Icosapent ethyl, a high-purity ethyl ester of eicosapentaenoic acid (EPA), has demonstrated cardiovascular benefit in clinical trials; however, its effects on post-myocardial infarction (MI) cardiac remodeling and the underlying cellular mechanisms remain incompletely understood. Here, we investigated the role of icosapent ethyl in regulating post-MI remodeling using a murine MI model with myeloid-specific deletion of the omega-3 fatty acid receptor GPR120. Icosapent ethyl treatment significantly improved survival, preserved left ventricular systolic function, attenuated adverse ventricular remodeling and interstitial fibrosis, reduced cardiomyocyte apoptosis, and preserved myocardial microvascular density after MI. The protective effects of icosapent ethyl were markedly attenuated in myeloid GPR120-deficient mice. Mechanistically, icosapent ethyl activated GPR120 signaling in myeloid cells, suppressed CXCL10 expression, and reduced recruitment of proinflammatory CXCR3+ leukocytes into the infarcted myocardium. Pharmacological inhibition of CXCR3 rescued adverse cardiac remodeling in myeloid GPR120-deficient mice, supporting a functional link between myeloid GPR120 activation and CXCR3-dependent inflammatory responses. These findings identify the myeloid GPR120-CXCL10/CXCR3 signaling axis as a critical immunomodulatory pathway by which icosapent ethyl improves post-MI cardiac remodeling, highlighting therapeutic potential of icosapent ethyl to limit inflammation-driven cardiac dysfunction after ischemic injury.
Canonical Wnt/β-catenin pathway activation can promote cardiomyocyte (CM) cell cycle activity, but translation is limited by off-target and functional liabilities associated with global pathway activation. We identified two small molecules, LRN9 and DF6, which potentiate Wnt/β-catenin signaling through a non-GSK3β mechanism and induce CM cell-cycle re-entry in human iPSC-CMs. In cardiac organoids, the effects was largely restricted to CMs and were accompanied by minimal changes in contractile and relaxation parameters, in contrast to reported impairment with GSK3β inhibition. RNA-sequencing showed enrichment of DNA replication and cell-cycle pathways. In embryonic zebrafish, both compounds increased ventricular growth consistent with CM hyperplasia.
Cardiac mitochondrial remodelling is a hallmark of type 2 diabetes-linked heart failure (T2DM-HF). We previously reported that mitochondrial morphological changes occur in early-stage disease and identified down-regulation of the mitochondrial protein Miro1 (Rhot1). Neuronal Miro1 regulates mitochondrial movement but the role of cardiac Miro1 remains poorly understood. Therefore, we generated a cardiac-specific Miro1 knockout (Miro1cko) mouse model to investigate how cardiomyocyte-Miro1 deficiency affects cardiac and mitochondrial structure-function. Miro1cko mice compared to controls develop mild diastolic and systolic dysfunction and electrical abnormalities, cellular hypertrophy and fibrosis. Miro1cko leads to aberrant mitochondrial respiration and elevated H₂O₂ production, consistent with electron microscopy showing disrupted cristae morphology, with putative links to Myosin19 down-regulation. Three-dimensional electron microscopy identified mitochondrial remodelling with interfibrillar mitochondria (IFM) ∼50% smaller with an increased surface complexity. Since fusion-fission protein expression was unchanged these data identify Miro1 as a regulator of mitochondrial morphology. Mitochondrial density increases (34% Miro1cko; 30% control), with abnormal IFM clustering, which we suggest is associated with impaired mitophagy since PINK1 and Parkin are down-regulated (∼80% and ∼ 60% respectively) and imaging flow cytometry of isolated primary cardiomyocytes identified an ∼2-fold reduction to mitochondrial clearance indicative of blunted mitophagy. Heterozygous knockout mice, which display a milder cardiac phenotype, rapidly developed HF symptoms when given a high fat diet with L-NAME. In conclusion, loss of Miro1 drives multiple aberrant mitochondrial remodelling events culminating in cardiac dysfunction and predisposes towards accelerated metabolic-HF development. Loss of Miro1 may represent a critical mechanistic link in T2DM-HF pathogenesis and therefore a potential therapeutic target.
