Application of rottlera to preparation of medicine for preventing and treating heart failure

Abstract

The application belongs to the technical field of biological medicine, and relates to application of Anchusa italica Retz. in preparation of a medicine for preventing and treating heart failure. It is proved by experiments that when Anchusa italica Retz. is used in a zebra fish heart failure model, the pericardial area, venous congestion area, distance between venous sinus and arteriospinal ball, heart rate, short axis shortening rate and ejection fraction of the zebra fish can be reduced, and the number of myocardial cell apoptosis of the zebra fish can be reduced, and the pathological state of the heart can be relieved. Anchusa italica Retz. can be used as a heart failure medicine, and has potential application prospects in the fields of heart failure treatment or functional food processing.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology and relates to the application of *Houttuynia cordata* in the preparation of drugs for the prevention and treatment of heart failure. Background Technology

[0002] Heart failure (HF) is a complex clinical syndrome, representing the end-stage of various heart diseases and serving as a complication of many other conditions. Traditional Chinese medicine (TCM) offers advantages such as multiple components, multiple pathways, and multiple targets, making it effective in improving clinical symptoms, enhancing quality of life, and increasing exercise tolerance in HF patients.

[0003] *Anchusa italica* Retz., belonging to the Boraginaceae family, is a plant with properties that generate dampness and heat, replenish abnormal spleen fluids upon maturity, nourish the brain, dispel cold and nourish the heart, refresh the mind, moisten dryness and reduce inflammation, and relieve cough and asthma. It is used to treat palpitations. Current research indicates that *Anchusa italica* possesses various biological activities, including resistance to myocardial ischemia / reperfusion injury, antibacterial activity, antioxidant activity, and anti-inflammatory and antitussive effects. Reported uses include dry brain deficiency, cold-type heart deficiency, palpitations, depression, dry pleurisy, pneumonia and tuberculosis, cold-type cough, colds, and asthma. However, whether *Anchusa italica* has the function of preventing and treating heart failure, especially acute heart failure, has not yet been explored. Summary of the Invention

[0004] The purpose of this invention is to expand the application of Anchusa italica Retz. in the preparation of drugs for the prevention and treatment of heart failure, and in particular to clarify the role of Anchusa italica in the prevention and treatment of heart failure, especially in the prevention and treatment of acute heart failure.

[0005] This invention provides the application of *Houttuynia cordata* in the preparation of drugs for the prevention and treatment of heart failure.

[0006] The *Hylocereus undatus* species involved in this invention are short segments with angular stems, a pale green surface, longitudinal wrinkles, white hard thorns, and slightly raised white thorn marks after thorns have fallen. The stems are hard and brittle, with a yellowish-white cross-section, and are mostly hollow. The leaves are mostly broken, curled, or wrinkled, with a yellowish-green upper surface and a pale yellowish-green to grayish-white lower surface. Both surfaces have numerous white hard thorns or white marks after thorns have fallen. The petioles are triangular and often twisted, with white thorns and thorn marks. The veins on both sides often curl upwards to the upper surface. When a complete leaf is unfolded, the apex is blunt and rounded, the leaf is thick, entire, and shaped like a cow's tongue. It has a slightly aromatic odor, a bland taste, and is sticky.

[0007] According to practical application needs, the *Houttuynia cordata* described in this invention can be prepared into a solvent extract or an extract according to methods known to those skilled in the art. Specifically, the solvent extract includes an alcohol extract, an aqueous extract, and a water distillate; the alcohol extract includes an ethanol extract or a methanol extract. Specifically, the extract includes a petroleum ether extract, a n-butanol extract, an ethyl acetate extract, and a chloroform extract.

[0008] For example, the conventional method for preparing the water extract of *Hylocereus undatus* in the prior art of the present invention includes: boiling *Hylocereus undatus* in water 2 to 3 times, each time boiling for 1 hour, combining the decoctions, and concentrating them for later use.

[0009] This invention uses verapamil (Ver) to establish a zebrafish heart failure model and verifies the efficacy of *Hedyotis diffusa* in preventing and treating heart failure. Therefore, this invention further requests protection for the use of *Hedyotis diffusa* in the preparation of drugs for the prevention and treatment of acute heart failure.

