Methods of targeting th17 cells and il17a for heart failure treatment

Abstract

The present disclosure relates methods of treating heart failure, such as heart failure with preserved ejection fraction, wherein said methods reduce cardiac inflammation and / or improve cardiac function by targeting pro-inflammatory cells and cytokines in a subject, including but not limited to subjects in the aging population.

Description

[0001]^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^METHODS OF TARGETING TH17 CELLS AND IL17A FOR HEART FAILURE TREATMENT RELATED APPLICATION ^^ This PCT application claims priority to, and the benefit of, U.S. Provisional Patent Application No.63 / 694,292, filed September 13, 2024, entitled “Strategies for Targeting TH17 Cells and IL17A for Heart Failure Treatment (HFpEF),” which is incorporated by reference herein in its entirety. ^^^ FIELD The present disclosure relates methods of treating heart failure by targeting pro- inflammatory cells and cytokines in cardiac adipose tissues. BACKGROUND ^^^ Heart failure with preserved ejection fraction (HFpEF) is strongly correlated with age and predominantly affects elderly patients, particularly postmenopausal women. Notably, HFpEF has emerged as a leading cause of morbidity, hospitalization, and mortality in individuals aged 65 years and older. Despite its growing prevalence, effective therapies for HFpEF remain elusive, underscoring the urgent need for novel, targeted therapeutic strategies ^^^ tailored to the aging population. The methods disclosed herein address the need for therapeutic methods of treating cardiac dysfunction, such as for example HFpEF, in the aging population. SUMMARY ^^^ The present disclosure provides methods of treating, preventing, decreasing, ameliorating, and / or reducing a heart failure condition in a subject. In some aspects, disclosed herein is a method of treating a subject with a heart failure condition, the method comprising administering to the subject a therapeutically effective amount of a small molecule and pharmaceutically acceptable carrier, wherein the small ^^^ molecule prevents activation of a T helper 17 (Th17) cell and inhibits expression of interleukin 17 (IL17). In some aspects, disclosed herein is a method of improving cardiac function in a subject in need thereof, the method comprising administering to the subject a therapeutically effective ^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^amount of a small molecule and pharmaceutically acceptable carrier, wherein the small molecule improves diastolic function in the subject relative to an untreated control. In some aspects, disclosed herein is a method of reducing cardiac inflammation in a subject in need thereof, the method comprising administering to the subject a therapeutically ^^ effective amount of a small molecule and pharmaceutically acceptable carrier, wherein the small molecule prevents activation of a T helper 17 (Th17) cell and inhibits expression of interleukin 17 (IL17). In some embodiments, the small molecule prevents activation of a T helper 17 (Th17) cell and inhibits expression of interleukin 17 (IL17). ^^^ In some embodiments, the small molecule comprises an anti-IL17 antibody or an inhibitor of Th17 cell differentiation. In some embodiments, the anti-IL17 antibody comprises secukinumab, or a variant thereof. In some embodiments, the inhibitor of Th17 cell differentiation inhibits transcription factors selected from ROR^t, IRF4, BATF, FoxP3, T-bet, PPAR^, E-FABP, or SOCS. In some embodiments, the inhibitor of Th17 cell differentiation ^^^ comprises S18-000003, A213, SHR168442, TMP778, BMS-986251, BMS-986313, A-9758, digoxin, FC99, Cpd1, JNJ-61803534, JNJ-54271074, SR2211, Ursolic acid, SR1001, TAK- 828F, GSK805, VPR-254, Bl119, CQMU151, CQMU152, BIX119, or a variant thereof. In some embodiments, the heart failure condition comprises heart failure with preserved ejection fraction (HFpEF). In some embodiments, the method of any preceding aspect ^^^ improves diastolic function in the subject relative to an untreated control. In some embodiments, the method of any preceding aspect maintains systolic function in the subject relative to an untreated control. In some embodiments, the method of any preceding aspect reduces inflammation in the subject relative to an untreated control. In some embodiments, the method of any preceding aspect reduces adipocyte hypertrophy in the subject relative to an ^^^ untreated control. In some embodiments, the subject is 65 years or older. In some embodiments, the subject is a postmenopausal woman. BRIEF DESCRIPTION OF FIGURES ^^^ The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects described below. Figures 1A, 1B, 1C, 1D, 1E, and 1F show a comprehensive overview of T cell heterogeneity, functional states, and inflammatory gene expression in mouse paracardial fat across different ages and sexes. Figure 1A shows the two-dimensional uniform manifold ^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^approximation and projection (UMAP) plots showing the T cell atlas of mouse paracardial fat (PF). Figure 1A also illustrates the diverse landscape of T cell populations using UMAP clustering, highlighting distinct subtypes within PF. Figure 1B shows the dotplot of artificial signature genes from CD4+ T cells. Figure 1B also presents signature gene expression profiles ^^ of CD4^ T cells, aiding in the identification of functional subsets. Figure 1C shows the UMAP plots showing the T cell subclusters in the mouse PF across age and sexes. Trajectory analysis showed that Th1 / Th17 cells might be derived from Th17 cells. The arrows indicated the transdifferentiation direction. Figure 1C also shows that T cell subclusters vary by age and sex, with trajectory analysis suggesting that Th1 / Th17 cells may originate from Th17 cells, ^^^ indicating cellular plasticity. Figure 1D shows the distribution of T cell subsets in PF. Each group of PF was pooled from 5 mice. Tcm: central memory T cells; Tfh: follicular helper T cells; Treg: regulatory T cells. Figure 1D also quantifies the distribution of key T cell subsets (Tcm, Tfh, Treg) across pooled samples, providing insight into immune composition. Figures 1E and 1F show the IL17A and IFNG (IFN-^) mRNA expression in paracardial fat (PF) from ^^^ C57 / BL6 mice of different age (3 and 24 months) and sexes by qPCR. Figures 1E and 1F also demonstrate age- and sex-dependent differences in IL17A and IFNG mRNA expression, showing dynamic regulation of inflammatory responses in PF. N = 5, *P<0.01; **P<0.01; ****P<0.0001, ns: no significance.2-way ANOVA followed by Bonferroni post-hoc analysis. YF / YM: young male / female mice (3 months); OM / OF: old male / female mice (23 or 24 ^^^ months). Figures 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, and 2K shows the human IL17 mRNA delivery to paracardial fat (PF) induces tissue remodeling and diastolic dysfunction. Figure 2A shows the schematic of the experimental design for IL-17 mRNA injection into the PF of young male and female C57BL / 6 mice. Figures 2B and 2C show the gross morphology and H&E ^^^ staining of PF tissue. Figure 2D shows the quantification of unilocular and multilocular adipocytes and their size (300 cells of 18 sections from 6 mice per group). Figure 2E shows the WGA staining of mouse hearts and quantification of cardiomyocyte size.600 cells from 6 mice in each group. Figure 2F shows the representative images of CD68 in mouse hearts and quantification.42 sections from 7 mice in each group. Figure 2G shows there was no significant ^^^ changes of systolic function (EF and FS). Figures 2H, 2I, 2J, and 2K show the E / E’, IVRT, GLS, and rLSR, respectively. n=7. *P<0.05, ***P<0.001, ****P<0.0001. Ctrl: control. GLS: global longitudinal strain; GRS: global radial strain; rLSR: reverse longitudinal strain rate. **P<0.0001. ns: no significance. Unpaired Student 2-tailed t-test. ^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^Figures 3A, 3B, 3C, 3D, 3E, and 3F show the N=neutralization of IL17A improves diastolic function in aged female mice. Figure 3A shows the schematic of secukinumab (anti- IL17) treatment. Figure 3B shows the representative M-mode echocardiography, pulse wave (PW) doppler images of the mitral valve, and tissue doppler imaging (TDI) of the mitral ^^ annulus. Figure 3C shows the left ventricular ejection fraction (EF) and fractional shortening (FS). Figure 3D shows the diastolic function parameters: E / E^ ratio and isovolumic relaxation time (IVRT). n = 8-10. Figure 3E shows the representative images of HE stained of PF. Black arrows indicate inflammatory cell infiltration. Figure 3F shows the anti-IL17A treatment reduced the number of unilocular adipocytes and increased the number of large multilocular ^^^ adipocytes in PF compared to IgG1-treated controls. 15 sections from 5 mice in each group. 300 cells from 5 mice in each group were analyzed. *P<0.05, ****P<0.0001. ns: no significance. Unpaired Student 2-tailed t-test. DETAILED DESCRIPTION ^^^ The following description of the disclosure is provided as an enabling teaching of the disclosure in its best, currently known embodiment(s). To this end, those skilled in the relevant art will recognize and appreciate that many changes can be made to the various embodiments of the invention described herein, while still obtaining the beneficial results of the present disclosure. It will also be apparent that some of the desired benefits of the present disclosure ^^^ can be obtained by selecting some of the features of the present disclosure without utilizing other features. Accordingly, those who work in the art will recognize that many modifications and adaptations to the present disclosure are possible and can even be desirable in certain circumstances and are a part of the present disclosure. Thus, the following description is provided as illustrative of the principles of the present disclosure and not in limitation thereof. ^^^ Reference will now be made in detail to the embodiments of the invention, examples of which are illustrated in the drawings and the examples. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. ^^^ Terminology Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. The term “comprising” and variations thereof as used herein is used synonymously with the term “including” and variations thereof and are open, non-limiting terms. Although ^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^the terms “comprising” and “including” have been used herein to describe various embodiments, the terms “consisting essentially of” and “consisting of” can be used in place of “comprising” and “including” to provide for more specific embodiments and are also disclosed. As used in this disclosure and in the appended claims, the singular forms “a”, “an”, “the”, ^^ include plural referents unless the context clearly dictates otherwise. The following definitions are provided for the full understanding of terms used in this specification. The terms "about" and "approximately" are defined as being “close to” as understood by one of ordinary skill in the art. In one non-limiting embodiment the terms are defined to be ^^^ within 10%. In another non-limiting embodiment, the terms are defined to be within 5%. In still another non-limiting embodiment, the terms are defined to be within 1%. As used herein, the terms "may," "optionally," and "may optionally" are used interchangeably and are meant to include cases in which the condition occurs as well as cases in which the condition does not occur. Thus, for example, the statement that a formulation ^^^ "may include an excipient" is meant to include cases in which the formulation includes an excipient as well as cases in which the formulation does not include an excipient. "Comprising" is intended to mean that the compositions, methods, etc. include the recited elements, but do not exclude others. "Consisting essentially of'' when used to define compositions and methods, shall mean including the recited elements, but excluding other ^^^ elements of any essential significance to the combination. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like. "Consisting of'' shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the ^^^ compositions provided and / or claimed in this disclosure. Embodiments defined by each of these transition terms are within the scope of this disclosure. An "increase" can refer to any change that results in a greater amount of a symptom, disease, composition, condition, or activity. An increase can be any individual, median, or average increase in a condition, symptom, activity, composition in a statistically significant ^^^ amount. Thus, the increase can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100% or more increase so long as the increase is statistically significant. A "decrease" can refer to any change that results in a smaller amount of a symptom, disease, composition, condition, or activity. A substance is also understood to decrease the ^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^genetic output of a gene when the genetic output of the gene product with the substance is less relative to the output of the gene product without the substance. Also, for example, a decrease can be a change in the symptoms of a disorder such that the symptoms are