The use of cardiac stereotactic body radiation therapy for the treatment of ventricular tachycardia (VT), also termed stereotactic ablative radiation therapy or, increasingly, stereotactic arrhythmia radioablation (STAR), is increasingly used in select patients. STAR has emerged as a promising alternative to invasive catheter ablation (CA) for patients with high-risk refractory VT who have failed prior medical therapy or catheter ablation. Since the publication of the first case series using STAR, our understanding of the mechanisms of STAR, longer-term clinical outcomes, potential side effects, and barriers to widespread adoption of cardiac radioablation has become increasingly clear. In this review, we discuss these topics, the increased adoption of STAR, as well as the challenges that lie ahead for this therapy. In addition, as data strongly suggest that fibrosis alone cannot account for the early decreases in VT events observed post-STAR, we propose adopting the STAR acronym to instead stand for stereotactic arrhythmia radiation therapy.

BACKGROUND:MGP (matrix Gla-protein), a known inhibitor of vascular calcification, becomes biologically active by vitamin K-dependent carboxylation. Circulating levels of dpucMGP (dephospho-uncarboxylated matrix Gla-protein), the inactive form of MGP, have been associated with large artery stiffening and reduced skeletal muscle mass in heart failure (HF). Whether dpucMGP is related to adverse outcomes in patients with HF is unknown. METHODS:In this cohort study, we measured plasma dpucMGP among 2247 PHFS (Penn HF Study) participants. We examined the relationship between dpucMGP and ≈5000 other proteins (SomaScan assay) to identify biological pathways associated with dpucMGP. We assessed the association between dpucMGP levels and (1) death or HF-related hospital admission; (2) all-cause death. RESULTS:Participants' median age was 61 years (interquartile range, 53-70 years), 64% were male, and 71% were White. dpucMGP exhibited prominent proteomic associations with acute phase response, coagulation, complement system, fibrosis, cell signaling, and metabolic pathways. Greater dpucMGP was associated with older age, renal dysfunction, and warfarin use, whereas Black ethnicity was associated with lower dpucMGP. Increased dpucMGP levels were associated with an increased risk of death or HF-related hospital admission (standardized hazard ratio, 1.23 [95% CI, 1.17-1.28]; P<0.0001) and all-cause death (standardized hazard ratio, 1.32 [95% CI, 1.25-1.40]; P<0.0001), particularly among participants with nonischemic HF. Associations between dpucMGP and outcomes were dependent on warfarin use, and higher dpucMGP levels were found to mediate the association between warfarin use and adverse outcomes (death [total effect: P=0.005; indirect effect: P<0.001] and death or HF-related hospital admission [total effect: P<0.001; indirect effect: P=0.002]). CONCLUSIONS:Higher dpucMGP is associated with multiple biological pathways and with an increased risk for adverse outcomes in HF. Greater dpucMGP levels mediated the relationship between warfarin use and adverse outcomes. Further studies are required to determine the role of therapeutic interventions to reduce dpucMGP levels in this patient population.

Cellular metabolism is governed by the coordinated organization of macromolecules, including lipids and proteins, together with redox-active cofactors such as NADH and FAD. However, resolving these biochemical features quantitatively and spatially at subcellular resolution remains challenging because no single imaging modality can capture molecular composition, redox state, and tissue architecture simultaneously without labeling. Here, we present MANIFEST ( M ulti-mod A l N onlinear I maging with F luorescence E xcitation and S tatistical T emporal-resolved spectroscopy), a label-free imaging platform that integrates stimulated Raman scattering (SRS), second harmonic generation (SHG), multiphoton fluorescence (MPF), and fluorescence lifetime imaging microscopy (FLIM). The MANIFEST combines chemical imaging of lipids with autofluorescence- and lifetime-based quantification of NADH and FAD metabolism, enabling spatially resolved analysis of metabolic heterogeneity at organelle and tissue-compartment levels. We apply this framework to four distinct aging or disease models: amyloid-beta-treated tri-cultured brain cells, high-fat diet mouse liver, human non-ischemic cardiomyopathy tissue, and aging mouse retina. Across these systems, MANIFEST reveals disease-associated lipid remodeling, redox imbalance, disrupted metabolic zonation, collagen reorganization, and layer-specific metabolic changes. By integrating complementary nonlinear optical modalities into a single label-free platform, MANIFEST provides a generalizable approach for high-resolution metabolic phenotyping in complex biological systems and offers new opportunities for studying disease mechanisms, aging biology, and metabolism-driven tissue pathology.