[0010] The present invention has shown through experiments that the herb *Hedyotis diffusa* reduces at least one of the following: pericardial area, venous congestion area, and SV-BA distance.

[0011] The present invention has shown through experiments that the herb *Hedyotis diffusa* restores cardiac function, and the restoration of cardiac function includes at least one of increasing heart rate, fractional shortening, and ejection fraction.

[0012] The present invention has shown through experiments that the herb *Hedyotis diffusa* accelerates blood flow.

[0013] The present invention has shown through experiments that the herb described can alleviate the psychological state of heart disease.

[0014] The present invention has shown through experiments that the relief of cardiac pathological state is achieved by at least one of reducing the number of cardiomyocyte apoptosis, improving ventricular dilation, and increasing the thickness of the heart wall.

[0015] Furthermore, the present invention provides a drug for preventing and treating heart failure or an acute heart failure drug, the components of which include *Houttuynia cordata* or its extract.

[0016] Furthermore, the formulation of the drug for preventing or treating heart failure or acute heart failure contains *Houttuynia cordata* or its extract, with the remainder being pharmaceutically acceptable, non-toxic, and inert pharmaceutically viable carriers and / or excipients for humans and animals. The pharmaceutically viable carriers or excipients are one or more selected from solid, semi-solid, and liquid diluents, fillers, and pharmaceutical excipients.

[0017] Furthermore, the formulation is an oral or injectable preparation. The oral preparation includes tablets, sustained-release tablets, controlled-release tablets, capsules, pellets, micro-pellets, suspensions, emulsions, powders or granules, oral liquids, etc.; the injectable preparation includes sterile aqueous or oily solutions, sterile powder injections, liposomes, or emulsions, etc.

[0018] Compared with the prior art, the technical solution provided by the present invention has at least the following beneficial effects or advantages.

[0019] This invention provides the application of *Houttuynia cordata* and its extracts in the preparation of drugs for the prevention and treatment of heart failure. This invention verifies that *Houttuynia cordata* and its extracts have a good effect on improving heart failure, reducing pericardial area, venous congestion area, sinus venosus-bulbar distance, increasing heart rate, fractional shortening, and ejection fraction, reducing the number of cardiomyocyte apoptosis in zebrafish, and alleviating cardiac pathological conditions. Guided by the mainstream research approach of safety and multi-target treatment concepts, this invention holds promise for developing a drug based on traditional Chinese medicine, and it provides scientific experimental data on the efficacy and material basis of *Houttuynia cordata*. Attached Figure Description

[0020] To more clearly illustrate the technical solution of the present invention, the accompanying drawings involved in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings in the description are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0021] Figure 1 This diagram illustrates the effects of different concentrations of NSC on Ver-induced heart failure in zebrafish. The black dashed lines represent the pericardial area, and the red dashed lines represent the area of ​​venous congestion.

[0022] Figure 2 This is a bar chart showing the effects of different concentrations of NSC on pericardial area, venous congestion area, and sinus venous bulb-arterial bulb (SV-BA) in zebrafish with Ver-induced heart failure. In the chart, # indicates the model group compared to the control group, and * indicates the positive control group, different concentration sample groups compared to the model group. * P<0.05, ** P<0.01, *** P<0.001, **** / #### P<0.0001.

[0023] Figure 3 This diagram illustrates the effects of different concentrations of NSC on the end-systolic and end-diastolic phases of the heart in zebrafish with Ver-induced heart failure. In this diagram, A represents the atrium, V represents the ventricle, and the white lines represent the short and long axes of the ventricle, with a representing the short axis and b representing the long axis.

[0024] Figure 4This is a bar chart showing the effects of different concentrations of NSC on mean heart rate, fractional shortening, and ejection fraction in zebrafish with Ver-induced heart failure. Here, bpm represents the number of heartbeats per minute (heart rate), # indicates the model group compared to the control group, and * indicates the positive control group; different concentrations of sample groups compared to the model group... * P<0.05, ** P<0.01, *** / ### P<0.001, **** / #### P<0.0001.

[0025] Figure 5 This is a schematic diagram showing the effect of different concentrations of NSC on the mean blood flow velocity in zebrafish with Ver-induced heart failure.