Fibrosis is a maladaptive process common to many diseases throughout the human body. During fibroblast activation, the cell undergoes metabolic reprogramming to increase glycolysis and support increased cellular growth. Alterations in metabolism have been shown to play a significant role in determining cell identity and function. However, the contribution of many ancillary metabolic pathways in cardiac fibroblasts remains poorly defined. Here we investigate the role of Gfpt2, the rate-limiting enzyme of the hexosamine biosynthesis pathway, and metabolism in fibroblast activation. We demonstrate loss of Gfpt2 in cardiac fibroblasts results in a shift towards an activated fibroblast phenotype suggesting Gfpt2 acts as a regulator of fibroblast activation. Furthermore, untargeted metabolomics identifies glutathione metabolism as a downstream pathway and shows decreased glutathione following Gfpt2 loss. Consistent with this result, treatment with glutathione following either Gfpt2 knockdown or TGFβ stimulation is sufficient to prevent fibroblast activation. Finally, screening fibroblasts from other tissues illustrates that the Gfpt2-glutathione regulatory axis is shared across some, but not all, tested fibroblast populations. Overall, our study highlights the nuanced role of metabolism in cardiac fibroblasts and identifies a novel regulatory axis that could be a shared pathway in fibroblast activation.
Heart failure with preserved ejection fraction (HFpEF) predominantly affects older women. The widely used two-hit model of HFpEF has mostly been applied to young animals and fails to induce HFpEF in female mice, limiting clinical and epidemiologic relevance. We challenged 19-month-old female mice with the two-hit protocol. Unlike young female mice, aged mice developed HFpEF, coinciding with impaired cardiac mitochondrial function and disrupted mitochondrial proteostasis. Our findings connect aging with increased female susceptibility to cardiometabolic stress and demonstrate the contribution of mitochondrial dysfunction in HFpEF. Incorporating aging into the two-hit model enables future investigation of sex-specific mechanisms of HFpEF.
Hypertrophic cardiomyopathy (HCM) is a condition characterized by variable patterns of myocardial hypertrophy. Progressive functional remodeling of material properties contributes to symptoms, disease progression, and variability in treatment response. However, it is not clear how these properties interact to determine cardiac performance and response to treatment. We quantified how cardiac anatomy variability, functional remodeling, and pharmacological treatment influence the relative importance of biophysical mechanisms that govern cardiac function. We built five four-chamber electromechanical heart models representing anatomical clusters. We performed global sensitivity analyses on 46 parameters across 32 outputs. We repeated this process 18 times to model different types of functional remodeling and two times to model mavacamten and aficamten. Across all representative HCM phenotypes, sensitivity profiles were preserved. Within the parameter ranges examined, ventricular afterload explained the largest share of variance in hemodynamic outputs across anatomies (up to 69%). Functional remodeling led to shifts in parameter importance, mostly when ventricular stiffness was increased. The modeling of pharmacological treatments led to modest but targeted changes, with mavacamten and aficamten producing comparable effects, particularly for outputs related to arterial pressures. Across major anatomical phenotypes of hypertrophic cardiomyopathy, functional remodeling, rather than anatomy alone, reshaped the relative importance of cellular, myocardial, and loading-related parameters, with the largest shifts under increased ventricular stiffness and under aficamten in obstructive physiology. These hypothesis-generating results suggest that the integration of biomarkers reflecting ventricular-arterial coupling, myocardial stiffness, and contractile state may help anticipate symptoms and treatment response in HCM.