Background Despite heightened awareness of cardiac amyloidosis (CA), the care of patients with CA remains challenging, particularly at the Veterans Affairs (VA), where populations are predominantly older and male. Objectives This study aimed to characterize the current landscape of CA care across the VA. Methods As a quality improvement study, a survey instrument was developed and disseminated to all 127 VA cardiology programs from March to May 2025. The survey captured data on diagnostic modality availability, therapeutic resources, multidisciplinary care team composition, and self-designated amyloidosis center designation. Results Complete responses were received from 54 cardiology programs (42.5%). There was substantial variability in program-level experience, clinician comfort, access to diagnostics, and therapeutics regardless of clinical complexity index designation. Thirty-one survey respondents (57.4%) reported feeling “very comfortable” treating CA, although 7 (13.0%) reported being “hesitant” to provide care for Veterans with CA. Twelve programs (22.2%) reported having only one cardiologist managing CA patients, and 7 (13.0%) indicated that no cardiologists at their center treated Veterans with CA. Only 4 programs (7.4%) reported having a formalized multidisciplinary CA team. Lastly, facility complexity did not have an obvious relationship to size, scope, or readiness to care for Veterans with CA. Conclusions The VA appears strongest at the initial diagnostic stages, with high availability to initiate a workup for transthyretin CA, with considerable latent capacity to support comprehensive CA care including a high-risk patient population, widespread diagnostic capabilities, national access to therapies, and robust telehealth infrastructure. Targeted implementation to standardize CA care delivery, while leveraging existing strengths, could meaningfully improve care for Veterans with CA.

OBJECTIVES:. Understanding the mechanistic impact of fostamatinib, a spleen tyrosine kinase inhibitor, in severe COVID-19 using biomarkers associated with disease severity is crucial for the development of host-directed therapeutics. We analyzed samples from a randomized clinical trial to investigate the impact of fostamatinib on multiple inflammatory biomarkers associated with COVID-19 disease severity. DESIGN:. Secondary analyses of biomarkers from a randomized clinical trial. SETTING:. Multicenter randomized clinical trial. PATIENTS:. A total of 400 adults hospitalized with COVID-19 were enrolled in a phase 3 randomized clinical trial. Absolute neutrophil counts (ANCs) were analyzed across 392 patients and biomarkers were measured in 190 patients with available plasma samples. INTERVENTIONS:. Adults hospitalized with COVID-19 were randomized to receive either fostamatinib (150 mg bid) or placebo. ANCs and 24 biomarkers were assessed at day 0 and over time using a multiplexed Meso Scale Discovery assay (Meso Scale Diagnostics LLC, Rockville, MD). MEASUREMENTS AND MAIN RESULTS:. At day 0, participants with World Health Organization ordinal scale 5–7 had elevated ANC counts, compared with ordinal scale 4. In addition, the levels of neutrophil-associated biomarkers, inflammatory cytokines, and mediators of endothelial dysfunction at day 0 were increased in the participants who were ordinal scale 5–7 vs. ordinal scale 4. Randomization to fostamatinib compared with placebo resulted in a decrease in ANC and several neutrophil-associated biomarkers, pro-inflammatory cytokines, and mediators of endothelial dysfunction/tissue damage. This differential finding was also demonstrated in a subgroup of patients (n = 85) with a hypoinflammatory phenotype. LIMITATIONS:. Missing plasma samples and neutral phase 3 trial results. CONCLUSIONS:. Randomization to fostamatinib resulted in lower neutrophil counts and levels of circulating biomarkers in hospitalized patients with COVID-19; however, the observed impact of fostamatinib was modest compared with prior studies.

