conjunction with the drawings and specific examples, but the examples do not limit the present application in any form. Unless otherwise specified, the reagents, methods and equipment used in the present application are conventional reagents, methods and equipment in the technical field.

[0060] Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0061] Example 1 Obtaining of the heteroterpene compound I from marine fungi

[0062] The heteroterpene compound I is separated and purified from a fermentation culture of the marine fungus Aspergillus terreus GZU-311. The marine fungus Aspergillus terreus GZU-311 has been preserved in the Guangdong Microbial Culture Collection Center on December 17, 2019, with a preservation number of GDMCC No: 60789, and a preservation address of 5th Floor, No. 59 Building, Institute of Microbiology of Guangdong Province, 100 Middle Liangxie Road, Guangzhou. The related separation and identification information has been disclosed in the patent application with a publication number of CN111139188A.

[0063] The separation, purification and identification process of the heteroterpene compound I is as follows:

[0064] 1. Separation of the compound

[0065] The separation method of the compound comprises the following steps:

[0066] (1) The marine fungus Aspergillus terreus GZU-311 is inoculated into a slant medium (the formula of the slant medium is: 0.3% glucose, 0.1% yeast extract, 0.5% peptone, 2.5% agar, 3% sodium chloride, and water to make up 100%), and then inoculated into a liquid medium (the formula is the same as that of the slant medium, except that it does not contain agar), and cultured at 30°C for 6 days to obtain a seed liquid;

[0067] (2) The seed liquid is inoculated into a solid corn medium (the formula of the solid corn medium is: corn: seawater = 1:1 by mass ratio), and incubated at 30°C for 60 days to obtain a fermentation culture (fermentation stock solution);

[0068] (3) The fermentation culture is extracted with methanol for 3 times, and the extract is concentrated into a paste. The obtained concentrated extract is extracted with ethyl acetate to obtain a crude ethyl acetate extract;

[0069] (4) After the crude ethyl acetate extract is separated by normal phase silica gel chromatography, gradient elution is carried out with petroleum ether / ethyl acetate mixed solutions with volume fractions of 10%, 20%, 30%, 40%, 50%, 60% and 70% of petroleum ether, respectively. The eluate part of the 40% petroleum ether / ethyl acetate is collected, and then separated and purified by silica gel, gel and C-18 reverse phase column chromatography separation technology. The obtained compound is identified;

[0070] 2. Identification of the compound

[0071] The structure of the compound obtained by the above separation and purification is tested and analyzed by high resolution mass spectrometry and nuclear magnetic resonance (NMR), and the following experimental data is obtained:

[0072] Molecular formula of the compound: C 26 H 32 O9, high resolution mass spectrum (HRESI-MS): 487.1959 [M-H] - (cald forC 26 H 31 O9 487.19626)。

[0073] The structural formula of the compound is shown as follows (formula (I)):

[0074]

[0075] The nuclear magnetic resonance data of the compound are shown in Table 1.

[0076] Table 1 NMR data (CDCl3, 400MHz / 100MHz, ppm)

[0077]

[0078]

[0079] The compound obtained by separation and purification is identified as a heteroterpene compound, which is named as heteroterpene compound I.

[0080] Example 2 Effect of heteroterpene compound I in treating heart failure induced by doxorubicin

[0081] 1. Experimental method

[0082] 8-week-old C57BL / 6 male mice were randomly divided into 6 groups (8 mice in each group): control group (Control), model group (Model), heteroterpene compound I low-dose group (I (10 mg / kg)), heteroterpene compound I medium-dose group (I (200 mg / kg)), heteroterpene compound I high-dose group (I (40 mg / kg)) and positive drug XST (XST).

[0083] The daily intragastric administration dose is as follows: heteroterpene compound I (dissolved in 10% DMSO + physiological saline) is 10, 20, 40 mg / kg dose respectively; positive drug XST (40 mg / kg); the control group and the model group are given the same amount of blank solvent (10% DMSO + physiological saline). At the same time, doxorubicin is injected subcutaneously once a week, with a single dose of 5 mg / kg, and the control group is injected with the same amount of physiological saline. The specific intragastric administration dose is set according to the weight of the mouse, for example, “10 mg / kg” means that a mouse weighing 1 kg is given 10 mg of medicine.