less than previously observed. A decrease can be any individual, median, or average decrease in a condition, ^^ symptom, activity, composition in a statistically significant amount. Thus, the decrease can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100%, or more decrease so long as the decrease is statistically significant. "Inhibit," "inhibiting," and "inhibition" mean to decrease an activity, response, condition, disease, or other biological parameter. This can include but is not limited to the ^^^ complete ablation of the activity, response, condition, or disease. This may also include, for example, a 10% reduction in the activity, response, condition, or disease as compared to the native or control level. Thus, the reduction can be a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction below, above, or in between the given ranges as compared to native or control levels. ^^^ By “reduce” or other forms of the word, such as “reducing” or “reduction,” means lowering of an event or characteristic (e.g., tumor growth). It is understood that this is typically in relation to some standard or expected value, in other words it is relative, but that it is not always necessary for the standard or relative value to be referred to. For example, “reduces tumor growth” means reducing the rate of growth of a tumor relative to a standard or a control. ^^^ By “prevent” or other forms of the word, such as “preventing” or “prevention,” is meant to stop a particular event or characteristic, to stabilize or delay the development or progression of a particular event or characteristic, or to minimize the chances that a particular event or characteristic will occur. Prevent does not require comparison to a control as it is typically more absolute than, for example, reduce. As used herein, something could be reduced but not ^^^ prevented, but something that is reduced could also be prevented. Likewise, something could be prevented but not reduced, but something that is prevented could also be reduced. It is understood that where reduce or prevent are used, unless specifically indicated otherwise, the use of the other word is also expressly disclosed. The term “subject” refers to any individual who is the target of administration or ^^^ treatment. The subject can be a vertebrate, for example, a mammal. In one aspect, the subject can be human, non-human primate, bovine, equine, porcine, canine, or feline. The subject can also be a guinea pig, rat, hamster, rabbit, mouse, or mole. Thus, the subject can be a human or veterinary patient. The term “patient” refers to a subject under the treatment of a clinician, e.g., physician. ^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^“Composition” refers to any agent that has a beneficial biological effect. Beneficial biological effects include both therapeutic effects, e.g., treatment of a cardiovascular dysfunction including but not limited to a heart failure condition. The terms also encompass pharmaceutically acceptable, pharmacologically active derivatives of beneficial agents ^^ specifically mentioned herein, including, but not limited to, a vector, polynucleotide, cells, salts, esters, amides, proagents, active metabolites, isomers, fragments, analogs, and the like. When the term “composition” is used, then, or when a particular composition is specifically identified, it is to be understood that the term includes the composition per se as well as pharmaceutically acceptable, pharmacologically active vector, polynucleotide, salts, esters, ^^^ amides, proagents, conjugates, active metabolites, isomers, fragments, analogs, etc. The term “therapeutically effective amount” refers to the amount of the composition (such as for example a composition comprising the small molecule of any aspect disclosed herein) used is of sufficient quantity to ameliorate one or more causes or symptoms of a disease related to cardiovascular dysfunction. Such amelioration only requires a reduction or alteration, ^^^ not necessarily elimination. The term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder, such as for example cardiovascular dysfunction. This term includes active treatment, that is, treatment directed specifically toward the improvement of a cardiovascular dysfunction, and also ^^^ includes causal treatment, that is, treatment directed toward removal of the cause of the associated cardiovascular dysfunction. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the cardiovascular dysfunction; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the cardiovascular dysfunction; and supportive ^^^ treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the cardiovascular dysfunction. “Inhibitors” or “antagonist” of expression or of activity are used to refer to inhibitory molecules, respectively, identified using in vitro and in vivo assays for expression or activity of a described target protein, e.g., ligands, antagonists, and their homologs and mimetics. ^^^ Inhibitors are agents that, e.g., inhibit expression or bind to, partially or totally block stimulation or activity, decrease, prevent, delay activation, inactivate, desensitize, or down regulate the activity of the described Th17 or IL17, e.g., antagonists. Control samples (untreated with inhibitors) are assigned a relative activity value of 100%. Inhibition Th17 cells ^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^or IL17 is achieved when the activity value relative to the control is about 80%, optionally 50% or 25%, 10%, 5%, or 1% or less. The term “administer,” “administering”, or derivatives thereof refer to delivering a composition, substance, inhibitor, or medication to a subject or object by one or more the ^^ following routes: oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, rectal, vaginal, by inhalation or via an implanted reservoir. The term “parenteral” includes subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial ^^^ injections or infusion techniques. As used herein, the term “chemical compound” or “compound”, refers to a chemical substance consisting of two or more different types of atoms or chemical elements in a fixed stoichiometric proportion. These compounds have a unique and defined chemical structure held together in a defined spatial arrangement by chemical bonds. Chemical compounds can be held ^^^ together by covalent bonds, ionic bonds, metallic ions, or coordinate covalent bonds. In some embodiments, the small molecule of any aspect disclosed herein can be a chemical compound. The terms “treat,” “treating,” and grammatical variations thereof as used herein, include partially or completely delaying, alleviating, mitigating or reducing the intensity