ABSTRACT Diabetes and obesity increase cardiac lipid levels leading to cardiomyopathy and heart failure. We hypothesized that intermittent fasting would reduce cardiac lipid levels. Surprisingly, intermittent fasting increased myocardial triglyceride content, but rescued mortality and attenuated cardiomyopathy in mice overexpressing cardiomyocyte acyl-CoA synthetase 1 (MHC-ACSL1). Lipid overload caused cardiomyocyte accumulation of polyubiquitinated protein aggregates containing desmin, a scaffolding intermediate filament protein, which intermittent fasting prevented. Furthermore, intermittent fasting reversed elevated myocardial C16:0 ceramide content, and knockdown of ceramide synthase CerS5 and CerS6 reduced palmitate-induced protein aggregation, highlighting a role for C16:0 ceramides in this pathology. Conversely, impairing aggrephagy with cardiomyocyte-specific p62 ablation induced heart failure in mice fed a high-fat diet, with paradoxically reduced cardiac lipid content. Crucially, non-failing diabetic human hearts also exhibited protein aggregate pathology. Taken together, these results demonstrate that impaired proteostasis characterizes cardiomyopathy from cardiac lipid overload and identify a promising new therapeutic target for this condition.

Background The Reprieve System is designed to overcome barriers limiting safe and rapid decongestion with individualized automated diuretic titration, real-time diuretic response monitoring, and individualized sodium chloride replacement to prevent cardio-renal dysfunction. Objectives This study aims to establish proof-of-concept that the Reprieve System can facilitate rapid and safe decongestion. Methods FASTR (Fluid Management of Acute Decompensated Heart Failure Subjects Treated With Reprieve Decongestion Management System [DMS]) was a randomized pilot trial comparing the Reprieve System vs a control strategy of optimal diuretic therapy (ODT) in hospitalized patients with acute heart failure. The primary efficacy endpoint was 24-hour natriuresis, and the primary safety endpoint was a composite of dialysis or doubling of creatinine levels, severe electrolyte abnormalities, hypotension, or hypertensive emergency. Results A total of 100 patients were enrolled, with 96 receiving randomized treatment (Reprieve, n = 52; ODT, n = 44). At baseline, the median estimated glomerular filtration rate was 49 mL/min/1.73 m2 (Q1-Q3: 36-78 mL/min/1.73 m2) with estimated excess fluid volume of 20 lbs (Q1-Q3: 15-35 lbs). Twenty-four-hour natriuresis was significantly greater with the Reprieve System (1,082 ± 487 mmol) vs ODT (423 ± 290 mmol; P < 0.001). The safety endpoint occurred in 31% of the Reprieve group vs 39% of the ODT group (P = 0.42). Intravenous diuretic therapy duration was shorter with Reprieve [46 hours [Q1-Q3: 29-80 hours]) vs ODT (88 hours [Q1-Q3: 44-143 hours]; P = 0.014). The rate of weight loss (P = 0.002), net fluid loss (P = 0.03), and net natriuresis (P < 0.001) were significantly faster with Reprieve. Change in serum creatinine levels did not differ between the Reprieve (0.19 ± 0.24 mg/dL) and ODT (0.31 ± 0.39 mg/dL; P = 0.07) groups. Conclusions In this pilot trial, the Reprieve System safely produced significantly faster decongestion compared with ODT. Confirmation of these findings in the ongoing pivotal trial is required. (Fluid Management of Acute Decompensated Heart Failure Subjects Treated With Reprieve Decongestion Management System [DMS] [FASTR]; NCT05174312)

