Commentary: Unveiling a Metabolic-Lymphatic Axis in the Pathogenesis of Heart Failure With Preserved Ejection Fraction

Introduction of heart failure with preserved ejection fraction (HFpEF) puzzle HFpEF represents a growing clinical and therapeutic challenge in the current clinical setting, as it is difficult to diagnose and lacks consistently effective management guidelines.1,2 Despite accounting for over half of all heart failure cases, HFpEF remains notoriously difficult to treat, with most therapeutic options demonstrating limited efficacy.3 Unlike heart failure with reduced ejection fraction (HFrEF), where neurohormonal blockade and inotropic agents have led to significant clinical advances and clarity of mechanisms,4 HFpEF lacks clearly defined molecular targets, in part due to its heterogeneity. Multiple factors have been implicated in HFpEF pathogenesis, including systemic inflammation, endothelial dysfunction, myocardial fibrosis, microvascular rarefaction, and altered cardiomyocyte stiffness.5 However, a unifying mechanistic framework has proven elusive. Among the emerging hallmarks of HFpEF is metabolic dysregulation,6 particularly in the context of obesity, insulin resistance, and hypertension—key comorbidities that dominate the HFpEF phenotype. Metabolism is fundamental to cardiovascular homeostasis; it governs the energetic demands of cardiomyocytes, the inflammatory tone of immune cells, and increasingly, the behavior of vascular and lymphatic endothelium.7 Disrupted metabolic pathways—ranging from glucose and fatty acid oxidation to amino acid catabolism—can perturb cellular signaling, redox balance, and structural remodeling, all of which contribute to disease progression.7 In this context, the recent work by Guo et al1 is especially noteworthy for spotlighting a previously overlooked metabolic pathway—branched-chain amino acid (BCAA) catabolism in lymphatic endothelial cells (LECs)—and demonstrating its pivotal role in maintaining cardiac lymphatic integrity and preventing HFpEF. Their findings not only introduce a novel metabolic-vascular axis but also offer actionable insights into therapeutic intervention, potentially redefining our understanding of HFpEF pathobiology. 2. Disruption of cardiac lymphatics in HFpEF: a paradigm shift Historically, cardiac lymphatics have been underappreciated in heart failure pathophysiology. However, mounting evidence suggests that the lymphatic system plays a crucial role in maintaining cardiac homeostasis through interstitial fluid clearance, immune modulation, and lipid transport.8 Prior studies demonstrated compensatory lymphangiogenesis in HFrEF, particularly post-myocardial infarction or pressure overload.9 In contrast, Guo et al1 identify a diametrically opposite phenotype in HFpEF—a disease marked by obesity, hypertension, and metabolic dysfunction—where the cardiac lymphatic network is structurally and functionally impaired. Using a 2-hit murine model that combines high-fat diet and nitric oxide synthase inhibition, the authors comprehensively documented cardiac lymphatic rarefaction, reduced LEC density, and compromised drainage function. These findings were corroborated in ZSF1-obese rats and in myocardial samples from HFpEF patients, which substantiating their clinical relevance. Importantly, lymphatic disruption was detectable prior to overt diastolic dysfunction, suggesting a causative rather than reactive role in HFpEF progression. This challenges traditional views and positions cardiac lymphatic impairment as a central pathomechanism. Although the mechanisms have been thoroughly explored, further details regarding the role of lymphatics in diabetes and hypertension models, as well as their differential contributions in each context, will enhance our understanding of lymphatics’ role in the development of heart failure and its specific involvement in HFpEF. 