Increased cardiac risk in diabetes has been linked to disturbances in myocardial metabolism. Circulating and cardiac fructose levels are elevated in diabetes but the relationship between fructose and cardiac pathology is unclear. The goal of this study was to assess myocardial capacity for fructose metabolism and evaluate the time-course of cardiac fructose accumulation relative to the emergence of cardiac functional impairment in diabetic rats. Cardiac capability for fructose metabolism to support function was demonstrated in ex vivo working mouse hearts perfused with 11 mM fructose. Using isotope-labeled fructose [U13C], we observed 13C enrichment into downstream metabolites glyceraldehyde, glycerate, pyruvate, lactate, and mitochondrial acetyl-CoA in perfused working mouse hearts. Metabolite profiling demonstrated that relative to glucose, myocardial fructose metabolism favored glycerate production. In diabetic rats (streptozotocin, 55 mg/kg), cardiac fructose elevation was evident prior to the onset of cardiac dysfunction. This study provides proof-of-principle evidence that fructose metabolism is operational in the working heart and identifies key fructose-derived metabolites. The finding that cardiac fructose elevation precedes functional impairment supports the contention that fructose may be an early instigator of diabetic cardiomyopathy and further investigation is now warranted. New and Noteworthy (<75 words) Circulating and cardiac fructose levels are elevated in diabetes but the relationship between fructose and cardiac pathology is unclear. This study provides proof-of-principle evidence that fructose metabolism is operational in the working heart and identifies that cardiac fructose metabolism favors production of glycerate. In diabetes, cardiac fructose elevation precedes functional impairment supporting the contention that fructose may be an early instigator of diabetic cardiomyopathy.
Biallelic titin truncation variants (TTNtvs) are linked to severe cardiac and skeletal muscle diseases, due to unclear mechanisms. Using induced pluripotent stem cell-derived cardiomyocytes from a biallelic TTNtv patient with dilated cardiomyopathy, we investigated sarcomere structure/function. Only the longest of the TTNtvs was detected as protein, and this nearly full-length titin was incorporated into the sarcomere. Subtle structural alterations occurred, with shortened A-bands observed in a subset of sarcomeres. Resulting reduction and imbalance of force development was linked to lowered contractility, and many sarcomeres being stretched by their neighbors. Thus, inefficient sarcomere assembly and interaction promotes cardiomyopathy in biallelic TTNtv.
Limited proliferative capacity of cardiomyocytes (CMs) underlies persistent CMs loss and cardiac dysfunction after myocardial infarction (MI). Although neonatal mammalian hearts retain transient regenerative potential, the molecular mechanisms governing this process remain incompletely understood. Protein phosphatase 2A (PP2A) has been implicated in cardiac protection; however, its role in CMs proliferation and heart regeneration is unclear. Here, using neonatal mouse MI models, cardiomyocyte-specific PP2Acα knockdown mice, pharmacological inhibition with LB-100, adenoviral mediated gain and loss of function approaches, and transcriptomic analysis, we investigated the functional significance and molecular mechanism of PP2Acα in cardiac regeneration. We found that PP2Acα was highly expressed in neonatal hearts, declined with postnatal maturation, and was reinduced following neonatal MI. Cardiomyocyte-specific PP2Acα knockdown markedly reduced CMs proliferation, impaired neonatal heart regeneration, exacerbated post MI cardiac dysfunction, and increased fibrosis, while pharmacological inhibition of PP2A similarly suppressed CMs proliferation both in vivo and in vitro. In contrast, PP2Acα overexpression significantly enhanced mitotic activity in neonatal mouse cardiomyocytes. Mechanistically, co-immunoprecipitation and molecular docking analyses revealed that PP2Acα directly interacted with Yes-associated protein (YAP) and reduced its phosphorylation, thereby promoting YAP nuclear translocation and activation of cell cycle-related gene transcription. YAP knockdown abolishes PP2Acα-induced cardiomyocyte proliferation. Conversely, LB-100 increased YAP phosphorylation without altering its mRNA expression, indicating regulation dependent on phosphatase activity. Collectively, these findings identify PP2Acα as a critical phosphatase that promotes neonatal cardiac regeneration by directly dephosphorylating YAP and activating the Hippo-YAP signaling axis, uncovering a previously unrecognized regulatory mechanism controlling cardiomyocyte proliferation and highlighting a potential therapeutic target for cardiac repair.