AIMS:Sodium-glucose co-transporter 2 inhibitors are widely used to treat patients with type 2 diabetes and exhibit beneficial cardiovascular effects beyond glucose lowering. In this study, we investigated their potential to alleviate vaso-occlusive events and organ damage in sickle cell disease (SCD) mice. METHODS AND RESULTS:Intravital and immunofluorescence microscopy reveal that a 4-day oral administration of dapagliflozin (DAPA) or sotagliflozin (SOTA) significantly reduces neutrophil adhesion and transmigration in cremaster venules, with SOTA showing greater inhibition, and down-regulates E-selectin and intercellular adhesion molecule-1 (ICAM-1) expression in cremaster venules of TNF-α-challenged SCD mice. Intriguingly, only SOTA improves mouse survival acutely. Similar inhibitory effects on neutrophil recruitment are observed in SCD mice subjected to hypoxia-reoxygenation. Flow chamber assays indicate that neither drug directly affects neutrophil or endothelial cell adhesive function. In addition, treatment of neutrophils and platelets from SCD mice and patients with DAPA or SOTA does not affect their activation. When administered for 4 months, DAPA or SOTA mitigates neutrophil recruitment and enhances microcirculation in cremaster venules of TNF-α-challenged SCD mice, while only SOTA confers a survival benefit. Both drugs reduce leucocyte infiltration in the liver or lungs, suggesting their ability to protect against organ damage. Co-administration with hydroxyurea for 4 months does not enhance these effects. Multiplex analysis shows that DAPA and SOTA lower plasma levels of soluble P-selectin, ICAM-1, S100A8/A9, and pro-inflammatory cytokines in SCD mice. CONCLUSION:Our findings suggest that DAPA and SOTA mitigate vaso-occlusive events in SCD, with SOTA providing superior benefits.

Introduction In obese states, cardiac hypertrophy is typically associated with elevated circulating and intramyocardial triglyceride content. However, the role of lipid degradation pathways, particularly lysosomal lipid hydrolysis, in modulating cardiac remodeling is unknown. In mammals, there is one critical acid lipase in the lysosome - lysosomal acid lipase, or LAL, that is responsible for breakdown of lipoproteins and lipid droplets. Based on observations made while studying lysosomal acid lipase knockout mice (LALKO), we tested the hypothesis that LAL is critical for maintaining lipid homeostasis and supporting cardiac hypertrophic responses, and that LAL deficiency disrupts these processes, leading to cardiac atrophy. Methods We utilized LAL whole-body knockout mice (LALKO), Mhc-Cre Lipaflox/flox (cardiomyocyte-specific LAL knockout, LALCMKO), pharmacological LAL inhibition, along with high-fat diet, transverse aortic constriction (TAC), and doxorubicin to investigate the effects of lysosomal lipolysis on myocardial growth. Results LALKO mice exhibited increased myocardial triglycerides, but atrophied hearts as evidenced by low LV mass and reduced cardiomyocyte area. WGA staining of cardiomyocytes showed that LALKO mice did not appropriately hypertrophy in response to TAC (Fig. 1A and 1B). Compared to littermate controls, LALKO mice developed reduced ejection fraction and increased fibrosis post-TAC (Fig. 1C-1F). LALKO hearts were also smaller than WT in response to doxorubicin, and pharmacological LAL inhibition with Lalistat increased doxorubicin-induced mortality (Fig 1G and 1H). LALCMKO mice also exhibited reduced cardiomyocyte cell area (∼30% decrease, P<0.01), increased TUNEL positive cells (∼102% increase, P<0.01), and fibrosis (∼44% increase, P<0.05) with doxorubicin (vs littermate controls), indicating a cell autonomous role for LAL in response to stress. Mechanistically, LALCMKO mice exhibited reduced mammalian target of rapamycin (mTOR) phosphorylation (∼56% decrease, P<0.01) and increased nuclear translocation of transcription factor EB (∼107% increase, P<0.05), while in vitro, high-content microscopy showed that LAL inhibition caused nuclear translocation of transcription factor EB, a transcription factor we previously published drives cardiomyocyte atrophy. High-fat diet feeding of mice improved survival and LV function in models of TAC and doxorubicin, respectively, but had no effect in LALKO mice, suggesting the translational potential of our findings. Conclusion Our studies reveal a fundamental role for lysosomal lipolysis through LAL, preventing excess cardiomyocyte catabolism and suggest that dietary lipids can improve outcomes in two murine heart failure models.