[0026] Figure 6 A bar chart showing the effect of different concentrations of NSC on the mean blood flow velocity in zebrafish with Ver-induced heart failure. Wherein, # indicates the model group compared to the control group, and * indicates the positive control group; different concentrations of sample groups compared to the model group... ** P<0.01, *** / ### P<0.001, #### P<0.0001.

[0027] Figure 7 The effect of different concentrations of NSC on Ver-induced apoptosis in zebrafish cardiomyocytes with heart failure. White arrows represent apoptotic cardiomyocytes.

[0028] Figure 8 The effect of different concentrations of NSC on Ver-induced heart failure pathology in zebrafish. The black line represents the thickness of the heart wall.

[0029] In the above figures, NSC is the water extract of *Houttuynia cordata*, and Ver is verapamil. Detailed Implementation

[0030] The technical solution of the present invention will be described below with reference to embodiments. However, the present invention is not limited to the following embodiments. Unless otherwise specified, the experimental methods and detection methods described in each embodiment are conventional methods; unless otherwise specified, the reagents and materials are all commercially available.

[0031] In the following examples, the extraction method of NSC (water extract of ox tongue grass) is a conventional method in the prior art. Ox tongue grass is taken, boiled in water three times, each time for 1 hour, the decoctions are combined and concentrated for later use.

[0032] The following examples use verapamil (Ver), which has been widely used in the academic community at home and abroad, to prepare a zebrafish heart failure model.

[0033] NSC was sourced from the Uyghur Medicine Hospital of Xinjiang Uyghur Autonomous Region; Digoxin was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.; Ver was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.; and the concentration of the water used for zebrafish juvenile culture was 5.0 mM NaCl, 0.17 mM KCl, 0.4 mM CaCl2, and 0.16 mM MgSO4.

[0034] Example 1

[0035] This embodiment provides a method for determining the concentration of NSCs administered.

[0036] (1) Determination of NSC dosage

[0037] Wild-type zebrafish juveniles with normal development and 2 days post-fertilization were selected and placed in 24-well plates, 10 fish per well. A control group and sample groups with different concentrations were set up. The control group was given fish tank water, while the sample groups were given NSC (0.1, 0.5, 2.5, 5, 25, 50 mg / mL). -1 The zebrafish were placed in a constant temperature incubator at 28℃. The mortality and deformity of zebrafish in each group were recorded, and the maximum safe concentration of NSC for zebrafish was determined as the maximum dosage concentration, as shown in Table 1.

[0038] (2) Experimental Results

[0039] Table 1: Effects of different NSC concentrations on mortality and deformity rate in zebrafish

[0040]

[0041]

[0042] Table 1 shows that when the NSC concentration is 50, 25, and 5 mg·mL... -1 At that time, the deformity rates of zebrafish were 100% and 20%, respectively, when the NSC concentration was 2.5 mg·mL. -1 At that time, the mortality and deformity rates of zebrafish were both 0, indicating that 2.5 mg / mL -1 To determine the maximum safe concentration of NSC for zebrafish, this invention selects 2.5, 0.5, and 0.1 mg / mL. -1 As the dosage concentration.

[0043] Example 2

[0044] This embodiment provides the effect of NSC on the heart of a zebrafish with Ver-induced heart failure.

[0045] (1) Experimental methods

[0046] Under a microscope, normally developed 2-day post-fertilization wild-type zebrafish juveniles were selected and placed into 24-well plates, with 10 juveniles per well. A control group, a model group (Verapamil), and a positive control group (Verapamil + 0.01 mg / mL) were established. -1 Digoxin), different concentration sample groups (Verapamil + 0.1 mg / mL) -1 NSC, Verapamil + 0.5 mg / mL -1 NSC, Verapamil + 2.5 mg / mL -1 (NSC). The positive control group and different concentration sample groups were given the corresponding concentrations of drug and incubated at 28℃ for 4.5 hours before the drug was washed off, followed by washing 2-3 times with fish tank water. Subsequently, the model group, positive control group, and different concentration sample groups were treated with Ver for 30 minutes. After treatment, the zebrafish were anesthetized with 0.3% tricaine for 1 minute. The morphology of the zebrafish hearts was observed and photographed under a microscope. ImageJ software was used to measure the pericardial area, venous congestion area, and SV-BA distance of each group of zebrafish.