of one or more attendant symptoms of a disorder or condition and / or alleviating, mitigating or impeding one ^^^ or more causes of a disorder or condition. Treatments according to the disclosure may be applied preventively, prophylactically, palliatively or remedially. Treatments are administered to a subject prior to onset (e.g., before obvious signs of cardiovascular dysfunction, such as for example heart failure), during early onset (e.g., upon initial signs and symptoms of cardiovascular dysfunction), or after an established development of cardiovascular ^^^ dysfunction. A “pharmaceutically effective amount” of a drug necessary to achieve a therapeutic effect may vary according to factors such as the age, sex, and weight of the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as ^^^ indicated by the exigencies of the therapeutic situation. "Pharmaceutically acceptable carrier" (sometimes referred to as a “carrier”) means a carrier or excipient that is useful in preparing a pharmaceutical or therapeutic composition that is generally safe and non-toxic and includes a carrier that is acceptable for veterinary and / or human pharmaceutical or therapeutic use. The terms "carrier" or "pharmaceutically acceptable ^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^carrier" can include, but are not limited to, phosphate buffered saline solution, water, emulsions (such as an oil / water or water / oil emulsion) and / or various types of wetting agents. Methods ^^ Cardiovascular diseases (CVDs) are a group of disorders of the heart and surrounding blood vessels, and are the leading cause of death worldwide, accounting for about 31% of deaths globally. These include, but are not limited to heart failure (e.g., heart failure with preserved ejection fraction), coronary artery diseases (e.g., angina and heart attacks), hypertensive heart disease, cardiomyopathies, congenital heart diseases, and arrythmia. The ^^^ underlying mechanisms for each type of CVD varies, but generally behavioral and environmental factors such as, for example tobacco use, unhealthy diet, obesity, age, physical activity, alcohol abuse, and air pollution, are known to contribute to the development of CVDs. Heart failure (HF), also known as congestive heart failure (CHF), is clinical syndrome of CVD caused by the inability of the heart to supply sufficient blood to the tissues to meet their ^^^ metabolic requirements. The severity of HF is mainly decided based upon ejection fraction and also measured by the severity of symptoms. Left-sided HF may be present with a reduced ejection fraction or with a preserved ejection fraction. As used herein, ejection fraction (EF) refers to the volumetric fraction of blood ejected from cardiac chamber (such as a ventricle or an atrium) with each contraction (or heartbeat). ^^^ The EF of the left heart, also known as the left ventricular EF (LVEF) is calculated by dividing the volume of blood pumped from the left ventricle per beat (stroke volume) by the volume of blood present in the left ventricle at the end of diastolic filling (end-diastolic volume). LVEF is an indicator of the effectiveness of pumping into systemic circulation. Measurements of EF involve use of imaging modalities, including but not limited to echocardiograms (Echo), ^^^ cardiac magnetic resonance imaging (MRI), cardiac computed tomography (CT) scan, and cardiac catheterization. In heart failure, there are two type of HF involving EF, those being heart failure with reduced ejection fraction (HErEF) and heart failure with preserved ejection fraction (HFpEF). The difference between HFrEF and HFpEF is significant because they appear in a subject differently and are treated differently. ^^^ Heart failure with preserved ejection fraction (HFpEF) is a form of heart failure in with the EF is normal, defined as greater than 50%. HFpEF is characterized by abnormal diastolic function with increased stiffness of the left ventricle, which causes relaxation of the left ventricle to decrease, all resulting in increased pressure and / or impaired filling of blood in the left ventricle. Symptoms of HFpEF include, but are not limited to shortness of breath, exercise ^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^induced dyspnea, paroxysmal nocturnal dyspnea, orthopnea, fatigue, elevated jugular venous pressure, and edema. Age-related HFpEF is a common condition wherein increasing age is a significant risk factor, often associated with systemic inflammation, cardiac structural changes, and worsening ^^ cardiovascular functions over time. In the elderly, HEpEF can be exacerbated by other age- related factors, including but not limited to chronic low-grade inflammation that increases with age and elevates in the presence of age-related diseases. Postmenopausal changes, particularly reduced estrogen, are also linked to HFpEF through mechanisms including, but not limited to increased inflammation, obesity, metabolic ^^^ dysfunction, and vascular stiffness, all of which impact diastolic function and myocardial relaxation. The hormonal shifts that occurs during menopause contribute to a pro-inflammatory environment, endothelial dysfunction, and alteration in calcium handling within the heart; thus, driving development of HFpEF in postmenopausal women. As of 2025, no medical treatment exists or has been proved to reduce mortality caused ^^^ by HFpEF. The present disclosure provides methods of treating, preventing, decreasing, ameliorating, and / or reducing a heart failure condition in a subject. In some aspects, disclosed herein is a method of treating a subject with a heart failure condition, the method comprising administering to the subject a small molecule, wherein the small molecule prevents activation of a T helper 17 (Th17) cell or inhibits expression of ^^^ interleukin 17 (IL17). In some aspects, disclosed herein is a method of improving cardiac function in a subject in need thereof, the method comprising administering to the subject a small molecule, wherein the small molecule improves diastolic function in the subject relative to an untreated control. In some aspect disclosed herein is a method of reducing cardiac inflammation in a ^^^ subject in need thereof, the method comprising administering to the subject a small molecule, wherein the small molecule prevents activation of a T helper 17 (Th17) cell or inhibits expression of interleukin 17 (IL17). In some embodiments, the small molecule of any preceding aspect prevents activation of a T helper 17 (Th17) cell and inhibits expression of interleukin 17 (IL17). ^^^ In some embodiments, the small molecule is an inhibitor, including but not limited to reversible