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Heart failure with preserved ejection fraction (HFpEF) is a major public health challenge, affecting millions worldwide and placing a significant burden on healthcare systems due to high hospitalization rates and limited treatment options. HFpEF is characterized by impaired cardiac relaxation, or diastolic dysfunction. However, there are no therapies that directly treat the primary feature of the disease. This is due in part to the complexity of normal diastolic function, and the challenge of isolating the mechanisms responsible for dysfunction in HFpEF. Without a clear understanding of the mechanisms driving diastolic dysfunction, progress in treatment development has been slow. In this review, we highlight three key areas of molecular dysregulation directly underlying impaired cardiac relaxation in HFpEF: altered calcium sensitivity in the troponin complex, impaired phosphorylation of myosin-binding protein C (cMyBP-C), and reduced titin compliance. We explore how targeting these pathways can restore normal relaxation, improve diastolic function, and potentially provide new therapeutic strategies for HFpEF treatment. Developing effective HFpEF therapies requires precision targeting to balance systolic and diastolic function, avoiding both upstream non-specificity and downstream rigidity. This review highlights three rational molecular targets with a strong mechanistic basis and potential for therapeutic success.

Type 2 diabetes mellitus (T2DM) is a metabolic disease and comorbidity associated with several conditions, including cardiac dysfunction leading to heart failure with preserved ejection fraction (HFpEF), in turn resulting in T2DM-induced cardiomyopathy (T2DM-CM). However, the molecular mechanisms underlying the development of T2DM-CM are poorly understood. It is hypothesized that molecular alterations in myopathic genes induced by diabetes promote the development of HFpEF, whereas cardiac myosin inhibitors can rescue the resultant T2DM-mediated cardiomyopathy. To test this hypothesis, a Leptin receptor-deficient db/db homozygous (Lepr db/db) mouse model was used to define the pathogenesis of T2DM-CM. Echocardiographic studies at 4 and 6 months revealed that Lepr db/db hearts started developing cardiac dysfunction by four months, and left ventricular hypertrophy with diastolic dysfunction was evident at 6 months. RNA-seq data analysis, followed by functional enrichment, revealed the differential regulation of genes related to cardiac dysfunction in Lepr db/db heart tissues. Strikingly, the level of cardiac myosin binding protein-C phosphorylation was significantly increased in Lepr db/db mouse hearts. Finally, using isolated skinned papillary muscles and freshly isolated cardiomyocytes, CAMZYOS® (mavacamten, MYK-461), a prescription heart medicine used for symptomatic obstructive hypertrophic cardiomyopathy treatment, was tested for its ability to rescue T2DM-CM. Compared with controls, MYK-461 significantly reduced force generation in papillary muscle fibers and cardiomyocyte contractility in the db/db group. This line of evidence shows that 1) T2DM-CM is associated with hyperphosphorylation of cardiac myosin binding protein-C and 2) MYK-461 significantly lessened disease progression in vitro, suggesting its promise as a treatment for HFpEF.

Background cMyBP‐C (Cardiac myosin binding protein‐C) regulates cardiac contraction and relaxation. Previously, we demonstrated that elevated myocardial S‐glutathionylation of cMyBP‐C correlates with diastolic dysfunction (DD) in animal models. In this study, we tested whether circulating S‐glutathionylated cMyBP‐C would be a biomarker for DD. Methods and Results Humans, African Green monkeys, and mice had DD determined by echocardiography. Blood samples were acquired and analyzed for S‐glutathionylated cMyBP‐C by immunoprecipitation. Circulating S‐glutathionylated cMyBP‐C in human participants with DD (n=24) was elevated (1.46±0.13‐fold, P=0.014) when compared with the non‐DD controls (n=13). Similarly, circulating S‐glutathionylated cMyBP‐C was upregulated by 2.13±0.47‐fold (P=0.047) in DD monkeys (n=6), and by 1.49 (1.22–2.06)‐fold (P=0.031) in DD mice (n=5) compared with the respective non‐DD controls. Circulating S‐glutathionylated cMyBP‐C was positively correlated with DD in humans. Conclusions Circulating S‐glutathionylated cMyBP‐C was elevated in humans, monkeys, and mice with DD. S‐glutathionylated cMyBP‐C may represent a novel biomarker for the presence of DD.