[0047] (2) Statistical methods

[0048] Statistical analysis of the data was performed using GraphPad Prism 8.0.2. Data were tested for normality and variance. A t-test was used to determine if the data met the criteria for normality and homogeneity of variance; otherwise, a rank-sum test was used. A p-value < 0.05 was considered statistically significant.

[0049] (3) Results Analysis

[0050] When Ver induces heart failure in zebrafish, the zebrafish exhibit pericardial edema and venous congestion, leading to an increase in the pericardial area and the area of ​​venous congestion. SV is the site where blood enters the atrium, and BA is the site where blood exits the ventricle. In heart failure zebrafish, the positions of the atria and ventricles change, and the overlap phenomenon no longer occurs, resulting in a corresponding change in the SV-BA distance.

[0051] Figure 1 A schematic diagram of zebrafish hearts affected by different concentrations of NSC in Ver-induced heart failure; where the black dashed line represents the pericardial area and the red dashed line represents the area of ​​venous congestion. Figure 2 This is a bar chart showing the effects of different concentrations of NSC on pericardial area, venous congestion area, and SV-BA distance in zebrafish with Ver-induced heart failure. Compared with the control group, the model group showed significantly increased pericardial area, venous congestion area, and SV-BA distance. Compared with the model group, the positive control group and the different concentration sample groups showed significantly decreased pericardial area, venous congestion area, and SV-BA distance.

[0052] Example 3

[0053] This embodiment provides the effect of NSC on cardiac function in zebrafish with Ver-induced heart failure.

[0054] (1) Experimental methods

[0055] Under a microscope, normally developed transgenic zebrafish juveniles with 2-day post-fertilization heart-labeled fluorescently labeled hearts were selected and placed into 24-well plates, with 10 fish per well. Three groups were set up: a control group, a model group (Verapamil), and a positive control group (Verapamil + 0.01 mg / mL). - 1 Digoxin), different concentration sample groups (Verapamil + 0.1 mg / mL) -1 NSC, Verapamil + 0.5 mg / mL -1 NSC, Verapamil + 2.5 mg / mL -1 (NSC). The positive control group and different concentration sample groups were given the corresponding concentrations of drug and incubated at 28℃ for 4.5 hours before the drug was washed off, followed by washing 2-3 times with fish tank water. Subsequently, the model group, positive control group, and different concentration sample groups were treated with Ver for 30 minutes. After treatment, the zebrafish were anesthetized with 0.3% tricaine for 1 minute, and their heart rate was recorded. The morphology of the zebrafish hearts was observed and photographed under a fluorescence microscope. ImageJ software was used to measure the short axis and long axis distances of each group of zebrafish, and the short axis shortening rate and ejection fraction were calculated.

[0056] Ventricular fractional shortening (%) = (End-diastolic width - End-systolic width) / End-diastolic width × 100%

[0057] Ejection fraction (%) = Stroke volume / End-diastolic volume of the ventricle × 100% (Stroke volume = End-diastolic volume - End-systolic volume)

[0058] (2) Statistical methods

[0059] Statistical analysis of the data was performed using GraphPad Prism 8.0.2. Data were tested for normality and variance. A t-test was used to determine if the data met the criteria for normality and homogeneity of variance; otherwise, a rank-sum test was used. A p-value < 0.05 was considered statistically significant.

[0060] (3) Results Analysis

[0061] Zebrafish heart rate refers to the number of times the zebrafish's heart beats per minute, Ver being Ca. 2+ Channel blockers, inhibiting Ca 2+It enters cardiomyocytes and vascular smooth muscle cells, weakening myocardial contractility and decreasing heart rate. In zebrafish, the ventricular volume is smallest at the end of ejection, known as the end-systolic volume; the ventricular volume is largest at the end of diastole, known as the end-diastolic volume. The short-axis shortening rate and ejection fraction are calculated using formulas based on the long and short axis distances at the end of systole and diastole in zebrafish. When zebrafish experience heart failure, their short-axis shortening rate and ejection fraction decrease.