inhibitor, an irreversible inhibitor, a competitive inhibitor, a noncompetitive inhibitor, an uncompetitive inhibitor, or mixed inhibitors. In some embodiments, the small molecule is a peptide / polypeptide (including, but not limited to a fusion peptide / fusion polypeptide or a chimeric peptide / chimeric polypeptide), a nucleic acid (including, but not ^^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^limited to deoxyribose nucleic acid (DNA), ribose nucleic acid (RNA), or a chimeric nucleic acid), a chemical compound, an antibody, an aptamer, a surfactant, or any combinations thereof or any variants thereof. In some embodiments, the small molecule comprises an anti-IL17 antibody or an ^^ inhibitor of Th17 cell differentiation. In some embodiments, the anti-IL17 antibody comprises secukinumab, or a variant thereof. In some embodiments, the inhibitor of Th17 cell differentiation inhibits transcription factors selected from ROR^t, IRF4, BATF, FoxP3, T-bet, PPAR^, E-FABP, or SOCS. In some embodiments, the inhibitor of Th17 cell differentiation comprises S18-000003, A213, SHR168442, TMP778, BMS-986251, BMS-986313, A-9758,^^^ digoxin, FC99, Cpd1, JNJ-61803534, JNJ-54271074, SR2211, Ursolic acid, SR1001, TAK- 828F, GSK805, VPR-254, Bl119, CQMU151, CQMU152, BIX119, or a variant thereof. In some embodiments, the small molecule of any preceding aspect targets cardiac adipose tissue. In some embodiments, the method of any preceding aspect is applicable to other forms of heart failure known in the art including, but not limited to heart failure with preserved ^^^ ejection fraction, coronary artery diseases (e.g., angina and heart attacks), hypertensive heart disease, cardiomyopathies, congenital heart diseases, and arrythmia. In some embodiments, the heart failure condition includes, but is not limited to heart failure with preserved ejection fraction (HFpEF). In some embodiments, the method of any preceding aspect improves diastolic function in the subject relative to an untreated control. In some embodiments, the ^^^ method of any preceding aspect maintains systolic function in the subject relative to an untreated control. In some embodiments, the method of any preceding aspect reduces inflammation in the subject relative to an untreated control. In some embodiments, the method of any preceding aspect reduces adipocyte hypertrophy in the subject relative to an untreated control. ^^^ In some embodiments, the method of any preceding aspect involves administering a small molecule to inhibit Th17 cell activation or IL17 expression. In some embodiments, the method of any preceding aspect involves administering either one small molecule that inhibits Th17 cell activation or one small molecule that prevents expression of IL17. In some embodiments, the method of any preceding aspect involves administering two small molecules, ^^^ wherein one small molecule that inhibits Th17 cell activation and one small molecule that prevents expression of IL17. In some embodiments, the two small molecules can be administered simultaneously or concurrently. In some embodiments, the small molecule(s) of any preceding aspect may be administered in such amounts, time, and route deemed necessary in order to achieve the desired ^^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^result. The exact amount of the small molecule(s) of any preceding aspect will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the CVD, the particular the small molecule(s), the mode of administration, the mode of activity, and the like. The small molecule(s) of any preceding aspect are preferably ^^ formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the small molecule(s) of any preceding aspect will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the CVD being treated and the severity of the cardiac dysfunction; ^^^ the activity of the small molecule(s) of any preceding aspect employed; the specific small molecule(s); the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific small molecule(s) employed; the duration of the treatment; drugs used in combination or coincidental with the specific small molecule(s) employed; and like factors well known in the medical arts. ^^^ The small molecule(s) of any preceding aspect may be administered by any route. In some embodiments, the small molecule(s) of any preceding aspect are administered via a variety of routes, including oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, ^^^ buccal, enteral, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the small molecule(s) (e.g., the stability in the environment of the gastrointestinal tract), the condition of the subject (e.g., whether the subject is able to tolerate administration), etc. ^^^ The exact amount of the small molecule(s) of any preceding aspect required to achieve a therapeutically effective amount will vary from subject to subject, depending on species, age, and general condition of a subject, severity of the side effects, identity of the particular compound(s), mode of administration, and the like. In one aspect, disclosed herein are small molecule(s) of any preceding aspect and a ^^^ pharmaceutically acceptable carrier selected from an excipient, a diluent, a salt, a buffer, a stabilizer, a lipid, an emulsion, a nanoparticle, and a cream. One or more active agents can be administered in the “native” form or, if desired in the form of salts, esters, amides, prodrugs, or a derivative that is pharmacologically suitable. Salts, esters, amides, prodrugs, and other derivatives of the active agents can be prepared using standards procedures known to those ^^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^skilled in the art of synthetic organic chemistry and described, for example, by March (1992) Advanced Organic Chemistry; Reactions, Mechanisms, and Structure, 4thEd. N.Y. Wiley- Interscience. In some embodiments, the small molecule(s) of any preceding aspect are administered ^^ 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, or more times. In some embodiments, the small molecule(s) of any preceding aspect are administered ^^^ daily. In some embodiments, the small molecule(s) of any preceding aspect are administered every day, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, or more. In some embodiments, the small molecule(s) of any preceding aspect are administered every week, every 2 weeks, every 3 weeks, every 4 weeks, or more. In some embodiments, the small molecule(s) of any preceding aspect are administered every month, every 2 months, every ^^^ 3 months, every 4 months, every 5 months, every 6 months, every 7 months, every 8 months, every 9 months, every 10 months, every 11 