Heterozygosity for the pathogenic missense TBX5 (T-box transcription factor 5) variant p.G125R, identified in members of a family presenting with atypical Holt-Oram syndrome, is associated with supraventricular arrhythmias, including atrial fibrillation and disrupted sinus rhythm. Tbx5+/G125R mice recapitulated major aspects of the patient phenotype, including increased susceptibility for atrial arrhythmias, and revealed deregulation of the adult atrial cardiomyocyte transcriptional regulatory network and epigenetic state. Because TBX5 has also been implicated in the development and function of the sinus node and atria, and both patients and Tbx5+/G125R mice present with indications for sinus node dysfunction, we explored the impact of TBX5-p.G125R on gene expression in the fetal and adult sinus node and atria using spatial transcriptomics. We found that TBX5-p.G125R-mediated transcriptional alterations in the atria are initiated prior to birth, culminating in atrial arrhythmias in adult mice, while prenatal sinus node development and transcriptome were largely unaffected. However, TBX5-p.G125R induces a transcriptional state change in adult sinus node pacemaker cardiomyocytes, modifying pacemaker electrophysiology and disrupting intrinsic sinus node function. We conclude that alterations driven by TBX5-p.G125R in the transcriptional state of the postnatal sinus node contribute to sinus node dysfunction and atrial arrhythmias in adult Tbx5+/G125R mice. This emphasizes the critical role of TBX5 in maintaining pacemaker cardiomyocyte state and function.
The pericardial space is a biologically active inflammatory and cellular microenvironment with growing relevance to cardiac disease and surgical practice. Pericardial fluid contains bioactive mediators that frequently exceed systemic concentrations, and the anatomical proximity of this compartment to the myocardium highlights its potential role in cardiac pathology and post-surgical complications. Despite increasing recognition of its importance, the immune biology of the pericardial space remains incompletely characterized, and significant gaps persist in our understanding of its molecular and cellular dynamics. Available evidence indicates that pericardial cytokines, chemokines, and immune cell populations exhibit disease- and injury-specific patterns with relevance in myocardial ischemia, heart failure, cardiac transplantation, and post-operative atrial fibrillation. Following cardiac surgery, pericardial fluid sampled at pericardial opening and from post-operative mediastinal drainage demonstrates a compartmentalized inflammatory response with elevated pro-inflammatory mediators that exceed corresponding systemic levels. In the setting of ischemic injury, pericardial fluid is enriched in markers of tissue remodelling and fibrosis. After myocardial infarction, neutrophils become the dominant inflammatory cell, while resident pericardial macrophages are depleted but subsequently recover during the reparative phase. Collectively, these findings support a framework in which the pericardial space functions as a dynamic signalling reservoir that both reflects and modulates cardiac inflammatory and reparative processes. This review summarizes the current evidence on pericardial immune cells, cytokines, chemokines, and emerging molecular mediators across cardiac surgical populations and the spectrum of ischemic injury, heart failure, and post-operative atrial fibrillation.