Adipose tissue lipolysis is the process by which triglycerides in lipid stores are hydrolyzed into free fatty acids (FFAs), serving as fuel during fasting or cold-induced thermogenesis. Although cytosolic lipases are considered the predominant mechanism of liberating FFAs, lipolysis also occurs in lysosomes via lysosomal acid lipase (LIPA), albeit with unclear roles in lipid storage and whole-body metabolism. We found that adipocyte LIPA expression increased in adipose tissue of mice when lipolysis was stimulated during fasting, cold exposure, or β-adrenergic agonism. This was functionally important, as inhibition of LIPA genetically or pharmacologically resulted in lower plasma FFAs under lipolytic conditions. Furthermore, adipocyte LIPA deficiency impaired thermogenesis and oxygen consumption and rendered mice susceptible to diet-induced obesity. Importantly, lysosomal lipolysis was independent of adipose triglyceride lipase, the rate-limiting enzyme of cytosolic lipolysis. Our data suggest a significant role for LIPA and lysosomal lipolysis in adipocyte lipid metabolism beyond classical cytosolic lipolysis.

The pathophysiology of heart failure (HF), a complex and heterogenous condition, remains to be fully understood. Troponin and b-type natriuretic peptide are the only biomarkers that are utilized in clinical practice for HF clinical management. Recent advances in proteomics present a powerful tool to identify risk markers and ultimately, potential molecular mechanisms underlying HF pathogenesis. Herein, we explore traditional and novel heart biomarkers, highlighting their potential role in the pathogenesis of HF. Recent proteomic analyses have identified numerous proteins including Galectin-3, sST2, GDF-15, FGF21, Endotrophin, THSB-2, ADAMSTL, SVEP1, and anthracycline that are associated with clinical outcomes in HF. These biomarkers are not presently utilized in HF management but may be useful in the future for prediction of death or HF hospitalization. While traditional biomarkers remain essential, proteomic strategies have revealed additional targets that require further mechanistic exploration. Future research should focus on validating these biomarkers and translating proteomic insights into clinical practice to enhance HF management.

Background and Aims Translating human genomic discoveries into mechanistic insights requires linking genetic variations to candidate genes and their causal functional phenotypes. Genome-wide association studies have consistently identified LIPA (lipase A, lysosomal acid type) as a risk locus for coronary artery disease, with previous analyses prioritising LIPA as a likely causal gene. However, functional studies elucidating causal variants, regulatory mechanisms, target cell types, and their causal impact on atherosclerosis have been lacking. This study aims to address this gap by establishing the variant-to-function relationship at the LIPA locus.Methods Post-genome-wide association study pipelines and molecular biology techniques, including expression quantitative trait loci analysis, Tri-HiC, luciferase assay, CRISPRi, allele-specific binding, motif analysis, and electrophoretic mobility shift assay, were used to link functional variants to target genes and define the direction of their regulatory effects in causal cell types. To determine how increased myeloid LIPA impacts atherosclerosis, myeloid-specific Lipa overexpression mice on an Ldlr-/- background were generated.Results Coronary artery disease-risk alleles in the LIPA locus increase LIPA expression and enzyme activity specifically in monocytes/macrophages by enhancing PU.1 binding to an intronic enhancer region that interacts with the LIPA promoter. Myeloid-specific Lipa overexpression in Ldlr-/- mice fed a western diet resulted in larger atherosclerotic lesions, accompanied by altered macrophage function, characterized by increased accumulation of lesional macrophages derived from circulating monocytes, reduced neutral lipid content, and up-regulation of integrin and extracellular matrix pathway genes.Conclusions The work establishes a direct causal link between LIPA-risk alleles and increased monocyte/macrophage LIPA that exacerbates atherosclerosis, bridging human functional genomic evidence to the mechanistic understanding of coronary artery disease.