months, every 12 months, or more. In some embodiments, the small molecule(s) of any preceding aspect are administered every year, every 2 years, every 3 years, every 4 years, every 5 years, or more. In some embodiments, the small molecule can be administered with an additional ^^^ therapeutic agent deemed necessary to minimize any symptoms, side effects, or complications caused by HFpEF. In some embodiments, the small molecule is administered simultaneously with the additional therapeutic agent. In some embodiments, the small molecule is administered concurrently with the additional therapeutic agent. Non-limiting examples of additional therapeutic agents include antibiotics, anti-inflammatory compounds, anesthetic, and sedatives. ^^^ In some embodiments, the antibiotic includes, but is not limited to penicillins (including, but not limited to amoxicillin, clavulanate and amoxicillin, ampicillin, dicloxacillin, oxacillin, and penicillin V potassium), tetracyclins (including, but not limited to demeclocycline, doxycycline, eravacycline, minocycline, omadacycline, sarecycline, and tetracycline), cephalosporins (cefaclor, cefadroxil, cefdinir, cephalexin, cefprozil, cefepime, ^^^ cefiderocol, cefotaxime, cefotetan, ceftaroline, cefazidme, ceftriaxone, and cefuroxime), quinolones (also referred to as fluoroquinolones include, but are not limited to ciprofloxacin, delafloxacin, levofloxacin, moxifloxacin, and gemifloxacin), lincomycins (including clindamycin and lincomycin), macrolides (including, but not limited to azithromycin, clarithromycin, erythromycin, and fidaxomicin (ketolide)), sulfonamides (including ^^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^sulfamethoxazole and trimethoprim, and sulfasalazine), glycopeptides (including, but not limited to dalbavancin, oritavancin, telavancin, and vancomycin), aminoglycosides (including, but not limited to gentamicin, tobramycin, and amikacin), carbapenems (including, but not limited to imipenem and cilastatin, meropenem, and ertapenem), and topical antibiotics ^^ (including, but not limited to neomycin, bacitracin, polymyxin B, and praxomine) used alone or in combination. In some embodiments, the anti-inflammatory compound is a non-steroidal anti- inflammatory compound including, but is not limited to aspirin, ibuprofen, ketoprofen, naproxen, steroids, glucocorticoids (including, but not limited to betamethasone, budesonide, ^^^ dexamethasone, hydrocortisone, hydrocortisone acetate, methylprednisolone, prednisolone, prednisone, and triamcinolone), methotrexate, sulfasalazine, lefunomide, anti-Tumor Necrosis Factor (TNF) medications, cyclophosphamide, and mycophenolate. In some embodiments, the anesthetic includes, but is not limited to chloroprocaine, procaine, tetracaine, lidocaine, bupivacaine, ropivacaine, mepivacaine, and levobupivacaine. In some embodiments, the ^^^ sedative include, but is not limited to barbiturates, benzodiazepines, nonbenzodiazepines hypnotics, antihistamines, muscle relaxants, opioids, and methaqualone, or derivatives thereof. In some embodiments, the subject is 65 years or older. In some embodiments, the subject is a postmenopausal woman. ^^^ A number of embodiments of the disclosure have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims. By way of non-limiting illustration, examples of certain embodiments of the present ^^^ disclosure are given below. EXAMPLES The following examples are set forth below to illustrate the compositions, devices, methods, and results according to the disclosed subject matter. These examples are not intended ^^^ to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative methods and results. These examples are not intended to exclude equivalents and variations of the present invention which are apparent to one skilled in the art. ^^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^Example 1: Strategies for targeting Th17 cells and IL17 for heart failure with preserved ejection fraction in aging. Recently, adipose tissue has been recognized as a highly active organ that integrates metabolic and immune functions. The aging adipose tissue plays a critical role in age-related ^^ physiological dysfunctions, serving as a major source of chronic low-grade inflammation. Interestingly, both preclinical and clinical studies have demonstrated that strategies aimed at targeting adipose tissue during aging can mitigate age-associated physical dysfunction and prolong healthspan. Aging induces an imbalance between pro-inflammatory and anti- inflammatory immune responses, contributing to the development of age-related diseases. Such ^^^ an imbalance in immunological phenotypes could lead to local inflammation through the release of biologically active substances. The adipose tissue that surrounds the heart is known as pericardial fat. In humans, pericardial fat encompasses both paracardial fat (PF) and epicardial (EPF). EPF is situated between the myocardium and visceral pericardium. PF is located externally to the parietal pericardium. Clinical studies have linked pericardial fat ^^^ volume to diastolic dysfunction and HFpEF, showing PF also plays a significant role. It has been reported a strong association between PF and the left ventricular eccentricity index in HFpEF patients. PF also shows a stronger correlation with cardiometabolic risk factors than EPF12, factors known to contribute to HFpEF. Although both PF and EPF volumes increase post-menopause in humans, only PF volume is significantly associated with estradiol decline. ^^^ Moreover, the relationship between PF and coronary artery calcification is influenced by menopausal status, whereas EPF shows no such association. Collectively, these studies underscore the role of PF in the development of HFpEF among postmenopausal women. The T cells act as immune sentinels and play a critical role in maintaining homeostasis and metabolic balance within adipose tissue. According to specific cytokine profiles and ^^^ functions documented in previous studies, it is widely recognized that naïve CD4+ T cells can differentiate into one of the T helper cell lineages [Th1, Th2, follicular helper T (Tfh) and Th17] or into regulatory T cells (Treg). Th1 cells produce proinflammatory cytokines like IFN-^. Similarly, Th17 cells produce the proinflammatory cytokine IL17. Th2 cells primarily elicit an anti-inflammatory response. In addition, Th17 cells could directly transdifferentiate ^^^ into Th1-like cells (Th1 / Th17) to produce IL17 and IFN-^. The Th2 cell specific cytokine IL4 acts as a negative regulator of Th1 and Th17 inflammation. By analyzing the T cell subsets in the PF of mice across different sexes and age using