[0084] On the 29th day after intragastric administration, the heart structure and heart function of each group of mice were evaluated by VINNO 6 small animal high-resolution micro-ultrasound imaging system, and the ejection fraction (EF) and fractional shortening (FS) were calculated. Then the mice were dissected to take the heart for embedding section, and HE staining and Masson staining were performed.

[0085] 2. Data processing

[0086] The experimental results were statistically analyzed by GraphPad Prism 8.0 software, and the experimental results were expressed as Mean ± SEM. One-way ANOVA was used for comparison between groups.

[0087] 3. Experimental results

[0088] (1) Heart function evaluation

[0089] The echocardiogram of the adriamycin-induced mouse heart failure model and the mouse heart failure model treated with the heterocyclic compound I is shown in Figure 1 The heart function detection results of the adriamycin-induced mouse heart failure model and the mouse heart failure model treated with the heterocyclic compound I are shown in Figure 2 It can be seen from Figure 1 and Figure 2 that compared with the control group, the ejection fraction (EF) and fractional shortening (FS) of the heart of the mouse in the model group decreased significantly, and the left ventricular end-systolic volume and diastolic volume increased significantly, that is, the heart function of the adriamycin-induced mouse was significantly reduced. Compared with the model group, the ejection fraction and fractional shortening of the heart of the mouse treated with the heterocyclic compound I were significantly improved, and the left ventricular end-systolic volume and diastolic volume were reduced, which could significantly improve the heart function of the adriamycin-induced mouse.

[0090] (2) HE staining of heart sections

[0091] The HE staining diagram of the heart sections of the adriamycin-induced mouse heart failure model and the mouse heart failure model treated with the heterocyclic compound I is shown in Figure 3 It can be seen from Figure 3 that compared with the control group, the myocardial cells of the mouse in the model group were obviously damaged, while the myocardial cells of the mouse treated with the heterocyclic compound I at a dose of 40 mg / kg were not or rarely damaged, and the cells were arranged regularly and densely. It shows that the heterocyclic compound I can reduce the damage of myocardial cells and has a certain protective effect on heart tissue.

[0092] (3) Masson staining of heart sections

[0093] The Masson staining diagram of the heart sections of the adriamycin-induced mouse heart failure model and the mouse heart failure model treated with the heterocyclic compound I is shown in Figure 4 It can be seen fromFigure 4 It can be seen that only a small amount of connective tissue thickening area is observed in the control group, and a large area of connective tissue thickening area is observed in the model group; compared with the model group, treatment with 40 mg / kg dose of heteroterpene compound I can significantly reduce adriamycin-induced connective tissue thickening.

[0094] Example 3 Anti-Effect of Heteroterpene Compound I on Ischemic Heart Failure Induced by LAD Ligation

[0095] 1. Experimental method

[0096] (1) Experimental materials

[0097] 8-week-old C57BL / 6 male mice were purchased from Guangdong Zirun Biomedical Technology Co., Ltd., and were fed with standard feed, and free water and food.

[0098] (2) Experimental modeling

[0099] The left anterior descending branch (LAD) of the coronary artery was ligated in situ to model. First, the mice were anesthetized with intraperitoneal injection of 0.25% sodium pentobarbital, and the breathing tube was inserted. The breathing machine parameters were: tidal volume 11 cc, breathing ratio 1:2, breathing frequency 144 times / min, and physiological saline gauze was used to cover the wound; the left side of the sternum was cut open at the 3rd and 4th intercostal space for 1 cm, and 2 spreaders were used to open up and down and left and right with the ribs to expose the heart, the pericardium was picked up, and a modern standard code 6-0 silk thread and round needle were used to insert the needle at the bifurcation of the left coronary artery and the posterior descending branch 3-4 mm below the left atrial appendage, with a depth of about 1 mm and a width of about 2 mm. After the needle was inserted and the thread was tightened, the electrocardiogram was immediately observed to appear ST segment elevation or wide QRS wave, and the chest was sutured. After 4 weeks of postoperative feeding, small animal color Doppler ultrasound was used to detect heart function, and EF less than 45% was considered as successful modeling.