3. BCAA catabolism: a metabolic checkpoint for lymphangiogenesis A major conceptual advance of the study is the identification of defective BCAA catabolism as a metabolic hallmark in HFpEF cardiac LECs. The authors employed RNA sequencing to reveal downregulation of key catabolic enzymes, such as BCKDHA and DBT, along with accumulation of BCAAs and their derivatives. Notably, overexpression of BCKDK, an inhibitory kinase of BCAA catabolism, recapitulated lymphangiogenic defects in vitro—including reduced proliferation, migration, and tube formation of LECs—even in the absence of pathological stress. Conversely, genetic deletion of Bckdk in LECs preserved lymphatic architecture and function in HFpEF models. These mice displayed improved cardiac diastolic function, reduced edema and inflammation, and enhanced exercise capacity. Thus, the study demonstrates that intact BCAA catabolism is integral for preserving lymphatic integrity and, in turn, promoting cardiac health. This discovery is especially significant given the broader interest in BCAA metabolism in metabolic syndrome and cardiovascular disease. Previous literature has predominantly focused on systemic metabolic consequences;10,11 here, Guo et al1 expand the discussion to lymphatic vascular biology, demonstrating that intracellular amino acid metabolism directly governs LEC phenotype and function. 4. Mechanistic dissection: vascular endothelial growth factor receptor 3 (VEGFR3) trafficking, Akt signaling, and glucose metabolism One of the study’s most mechanistically detailed contributions is its explanation of how impaired BCAA catabolism derails VEGFR3 signaling, which is pivotal for lymphangiogenesis. In LECs with BCAA catabolic defects, VEGFR3 undergoes ligand-independent phosphorylation via Src kinase activity and is trafficked to lysosomes for degradation rather than being localized to the plasma membrane. This misrouting deprives cells of vascular endothelial growth factor C (VEGFC)-induced activation of Akt signaling, which in turn suppresses glucose transporter 1-mediated glucose uptake and glycolysis—a key metabolic pathway supporting lymphatic growth. These findings integrate metabolic dysfunction with receptor trafficking and signaling, offering a coherent molecular cascade that connects nutrient sensing with vascular remodeling. Restoration of either glucose transporter 1 or Akt activity reversed the lymphangiogenic deficits, reinforcing the causative link. The authors convincingly show that metabolic derailment in LECs is not an epiphenomenon but a pathogenic driver. 5. Therapeutic implications: precision targeting of the VEGFC–VEGFR3 axis Perhaps the most clinically relevant aspect of the study is the demonstration that targeted lymphangiogenic therapy can rescue the HFpEF phenotype. Delivery of a VEGFR3-specific VEGFC variant (VEGFCC156S) via adeno-associated virus selectively induced lymphangiogenesis, restored LEC density, improved lymphatic function, and mitigated hallmarks of HFpEF, including diastolic dysfunction, myocardial hypertrophy, fibrosis, and inflammation Table 1. Table 1 - Additional key findings and mechanistic insights from Guo et al.1* Other findings Key evidence (figures/sections) Implications for HFpEF Pathophysiology Targeted VEGFR3 stimulation also restored exercise capacity and relieved pulmonary congestion, while leaving blood pressure, body-weight, glycaemia and LVEF unchanged Treadmill-running distance was increased and lung wet/dry ratio was reduced in AAV9-VEGFCC156S-treated HFpEF mice (Figures 2D–2F). Systemic parameters in Figure S6A–S6E show no off-target effects Demonstrates that lymphangiogenic therapy confers functional benefits beyond cardiac mechanics and does so without systemic haemodynamic/metabolic disruption PP2 rescues VEGFR3 trafficking and lymphangiogenesis in BCKDK-overexpressing LECs PP2 reduced ligand-independent VEGFR3 phosphorylation, prevented lysosomal routing and reinstated Akt activation, glucose uptake, tube formation Figure S13) Pinpoints glycolysis and not FAO as the metabolic arm crippled by BCAA disruption, refining therapeutic targets (eg, GLUT1/Akt axis) Cardiac lymphatic loss occurs despite stable myocardial ECAR: Extracellular acidification rate; FAO: Fatty acid oxidation; FGFR1: Fibroblast growth factor receptor 1; GLUT1: Glucose transporter 1; HFpEF: Heart failure with preserved ejection fraction; LEC: Lymphatic endothelial cell; LVEF: Left ventricular ejection fraction; OCR: Oxygen consumption rate; PP2: Pharmacologic Src blockade; siRNA: Small interfering RNA; si-DBT: siRNA targeting DBT; VEGFC: Vascular endothelial growth factor C; VEGFR3: Vascular endothelial growth factor receptor 3. Importantly, this intervention did not affect systemic metabolic parameters or angiogenesis, indicating a highly tissue- and pathway-specific effect. This precision adds weight to the therapeutic rationale, particularly in a complex syndrome like HFpEF where systemic interventions often have off-target effects or limited efficacy. 