ErbB receptor tyrosine kinases orchestrate phosphorylation-based signaling in response to extracellular ligands and are key drivers in cancer biology. Although ErbB-targeted therapies have transformed cancer care, some agents cause cardiac adverse events. Yet, the acute phosphorylation programs engaged by ErbB ligands in the adult heart remain incompletely defined. Here, we applied in vivo quantitative phosphoproteomics with dual enrichment using TiO₂ and anti-phosphotyrosine antibodies to map acute cardiac phosphorylation responses to epidermal growth factor (EGF; EGFR/ErbB1) and neuregulin-1β (NRG1β; ErbB3/ErbB4) in adult mouse hearts. EGF triggered robust receptor tyrosine kinase signaling, convergence with insulin-associated nodes independent of insulin receptor activation, and phosphorylation of calcium-handling proteins including phospholamban, SERCA, NCX1, and CaV1.2, implicating CaMK2δ. NRG1β elicited a coordinated ErbB-dependent response featuring activation of Akt, MAPK, and stress kinases, with engagement of sarcomere and metabolic modules. Comparative analysis identified shared core signaling alongside ligand-specific differences in kinase and transcription factor phosphorylation, with EGF displaying broader network breadth. These data provide a phosphorylation-centric framework for ligand-resolved ErbB signaling in the heart and offer mechanistic insight into how ErbB-targeted therapies may influence cardiac function.
Cardiovascular diseases are strongly associated with metabolic disorders; particularly type 2 diabetes mellitus (T2DM), which profoundly alters cardiac energy metabolism. Quercetin (QCT), a dietary polyphenol with antioxidant and cardioprotective properties, has been shown to improve mitochondrial function in various disease settings. This study evaluated the effects of chronic QCT supplementation (20 mg/kg/day for 6 weeks) on antioxidant capacity and bioenergetic parameters in cardiac tissue of 6-month-old male Zucker Diabetic Fatty (ZDF) rats. As expected, T2DM caused significant hyperglycaemia and increased body weight in ZDF rats. This was accompanied by decreased plasma superoxide dismutase (SOD) and catalase (CAT) activity, together with increased lactate dehydrogenase (LDH) activity. Our observations revealed significant upregulation of Nrf2/Keap1 pathway and higher lipid peroxidation in response to T2DM. In isolated cardiac mitochondria, T2DM reduced oxygen consumption under States 2-4 respiration, as well as during respiration induced through complexes I and II. Chronic QCT supplementation significantly increased glutathione peroxidase (GPx4) expression and favourably modulated Bax/Bcl2 ratio, indicating anti-apoptotic, anti-ferroptotic, and antioxidant properties. Additionally, QCT administration reversed the effects of T2DM, increasing SOD and CAT activities and decreasing LDH activity. However, chronic QCT administration did not normalize respiration rates measured in isolated mitochondria. These findings indicate that T2DM is associated with alterations in cardiac bioenergetic parameters while QCT enhanced antioxidant defenses but did not normalize respiration measured in isolated mitochondria. The results suggest antioxidant therapy alone may by insufficient to normalize cardiac bioenergetic alterations associated with T2DM, highlighting the need for further studies targeting mitochondrial-related mechanisms.
AIMS:Small-conductance Ca2+-activated potassium channels (SK) are increasingly investigated as therapeutic targets for atrial fibrillation. Emerging evidence, however, indicates their functional relevance in ventricular pathologies. This study investigates the expression, localization, and functional role of SK2 and SK3 channel subtypes in ventricular myocardium from patients with and without valvular disease-associated remodeling. METHODS AND RESULTS:Human ventricular tissue was obtained from 125 patients undergoing cardiac surgery. mRNA levels of KCNN2 and KCNN3 were quantified with RT-qPCR. Protein levels and localization of SK2 and SK3 were analyzed via immunohistochemistry. Functional responses were evaluated by optical mapping of living ventricular myocardial slices. Gene expression was not significantly altered in remodeled myocardium. SK2 and SK3 were located in striated patterns, colocalizing with L-type Ca2+ channels in all patients. SK3 was also present at intercalated discs, although this pattern was significantly reduced in remodeled myocardium. Functionally, SK channels were inactive in non-remodeled myocardium, with neither apamin nor SKA-31 altering action potential duration (APD). In contrast, in remodeled myocardium, apamin prolonged and SKA-31 shortened APD. This response to SKA-31 was more pronounced in patients with reduced ejection fraction. Mechanistically, SKA-31 effects were abolished by L-type Ca2+ channel blockade or CaMKII inhibition, but not by PKA inhibition, suggesting that SK activation is Ca2+ and CaMKII-dependent. CONCLUSIONS:SK channels become functionally upregulated in the early stages of ventricular remodeling despite the absence of gene expression changes. SK activation might rely on post-translational modifications and calcium handling alterations. These findings highlight the need for caution in targeting SK channels therapeutically.