[0062] Figure 3 This diagram illustrates the effects of different concentrations of NSC on the end-systolic and end-diastolic phases of the heart in zebrafish with Ver-induced heart failure. In this diagram, A represents the atrium, V represents the ventricle, and the white lines represent the short and long axes of the ventricle, with a representing the short axis and b representing the long axis. Figure 4 This is a bar chart showing the effect of different concentrations of NSC on the mean heart rate, fractional shortening, and ejection fraction of zebrafish with Ver-induced heart failure. Compared with the control group, the model group showed significantly reduced heart rate, fractional shortening, and ejection fraction. Compared with the model group, the positive control group and the different concentration sample groups showed significantly increased heart rate, fractional shortening, and ejection fraction.

[0063] Example 4

[0064] This embodiment provides the effect of NSC on blood flow velocity in zebrafish with Ver-induced heart failure.

[0065] (1) Experimental methods

[0066] Under a microscope, normally developed 2-day post-fertilization wild-type zebrafish juveniles were selected and placed into 24-well plates, with 10 juveniles per well. A control group, a model group (Verapamil), and a positive control group (Verapamil + 0.01 mg / mL) were established. -1 Digoxin), different concentration sample groups (Verapamil + 0.1 mg / mL) -1 NSC, Verapamil + 0.5 mg / mL -1 NSC, Verapamil + 2.5 mg / mL -1 (NSC). The positive control group and different concentration sample groups were given the corresponding concentrations of drug and incubated at 28℃ for 4.5 hours before the drug was washed off, followed by washing 2-3 times with fish tank water. Subsequently, the model group, positive control group, and different concentration sample groups were treated with Ver for 30 minutes, and then washed 3 times with fish tank water. Blood flow velocity was recorded and analyzed using a microscope and Blood Flow v5.18.0.0 and MicroZebraLab BloodFlow v 3.4.6 software.

[0067] (2) Statistical methods

[0068] Statistical analysis of the data was performed using GraphPad Prism 8.0.2. Data were tested for normality and variance. A t-test was used to determine if the data met the criteria for normality and homogeneity of variance; otherwise, a rank-sum test was used. A p-value < 0.05 was considered statistically significant.

[0069] (3) Results Analysis

[0070] Vera has the effect of reducing coronary blood flow. When Vera causes heart failure in zebrafish, the blood flow velocity is significantly slowed down, and even the phenomenon of no blood flow occurs.

[0071] Figure 5 This is a schematic diagram showing the effect of different concentrations of NSC on the mean blood flow velocity in zebrafish with Ver-induced heart failure. Figure 6 This is a bar chart showing the mean blood flow velocity of zebrafish with Ver-induced heart failure at different concentrations of NSC. Compared with the control group, the blood flow velocity in the model group was significantly slower, and compared with the model group, the blood flow velocity in the sample groups with different concentrations was significantly faster.

[0072] Example 5

[0073] This embodiment provides the effect of NSC on Ver-induced apoptosis of cardiomyocytes in zebrafish with heart failure.

[0074] (1) Experimental methods

[0075] Under a microscope, normally developed 2-day post-fertilization wild-type zebrafish juveniles were selected and placed into 24-well plates, with 10 juveniles per well. A control group, a model group (Verapamil), and a positive control group (Verapamil + 0.01 mg / mL) were established. -1 Digoxin), different concentration sample groups (Verapamil + 0.1 mg / mL) -1 NSC, Verapamil + 0.5 mg / mL -1 NSC, Verapamil + 2.5 mg / mL -1 (NSC). The positive control group and different concentration sample groups were given the corresponding concentrations of drug and incubated at 28℃ for 4.5 hours before the drug was washed off, followed by washing 2-3 times with fish tank water. Then, the model group, positive control group, and different concentration sample groups were treated with Ver for 30 minutes. After treatment, the samples were washed 3 times with fish tank water, and after removing the fish tank water, 2 mL of acridine orange staining solution (5 μg / mL) was added to each well. -1 Incubate in a light-proof incubator for 30 minutes, wash three times with fish tank water, add 0.3% tricaine for 1 minute to anesthetize, and observe and photograph under a fluorescence microscope.

[0076] (2) Results Analysis

[0077] Cardiac cell apoptosis plays an important role in maintaining the relative stability of cardiac tissue morphology. 2+ Ver is a second messenger mediating apoptosis and plays an important role in the process. Ver is a calcium channel blocker, inhibiting calcium ion flow. 2+ It enters cardiomyocytes. Ver increased the number of cardiomyocyte apoptosis when it induced heart failure in zebrafish.