6. Contextualizing the findings: caveats and future directions While the study by Guo et al1 offers a mechanistically rich and therapeutically promising view into HFpEF, several contextual considerations merit further exploration. From a translational standpoint, although murine and human data are both presented, the extrapolation of findings from genetically engineered mouse models to heterogeneous human populations must be approached cautiously. Interspecies differences in cardiac lymphatic anatomy, immune response, and systemic metabolism could influence both the pathophysiology and therapeutic responsiveness. Furthermore, the long-term effects of modulating BCAA catabolism in specific cell types—especially using gene editing tools or viral vectors remain uncertain.12 Chronic BCAA depletion, for instance, may influence muscle metabolism, insulin sensitivity, and central nervous system function, given the systemic roles of these essential amino acids.13,14 At a broader level, this study opens important interdisciplinary intersections. The convergence of cardiovascular biology with nutrient signaling, vascular metabolism, and cellular trafficking pathways such as lysosomal degradation and membrane receptor recycling offers fertile ground for future research. The role of metabolic signaling in endothelial cell behavior is increasingly recognized across several vascular beds, including the retina, brain, and kidney.15 Analogously, tumor lymphangiogenesis is influenced by local metabolic cues, suggesting that the principles uncovered in this study could have relevance in oncology, particularly in modulating immune trafficking and edema within the tumor microenvironment. Moreover, immunometabolism—a field that examines how metabolic states shape immune cell function—may intersect with the lymphatic findings here, as impaired lymphatic drainage of immune cells in HFpEF could exacerbate low-grade myocardial inflammation.16,17 Another promising avenue involves the relationship between metabolic disease and lymphatic biology. Obesity and type 2 diabetes have been shown to impair peripheral lymphatic function, contributing to tissue inflammation and fibrosis.18 Thus, the concept that targeted metabolic correction within LECs can reverse cardiac dysfunction may also extend to other organs with dense lymphatic networks, such as the liver (in nonalcoholic steatohepatitis) or kidney (in hypertensive nephropathy). A compelling question raised by this work is whether BCAA-targeted therapies may be beneficial beyond HFpEF, particularly in HFrEF or other cardiomyopathies. While HFrEF is typically driven by ischemic injury and pressure overload, recent studies have identified metabolic remodeling—including increased reliance on ketone bodies and altered amino acid flux—as core features of myocardial adaptation.19,20 Interestingly, lymphangiogenesis is often compensatorily upregulated in HFrEF, unlike in HFpEF.21 Thus, whether BCAA catabolism modulates lymphatic function similarly in HFrEF remains to be explored. If lymphatic expansion in HFrEF is adaptive, enhancing BCAA breakdown may reinforce beneficial remodeling.22 Conversely, in settings where lymphangiogenesis is already sufficient or excessive, such therapies may be redundant or even deleterious. This again emphasizes the importance of context-dependent targeting—a recurring theme in metabolic therapy. Beyond heart failure, dysregulated BCAA homeostasis has been implicated across the broader spectrum of cardiovascular disease. Epidemiologic and mechanistic studies link elevated circulating BCAAs to incident hypertension and atherosclerotic events,11 in part through endothelial oxidative stress,23 mTORC1-driven inflammatory signaling,24 and macrophage-mediated plaque inflammation.25 In vascular beds, excess BCAAs can impair nitric-oxide dependent vasodilation and promote vascular stiffness,23 whereas experimental activation of extra-cardiac BCAA catabolism lowers blood pressure and mitigates cardiac stress in preclinical models.22 These data suggest that BCAA handling is not merely a myocardial issue but a system-level determinant of vascular tone, plaque biology, and cardiometabolic risk, raising the possibility that lymphatic BCAA pathways in HFpEF may intersect with mechanisms operative in atherosclerosis and hypertension. In addition, given