[0100] (3) Experimental grouping and data determination

[0101] The experimental mice were divided into the following 4 groups (5 mice in each group): blank control group (after opening the chest, suturing without ligating the coronary artery, Sham), model group (CHF), model group + heteroterpene compound I group (I (20 mg / kg)), and model group + sacubitril valsartan group (XST).

[0102] The dose of intragastric administration is as follows: the model group + heteroterpene compound I group (dissolved in 10% DMSO + physiological saline) is administered at a dose of 20 mg / kg; the model group + sacubitril valsartan group is administered at a dose of 26 mg / kg; the blank control group and the model group are given an equal amount of solvent (10% DMSO + physiological saline). The specific intragastric administration dose is set according to the body weight of the mice, for example, "20 mg / kg" means that a mouse weighing 1 kg is given 20 mg of the drug; intragastric administration is performed once a day for a total of 4 weeks.

[0103] On day 29 after intragastric administration, the heart structure and function of each group of mice were evaluated by VINNO 6 small animal high-resolution micro-ultrasound imaging system, and the ejection fraction (EF) and fractional shortening (FS) were calculated. Then the mice were dissected to take the heart for embedding section, and HE staining was performed.

[0104] 2. Data processing

[0105] The experimental data were statistically analyzed by GraphPad Prism 8.0 software, and the experimental results were expressed as Mean ± SEM. One-way ANOVA was used for comparison between groups.

[0106] 3. Experimental results

[0107] (1) Heart function evaluation

[0108] The echocardiogram of the mouse heart failure model induced by ligation of the left anterior descending branch of the coronary artery and the mouse heart failure model treated with the heterocyclic compound I is shown in Figure 5 The heart function detection results of the mouse heart failure model induced by ligation of the left anterior descending branch of the coronary artery and the mouse heart failure model treated with the heterocyclic compound I are shown in Figure 6 It can be seen from Figure 6 that compared with the blank control group, the ejection fraction (EF) and fractional shortening (FS) of the heart of the mice in the model group were significantly decreased, and the heart function of the mice in the model group was significantly reduced; compared with the model group, after treatment with the heterocyclic compound I at a dose of 20 mg / kg, the EF and FS values of the heart failure model induced by ligation of the left anterior descending branch of the coronary artery were significantly improved, and the heart function of the heart failure mice was improved.

[0109] (2) HE staining of heart sections

[0110] The HE staining diagram of the heart sections of the mouse heart failure model induced by ligation of the left anterior descending branch of the coronary artery and the mouse heart failure model treated with the heterocyclic compound I is shown in Figure 7 It can be seen from Figure 7 that compared with the control group, the myocardial cells in the model group were arranged in disorder, and a large number of inflammatory cells infiltrated; compared with the model group, after treatment with the heterocyclic compound I at a dose of 20 mg / kg, the inflammatory cell infiltration was significantly reduced, and the arrangement of myocardial cells was maintained.

[0111] The above results show that the heterocyclic compound I has an anti-heart failure effect, and can be applied to the preparation of an anti-heart failure drug, and has a good clinical application prospect.

[0112] The above embodiments are the preferred embodiments of the present application, but the embodiments of the present application are not limited to the above embodiments, and any changes, modifications, substitutions, combinations, simplifications, etc. made without departing from the spirit and principles of the present application should be equivalent replacement manners and should be included in the protection scope of the present application.

Claims

1. Use of a heteroterpene I for the preparation of a medicament against heart failure, characterized in that, The structural formula of the heteroterpene compound I is shown as formula (I): Formula (I).

2. Use according to claim 1, characterized in that, The heteroterpene compound I can improve heart function.

3. Use according to claim 2, characterized in that, The heteroterpene compound I can improve cardiac ejection fraction and short axis shortening rate.

4. The use according to claim 1, characterized in that, The heteroterpene compound I can reduce myocardial cell damage.

5. The use according to claim 1, characterized in that, The heteroterpene compound I can inhibit myocardial connective tissue thickening.

6. The use according to claim 1, characterized in that, The heteroterpene compound I can improve myocardial cell arrangement disorder.

7. Use according to claim 1, characterized in that, The heteroterpene compound I can reduce inflammatory cell infiltration.

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