Background: Dilated cardiomyopathy (DCM) is a relatively common clinical cardiac condition, and its progression will eventually lead to heart failure. Cardiac myosin-binding protein C (cMyBP-c) plays a vital role in the diastolic and contractile function of the heart muscle. At present, most of the relevant researches are focused on the genetic level. Our study discusses the expression of cMyBP-C in patients with DCM and its potential clinical application. Methodology: One hundred and twenty-two subjects were selected from the First Affiliated Hospital of Nanjing Medical University from August 2016 to October 2017. They were divided into two groups according to the left ventricular end-diastolic dimension (LVDd) as measured by echocardiography: normal (n = 34) and left ventricular enlargement (LVE) groups (n = 88). The LVE group was further divided into two subgroups according to the etiology: DCM (n = 57), and LVE due to hypertension (LVEH, n = 31). The left ventricular ejection fraction (EF%) was also defined in each group. Enzyme-linked immunosorbent assay (ELISA) was used for the determination of cMyBP-C in the serum. Results: (1) Serum cMyBP-C concentration was higher in DCM than in LVEH and control groups (P < 0.05) and (2) the LVDd, EF%, creatinine (Cr), urea (Ur), and uric acid (UA) in the DCM group were significantly higher than those in the LVEH group (P < 0.05). Conclusion: The serum level of cMyBP-C is expected to become a new biomarker for the diagnosis of DCM. Cr, Ur, and UA may be factors contributing to the development of DCM.

Myocardial injury is associated with inflammation and fibrosis. Cardiac myosin-binding protein-C (cMyBP-C) is cleaved by µ-calpain upon myocardial injury, releasing C0-C1f, an N-terminal peptide of cMyBP-C. Previously, we reported that the presence of C0-C1f is pathogenic within cardiac tissue and is able to activate macrophages. Fibroblasts also play a crucial role in cardiac remodeling arising from ischemic events, as they contribute to both inflammation and scar formation. To understand whether C0-C1f directly modulates fibroblast phenotype, we analyzed the impact of C0-C1f on a human fibroblast cell line in vitro by performing mRNA microarray screening, immunofluorescence staining, and quantitative real-time PCR. The underlying signaling pathways were investigated by KEGG analysis and determined more precisely by targeted inhibition of the potential signaling cascades in vitro. C0-C1f induced pro-inflammatory responses that might delay TGFβ-mediated myofibroblast conversion. TGFβ also counteracted C0-C1f-mediated fibroblast activation. Inhibition of TLR4 or NFκB as well as the delivery of miR-146 significantly reduced C0-C1f-mediated effects. In conclusion, C0-C1f induces inflammatory responses in human fibroblasts that are mediated via TRL4 signaling, which is decreased in the presence of TGFβ. Specific targeting of TLR4 signaling could be an innovative strategy to modulate C0-C1f-mediated inflammation.

Enhanced cardiac contractile function with increased sarcomere length (SL) is, in part, mediated by a decrease in the radial distance between myosin heads and actin. The radial disposition of myosin heads relative to actin is modulated by cardiac myosin binding protein-C (cMyBP-C), suggesting that cMyBP-C contributes to the length-dependent activation (LDA) in the myocardium. However, the precise roles of cMyBP-C in modulating cardiac LDA are unclear. To determine the impact of cMyBP-C on LDA, we measured isometric force, myofilament Ca2+-sensitivity (pCa50) and length-dependent changes in kinetic parameters of cross-bridge (XB) relaxation (krel), and recruitment (kdf) due to rapid stretch, as well as the rate of force redevelopment (ktr) in response to a large slack-restretch maneuver in skinned ventricular multicellular preparations isolated from the hearts of wild-type (WT) and cMyBP-C knockout (KO) mice, at SL’s 1.9µm or 2.1µm. Our results show that maximal force was not significantly different between KO and WT preparations but length-dependent increase in pCa50 was attenuated in the KO preparations. pCa50 was not significantly different between WT and KO preparations at long SL (5.82±0.02 in WT vs. 5.87±0.02 in KO), whereas pCa50 was significantly different between WT and KO preparations at short SL (5.71±0.02 in WT vs. 5.80±0.01 in KO; p