snRNA-sequencing, we identified 5 subclusters of CD4+ T cells (Tfh, Th17, Treg, Th1 / Th17 and Th2) and 3 subclusters of CD8+ T cells (cycling, proliferation and Tcm) and (Figures 1A and 1B). Trajectory analysis suggested ^^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^that Th1 / Th17 cells may originate from Th17 cells (Figure 1C). Notably, aging significantly increased the frequency of Th17 and Th1 / Th17 cells, with aged female mice exhibiting a higher accumulation of these subsets compared to their male counterparts (Figures 1C and 1D). Conversely, aged male mice showed a marked increase in Th2 cells relative to females, which ^^ may counterbalance the pro-inflammatory effects of Th17 and Th1 / Th17 cells (Figures 1C and 1D). Consistent with the T cell subcluster analysis, aging upregulated expression of IL17A and IFN-^ (cytokines secreted by Th17 and Th1 / Th17 cells) in PF, particularly in aged females (Figures 1E and 1F). IL17 is well-conserved in mammals, with high sequence similarity between human and mouse homologs. IL17 plays a central role in recruiting neutrophils and ^^^ macrophages and stimulating pro-inflammatory cytokine production. It also promotes IFN-^ expression by facilitating Th17-to-Th1 transdifferentiation. To model Th17 activation and IL17 production, lipid nanoparticles encapsulating IL17 mRNA (1.0 mg / kg) were injected into the PF of young male and female mice. Six weeks post-injection, IL17 mRNA induced PF remodeling (adipocyte hypertrophy and decreased number of multilocular adipocyte), ^^^ cardiomyocyte hypertrophy, increased CD68^ macrophage infiltration in the heart, and diastolic dysfunction, as evidenced by elevated E / E^ and IVRT and reduced rLSR (Figures 2H, 2I, and 2K). No significant differences were observed in EF or FS (Figure 2G), but impaired global longitudinal strain (GLS) was detected (Figure 2J). Neutralization of IL17 using secukinumab (anti-IL17A antibody; Figure 3A) improved diastolic function in aged mice ^^^ (Figures 3B and 3D), without affecting systolic function (Figure 3C). Improvement in diastolic parameters was associated with reduced inflammation and adipocyte hypertrophy in PF (Figures 3E and 3F). These data support that IL17 inhibition improves PF remodeling and diastolic dysfunction in aged mice. Collectively, the marked accumulation of proinflammatory Th17 and Th1 / Th17 cells,^^^ along with their cytokine product IL-17, plays a critical role in PF remodeling and disrupts PF- heart crosstalk. This contributes to age-associated HFpEF and highlights the therapeutic potential of targeting PF-derived IL17 signaling to mitigate age-related diastolic dysfunction. It is important to note that, beyond the association between PF and HFpEF, elevated IL-17 concentrations have been linked to more severe heart failure. Patients with higher IL17 levels ^^^ tend to experience more frequent current or prior hospitalizations for heart failure, higher New York Heart Association (NYHA) functional class, and elevated levels of N-terminal pro-B- type natriuretic peptide (NT-proBNP). Importantly, high IL-17 concentrations are independently associated with an increased risk of heart failure hospitalization and mortality. Additionally, HFpEF patients exhibit elevated levels of circulating Th17 cells. ^^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^It is worth to knowing that HFpEF is driven by multiple overlapping mechanisms, which vary across individuals and clinical subgroups. These include systemic inflammation, myocardial fibrosis and stiffness, cardiometabolic stress (obesity, diabetes), organ crosstalk, and age-related changes in the myocardium, vasculature, immune system and cellular ^^ senescence. Pirfenidone, approved for the treatment of idiopathic pulmonary fibrosis, is being investigated for HFpEF due to its anti-fibrotic, anti-inflammatory, and antioxidant properties. SGLT2 inhibitors (e.g., empagliflozin and dapagliflozin) have demonstrated significant benefits in HFpEF, as shown in the DELIVER and EMPEROR-Preserved trials. Their ^^^ mechanisms include metabolic reprogramming and potential anti-fibrotic effects. In contrast, the approach in the present disclosure is distinct, focusing on age-related changes in immune cell populations and PF-heart crosstalk, offering a novel immunomodulatory strategy for treating HFpEF. In summary, targeting Th17 cells and IL17 signaling represents a promising treatment ^^^ for HFpEF in the aging population. Experimental menthods In Figures 2A - 2K, IL17 mRNA (10 ^g) were directly injected into paracradial fat of young mice, and cardiac function was measured by echo. In Figures 3A – 3F, Secukinumab, ^^^ an FDA-approved IL17A-neutralizing antibody was injectied via tail vien in aged male and female C57BL / 6 mice (NIA aging cohort) : secukinumab (10 mg / kg weekly, IV); IgG1 (10 mg / kg weekly, IV).4 weeks later, histological anlsysis and cardiac function measurement were perfomed. Cardiac function assessment: Cardiac functions are assessed using the Vevo 3100 ^^^ Imaging System as in Figures 3A-3D. Images of left ventricles are captured at the parasternal long-axis and parasternal short-axis in both B- and M- modes. The apical 4-chamber view is used to acquire Doppler flow data using pulsed wave Doppler and to obtain tissue Doppler images. The EF and FS are measured using the cardiac measurement package under the LV trace. Cardiac global longitudinal strain and radial strain are measured on parasternal long-axis ^^^ view using the Vevo strain 2.0 package. To quantify the peak longitudinal strain rate and radial strain rate during early left ventricle filling, the “reverse peak” option is used. The mitral E wave, A wave and the mitral E’ wave and A’ wave, IVRT are measured using the cardiac measurement package. ^^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^Besides neutralizing IL17 by secukinumab, inhbition Th17 cell differentiation have beneficial effects as well. So the inhibitiors of key transcription factors of Th17 cell differentiation may also offer an effective thereapetutic stratergy. Th17 cells are controlled by several transcription factors such as ROR^t, IRF4, BATF, FoxP3, T-bet, PPAR^, E-FABP, and ^^ SOCSs. Specifically, ROR^t is the key trannscription factor. It will be apparent to those skilled in the art that various modifications and variations can be made in the present disclosure without departing from the scope or spirit of the invention. Other embodiments of the disclosure will be apparent to those skilled in the art from ^^^ consideration of the specification and practice of the methods disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims. ^^^