the established role of BCAA metabolism in skeletal muscle, insulin sensitivity, and neurological function,13,26,27 systemic BCAA manipulation may have broad physiological consequences. Therefore, strategies that selectively target cardiac or endothelial BCAA pathways, such as cell-specific gene editing, localized drug delivery, or precision RNA therapeutics, are particularly attractive.28 This highlights the need for collaboration across cardiovascular biology, molecular metabolism, systems pharmacology, and biomedical engineering to develop next-generation interventions that are both effective and safe. Outside of defining the downstream consequences of impaired BCAA breakdown, it will be important for future studies to clarify the upstream drivers of disrupted BCAA catabolism in HFpEF and other cardiometabolic diseases. Mitochondrial dysfunction,29,30 chronic low-grade inflammation,31 altered nutrient-sensing pathways (including mTORC1 signaling),32,33 and reduced expression or post-translational regulation of key catabolic enzymes such as BCAT2 and BCKD34–36 have all been implicated in limiting BCAA oxidative capacity in metabolic syndrome, hypertension, and atherosclerosis. These systemic and tissue-specific perturbations may help explain why BCAA accumulation occurs across diverse disease states. Understanding these causal factors is also essential when evaluating BCAA-directed therapies: enhancing BCAA catabolism could reduce metabolic stress,22,37 improve endothelial function,22,29 and attenuate inflammation,38–40 but overactivation of these pathways may risk excessive amino-acid depletion,41,42 impaired muscle metabolism,27,42 or unwanted effects in tissues where BCAA signaling is adaptive.39 Finally, while the lymphangiogenic approach proved efficacious in a controlled setting, its application in diverse patient populations with variable HFpEF phenotypes (eg, with atrial fibrillation, renal dysfunction, or pulmonary hypertension) needs careful stratification. 7. Conclusion: redefining the metabolic landscape of cardiac lymphatics Guo et al1 have set a new benchmark in HFpEF research by unveiling the critical role of BCAA metabolism in cardiac LEC function. Their study not only repositions lymphatic biology at the forefront of HFpEF pathogenesis but also introduces a novel metabolic-vascular axis that offers rich therapeutic potential. By bridging cellular metabolism, vascular biology, and cardiac physiology, this work provides a model of translational cardiovascular research with immediate and far-reaching implications. As the field moves forward, these insights invite a broader re-evaluation of lymphatic function in other forms of cardiac and systemic disease, and reinforce the idea that effective therapies may lie not only in modulating the heart itself, but in restoring the delicate metabolic and vascular ecosystems that support it. This study provides not only a disease-specific breakthrough but also a conceptual platform for understanding how metabolic circuits regulate vascular integrity, with potential implications extending across disciplines and disease contexts. As our understanding of endothelial and lymphatic metabolism deepens, targeted modulation of nutrient pathways such as BCAA catabolism could become a cornerstone of precision cardiovascular medicine. Funding This work was supported by awards from the National Institutes of Health (HL-96686, MPI; HL-123404 and HL167495) and the American Heart Association (24TPA1293530, 25PRE1377191). Author contributions John Zhang and Dhrubo Ahmad contributed to data collection and the initial drafting of the manuscript. Taslima Akter Shila was involved in drafting and revising the manuscript. Kayleigh Wyatt, Bo Wang, and Yuhui Yang contributed to the collection of relevant literature and provided revisions. Huilan Tan and Yanwen Liu assisted with checking the content for clarity, proofreading, and revisions. Jianli Zhao was responsible for conceptualization, data collection, and manuscript revision. Yajing Wang oversaw the construction of the manuscript and provided additional revisions. All authors have read and approved the final manuscript. Conflicts of interest None. Editor note: Yajing Wang is an Editorial Board Member of Cardiology Discovery. The article was subject to the journal’s standard procedures, with peer review handled independently of this editor and her research groups.