BACKGROUND:Estrogens affect repolarization and may act as phenotype modifiers in long QT syndrome (LQTS). In a LQT2 patient with the G628S-KCNH2 mutation (normal CACNA1C genes) the occurrence of arrhythmia-related symptoms followed 17-β estradiol (E2) administration. This study aims to test whether a mechanistic link can be established between the two events. METHODS:Membrane potential, ICaL and IKr were measured from mutant (LQT2) and wild-type (WT) hiPS-CMs exposed to 10 nM E2. Adequacy of E2 effects in accounting for patient's electrical phenotype was tested by in silico simulations using a "population" approach. Molecular characterization was carried out by qPCR and immunocytochemistry. RESULTS:LQT2 hiPS-CMs were characterized by marked prolongation of action potential duration (APD) and susceptibility to early afterdepolarizations (EADs), thus recapitulating the LQT2 phenotype. In LQT2 hiPS-CMs, IKr was absent, the ICaL window was increased and the recovery from inactivation was delayed. E2 reversed mutation's effects on APD and ICaL window, but failed to restore IKr and reduce EADs prevalence. E2 also introduced a fast component in ICaL recovery which contributed to ICaL availability during the AP plateau. E2 did not change the expression of KCNH2 channels, E2 receptors (GPER) and CaV1.2 channels (CACNA1C). Simulations indicate that the changes in ICaL gating are a major determinant of APD prolongation and EADs associated with the KCNH2 mutation. CONCLUSIONS:The KCNH2 mutation was associated with ICaL gating abnormalities crucially contributing to APD prolongation, which were largely corrected by E2. However, by accelerating ICaL recovery, E2 facilitated EADs despite APD shortening.
Pulmonary hypertension (PH) is a progressive cardiopulmonary disease characterized by pulmonary vascular remodeling, ultimately leading to right heart failure. In this study, a murine model of PH was established by exposing mice to chronic hypoxia for four weeks. Compared with normoxic controls, PH mice exhibited significantly elevated right ventricular systolic pressure and pronounced right ventricular (RV) remodeling. Single-nucleus RNA sequencing (snRNA-seq) was subsequently performed to characterize molecular changes in the RV secondary to PH. Cell communication analysis revealed Fn1-related signaling pathways in PH RV. This finding was further corroborated by consistent upregulation of Fn1 and its receptor Sdc4 in both human and rodent PH RV transcriptomic datasets. In murine PH RV, the proportion of Sdc4-expressing epicardial cells was notably increased. Pseudotime trajectory analysis further identified a distinct epicardial cell subpopulation (cluster 1), highly associated with PH progression, that was enriched in biological processes including cell growth and extracellular matrix (ECM)-receptor interactions. Functionally, Fn1 promotes epicardial cell proliferation and epithelial-mesenchymal transition (EMT) in a Sdc4-dependent manner. Crucially, epicardial cell specific Sdc4 knockdown ameliorated RV remodeling in PH models. Taken together, these findings elucidate the role of the Fn1-Sdc4 axis in RV remodeling and suggest its potential as a therapeutic target for mitigating RV dysfunction in PH.