Claims

^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^CLAIMS What is claimed is:

1. A method of treating a subject with a heart failure condition, the method comprising administering to the subject a therapeutically effective amount of a small molecule and pharmaceutically acceptable carrier, wherein the small molecule prevents activation of a T helper 17 (Th17) cell or inhibits expression of interleukin 17 (IL17).

2. The method of claim 1, wherein the small molecule comprises an anti-IL17 antibody or an inhibitor of Th17 cell differentiation.

3. The method of claim 2, wherein the anti-IL17 antibody comprises secukinumab, or a variant thereof.

4. The method of claim 2, wherein the inhibitor of Th17 cell differentiation inhibits transcription factors selected from ROR^t, IRF4, BATF, FoxP3, T-bet, PPAR^, E-FABP, or SOCS.

5. The method of claim 2, wherein the inhibitor of Th17 cell differentiation comprises S18-000003, A213, SHR168442, TMP778, BMS-986251, BMS-986313, A-9758, digoxin, FC99, Cpd1, JNJ-61803534, JNJ-54271074, SR2211, Ursolic acid, SR1001, TAK-828F, GSK805, VPR-254, Bl119, CQMU151, CQMU152, BIX119, or a variant thereof.

6. The method of any one of claims 1-5, wherein the small molecule prevents activation of a T helper 17 (Th17) cell and inhibits expression of interleukin 17 (IL17).

7. The method of any one of claims 1-6, wherein the heart failure condition comprises heart failure with preserved ejection fraction (HFpEF).

8. The method of any one of claims 1-7, wherein the method improves diastolic function in the subject relative to an untreated control.

9. The method of any one of claims 1-8, wherein the method maintains systolic function in the subject relative to an untreated control. ^^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^10. The method of any one of claims 1-9, wherein the method reduces inflammation in the subject relative to an untreated control.

11. The method of any one of claims 1-10, wherein the method reduces adipocyte hypertrophy in the subject relative to an untreated control.

12. The method of any one of claims1-11, wherein the subject is 65 years or older.

13. The method of any one of claims 1-12, wherein the subject is a postmenopausal woman.

14. A method of improving cardiac function in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a small molecule and pharmaceutically acceptable carrier, wherein the small molecule improves diastolic function in the subject relative to an untreated control.

15. The method of claim 14, wherein the small molecule comprises an anti-IL17 antibody or an inhibitor of Th17 cell differentiation.

16. The method of claim 15, wherein the anti-IL17 antibody comprises secukinumab, or a variant thereof.

17. The method of claim 15, wherein the inhibitor of Th17 cell differentiation inhibits transcription factors selected from ROR^t, IRF4, BATF, FoxP3, T-bet, PPAR^, E-FABP, or SOCS.

18. The method of claim 15, wherein the inhibitor of Th17 cell differentiation comprises S18-000003, A213, SHR168442, TMP778, BMS-986251, BMS-986313, A-9758, digoxin, FC99, Cpd1, JNJ-61803534, JNJ-54271074, SR2211, Ursolic acid, SR1001, TAK-828F, GSK805, VPR-254, Bl119, CQMU151, CQMU152, BIX119, or a variant thereof.

19. The method of any one of claims 14-18, wherein the small molecule prevents activation of a T helper 17 (Th17) cell. ^^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^20. The method of any one of claims 14-19, wherein the small molecule inhibits expression of interleukin 17 (IL17).

21. The method of any one of claims 14-20, wherein the method treats or prevent a heart failure condition. The method of claim 21, wherein the heart failure condition comprises heart failure with preserved ejection fraction (HFpEF).

23. The method of any one of claims 14-22, wherein the method improves diastolic function in the subject relative to an untreated control.

24. The method of any one of claims 14-23, wherein the method maintains systolic function in the subject relative to an untreated control.

25. The method of any one of claims 14-24, wherein the method reduces inflammation in the subject relative to an untreated control.

26. The method of any one of claims 14-25, wherein the method reduces adipocyte hypertrophy in the subject relative to an untreated control.

27. The method of any one of claims 14-26, wherein the subject is 65 years or older.

28. The method of any one of claims 14-27, wherein the subject is a postmenopausal woman.

29. A method of reducing cardiac inflammation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a small molecule and pharmaceutically acceptable carrier, wherein the small molecule prevents activation of a T helper 17 (Th17) cell or inhibits expression of interleukin 17 (IL17).

30. The method of claim 29, wherein the small molecule comprises an anti-IL17 antibody or an inhibitor of Th17 cell differentiation. ^^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^31. The method of claim 30, wherein the anti-IL17 antibody comprises secukinumab, or a variant thereof.

32. The method of claim 30, wherein the inhibitor of Th17 cell differentiation inhibits transcription factors selected from ROR^t, IRF4, BATF, FoxP3, T-bet, PPAR^, E-FABP, or SOCS.

33. The method of claim 30, wherein the inhibitor of Th17 cell differentiation comprises S18-000003, A213, SHR168442, TMP778, BMS-986251, BMS-986313, A-9758, digoxin, FC99, Cpd1, JNJ-61803534, JNJ-54271074, SR2211, Ursolic acid, SR1001, TAK-828F, GSK805, VPR-254, Bl119, CQMU151, CQMU152, BIX119, or a variant thereof.

34. The method of any one of claims 29-33, wherein the small molecule prevents activation of a T helper 17 (Th17) cell and inhibits expression of interleukin 17 (IL17).

35. The method of any one of claims 29-34, wherein the method treats or prevent a heart failure condition.

36. The method of claim 35, wherein the heart failure condition comprises heart failure with preserved ejection fraction (HFpEF).

37. The method of any one of claims 29-36, wherein the method improves diastolic function in the subject relative to an untreated control.

38. The method of any one of claims 29-37, wherein the method maintains systolic function in the subject relative to an untreated control.

39. The method of any one of claims 29-38, wherein the method reduces adipocyte hypertrophy in the subject relative to an untreated control.

40. The method of any one of claims 29-39, wherein the subject is 65 years or older.

41. The method of any one of claims 29-40, wherein the subject is a postmenopausal woman. ^^^

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