[0078] Figure 7 This study investigated the effects of different concentrations of NSC on Ver-induced apoptosis in zebrafish cardiomyocytes with heart failure. Compared to the control group, the number of apoptotic cardiomyocytes in the model group increased, while the number of apoptotic cardiomyocytes decreased in the positive control group and the different concentration groups compared to the model group.

[0079] Example 6: Effects of NSC on Ver-induced heart failure pathology in zebrafish

[0080] (1) Experimental methods

[0081] Under a microscope, normally developed 2-day post-fertilization wild-type zebrafish juveniles were selected and placed into 24-well plates, with 10 fish per well. A control group, a model group (Verapamil), and sample groups with different concentrations (Verapamil + 0.1 mg / mL) were set up. -1 NSC, Verapamil + 0.5 mg / mL -1 NSC, Verapamil + 2.5 mg / mL -1 (NSC). The positive control group and different concentration sample groups were given the corresponding concentrations of drug and placed in a 28℃ constant temperature incubator for 4.5 hours for pre-protection. The drug was then washed off, and the samples were washed 2-3 times with fish tank water. Subsequently, the model group, positive control group, and different concentration sample groups were treated with Ver for 30 minutes. After treatment, the samples were washed 2-3 times with fish tank water. Five to ten zebrafish were anesthetized with an appropriate amount of tricaine, then fixed in 4% paraformaldehyde for 96 hours. The zebrafish were then dehydrated using a gradient of ethanol, benzene, and xylene. After embedding in paraffin in an embedding machine, the sections were sectioned at 4 μm, dewaxed to water, rinsed with purified water, and stained with hematoxylin and eosin (HE). The sections were washed and placed in a gradient of ethanol and xylene for dehydration until clear. After drying, the sections were mounted with neutral resin and observed and photographed under a microscope.

[0082] (2) Results Analysis

[0083] When heart failure occurs, a large number of cardiomyocytes undergo apoptosis, and ventricular remodeling leads to dilation and thinning of the ventricular wall.

[0084] Figure 8 The effects of different concentrations of NSC on the pathological changes of Ver-induced heart failure in zebrafish were investigated. Compared with the control group, the ventricular wall thickness was thinner in the model group, while the ventricular wall thickness was increased in the different concentration groups compared with the model group.

[0085] The experimental results above show that NSC can significantly improve Ver-induced heart failure symptoms, including reducing pericardial area, venous congestion area, SV-BA distance, increasing heart rate, fractional shortening, ejection fraction, increasing blood flow velocity, reducing the number of cardiomyocyte apoptosis, improving ventricular dilation, and increasing heart wall thickness.

[0086] This invention is the first to discover that the water extract of *Hylocereus undatus* can be used to treat heart failure, which adds a new use to *Hylocereus undatus*, provides a new treatment method for heart failure, and also provides a reference for the application and development of *Hylocereus undatus*.

[0087] The embodiments described above are some, but not all, of the embodiments of the present invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the claimed invention, but merely to illustrate selected embodiments of the invention. All other embodiments obtained by those skilled in the art through related deductions and substitutions based on the inventive concept, without inventive effort, are within the scope of protection of the present invention.

Claims

1. Application of *Houttuynia cordata* water extract as the sole active ingredient in the preparation of drugs for the prevention and treatment of acute heart failure.

2. The application according to claim 1, characterized in that, The herb extract reduces at least one of the following: pericardial area, venous congestion area, and SV-BA distance.

3. The application according to claim 1, characterized in that, The water extract of *Houttuynia cordata* restores cardiac function.

4. The application according to claim 3, characterized in that, The restoration of cardiac function refers to at least one of the following: increased heart rate, fractional shortening, and ejection fraction.

5. The application according to claim 1, characterized in that, The herb extract from *Houttuynia cordata* accelerates blood flow.

6. The application according to claim 1, characterized in that, The herb extract of *Houttuynia cordata* relieves the psychological state of heart disease.

7. The application according to claim 6, characterized in that, The relief of cardiac pathological state includes at least one of reducing the number of cardiomyocyte apoptosis, improving ventricular dilation, and increasing the thickness of the heart wall.

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