BACKGROUND:Diabetic cardiomyopathy (DCM) is the main complication and the cause of high mortality of diabetes, upon which diet may have significant impacts. Therefore, investigating the potential therapeutic effects of normal dietary patterns on DCM is of critical clinical significance. METHODS:To investigate the effects of reverting to a normal diet (ND) on the development of DCM, we analyzed the transcriptome and proteome profiles of the myocardium after dietary intervention and assessed cardiac function in diabetic mice. Type 2 diabetes was induced in mice by an 8-week high-fat diet (HFD) followed by multiple low-dose streptozotocin (STZ) injections. Five weeks thereafter, the diabetic mice were divided into two subgroups: one group continued on HFD, while the other group was switched to ND for 8 weeks. Myocardial inflammation was evaluated using immunofluorescence staining and immunohistochemical analysis. Furthermore, the causal role of the JAK/STAT pathway in pyroptosis was functionally validated using the JAK inhibitor Ruxolitinib in DM-HFD mice and recombinant IFN-γ in DM-ND mice. RESULTS:The diabetic mice exhibited DCM, characterized by impaired myocardial contractility and myocardial hypertrophy following continued HFD feeding for 5 weeks after the establishment of diabetes. The restoration of ND for 8 weeks significantly alleviated the core symptoms of diabetes, improved insulin resistance, enhanced myocardial function, and mitigated pathological changes including myocardial fibrosis, lipid droplet accumulation, and macrophage infiltration evidenced as reduced CD68+ and iNOS+ fluorescence intensity, as well as corroborated by immunohistochemical analysis showing decreased CD68 expression. Transcriptomic and proteomic analyses demonstrated that DCM mice on HFD exhibited differential expression of 263 genes and 148 proteins compared to ND mice. Meanwhile, DCM mice on ND showed differential expression of 111 genes and 101 proteins relative to DCM mice on HFD. The most differentially expressed genes within this pathway, such as signal transducer and activator of transcription (STAT) 1 and STAT2 were subsequently validated using quantitative PCR. Western blotting experiments demonstrated that reverting to ND after HFD exposure alleviated diabetes-induced myocardial pyroptosis by modulating the JAK/STAT/CASPASE-11/GSDMD pathway. Crucially, JAK1/2 inhibition with Ruxolitinib attenuated myocardial pyroptosis and preserved cardiac function in DM-HFD mice, whereas activation of STAT1/STAT2 with IFN-γ abolished the protective effects of ND in DM-ND mice. CONCLUSIONS:Restoration of ND patterns may enhance cardiac function and attenuate myocardial inflammation in DCM subjects. Furthermore, the protective effect is robustly mediated via the suppression of the JAK/STAT-dependent pyroptosis pathway, highlighting the critical importance of dietary interventions for improving myocardial health in this population.
Heart failure remains a leading cause of morbidity and mortality worldwide, and current therapies largely focus on symptom management and slowing disease progression rather than correcting the underlying molecular abnormalities. Recent advances in genome editing technologies have created new opportunities to treat heart failure. Among these approaches, CRISPR-Cas9 base editing has emerged as a particularly promising strategy because it enables precise nucleotide conversions without introducing double-strand DNA breaks and demonstrates relatively high efficiency in vivo. While correction of disease-causing mutations by CRISPR-Cas9 base editing represents an important application of genome editing, an alternative strategy is to directly modulate key signaling pathways that drive cardiac dysfunction. Protein kinase C alpha (PKCα) functions as a key regulator of cardiac contractility and pathological remodeling. Precision editing of phosphorylation sites that control PKCα stability or activation may therefore represent an effective strategy to suppress maladaptive kinase signaling in cardiomyocytes. This concept of "precision signaling modification" may provide a broadly applicable therapeutic approach for heart failure. Similar strategies may also be applicable to other signaling molecules, including Ca2+/calmodulin-dependent protein kinase II delta (CaMKIIδ), and illustrate the broader potential of signaling-focused genome editing approaches. Despite these advances, several challenges remain for clinical translation, including efficient delivery of genome editing components to the adult heart, long-term safety, and potential immune responses. Continued advances in delivery technologies and genome editing platforms may ultimately enable durable, potentially one-time therapeutic interventions for heart failure.