BACKGROUND: Iron deficiency (ID) is currently defined as a serum ferritin level <100 or 100 to 299 ng/mL with transferrin saturation (TSAT) <20%. Serum ferritin and TSAT are currently used to define absolute and functional ID. However, individual markers of iron metabolism may be more informative than current arbitrary definitions of ID. METHODS: We assessed prognostic associations of ferritin, serum iron, and TSAT among 2050 participants with heart failure (HF) with reduced/mid-range (n=1821) or preserved (n=229) left ventricular ejection fraction enrolled in the PHFS (Penn HF Study), a prospective cohort study. We measured 4928 plasma proteins using an aptamer-based assay (SOMAScanv4) and assessed prognostic and proteomic associations of markers of iron metabolism. RESULTS: Ferritin concentrations were not associated with outcomes, whereas low TSAT and serum iron were associated with the risk of all-cause death (TSAT: standardized hazard ratio, 0.84 [95% CI, 0.76–0.93]; P =0.001; serum iron: standardized hazard ratio, 0.87 [95% CI, 0.79–0.96]; P =0.007). Similarly, TSAT was associated with the risk of death or HF-related admission (standardized hazard ratio, 0.89 [95% CI, 0.83–0.95]; P =0.0006). Significant interactions between TSAT and HF with preserved ejection fraction status were found such that TSAT was more strongly associated with the risk of death and death or HF-related admission in HF with preserved ejection fraction. We identified 359 proteins associated with TSAT, including TFRC (transferrin receptor protein; β, −0.455; P <0.0001) and CRP (C-reactive protein; β, −0.355; P <0.0001). Pathway analyses demonstrated associations with lipid metabolism, complement activation, and inflammation. In contrast to the robust associations between TSAT and outcomes, ID and absolute ID defined by current criteria were not associated with death or death or HF-related admission. TSAT was associated with outcomes regardless of the presence of functional versus absolute ID. CONCLUSIONS: Low TSAT, but not ferritin concentrations, is significantly associated with adverse outcomes in HF. Low TSAT is more strongly associated with outcomes in HF with preserved ejection fraction. Pathways related to inflammation and lipid metabolism are associated with low TSAT in HF.

Protein aggregates are emerging therapeutic targets in rare monogenic causes of cardiomyopathy and amyloid heart disease, but their role in more prevalent heart failure syndromes remains mechanistically unexamined. We observed mis-localization of desmin and sarcomeric proteins to aggregates in human myocardium with ischemic cardiomyopathy and in mouse hearts with post-myocardial infarction ventricular remodeling, mimicking findings of autosomal-dominant cardiomyopathy induced by R120G mutation in the cognate chaperone protein, CRYAB. In both syndromes, we demonstrate increased partitioning of CRYAB phosphorylated on serine-59 to NP40-insoluble aggregate-rich biochemical fraction. While CRYAB undergoes phase separation to form condensates, the phospho-mimetic mutation of serine-59 to aspartate (S59D) in CRYAB mimics R120G-CRYAB mutants with reduced condensate fluidity, formation of protein aggregates and increased cell death. Conversely, changing serine to alanine (phosphorylation-deficient mutation) at position 59 (S59A) restored condensate fluidity, and reduced both R120G-CRYAB aggregates and cell death. In mice, S59D CRYAB knock-in was sufficient to induce desmin mis-localization and myocardial protein aggregates, while S59A CRYAB knock-in rescued left ventricular systolic dysfunction post-myocardial infarction and preserved desmin localization with reduced myocardial protein aggregates. 25-Hydroxycholesterol attenuated CRYAB serine-59 phosphorylation and rescued post-myocardial infarction adverse remodeling. Thus, targeting CRYAB phosphorylation-induced condensatopathy is an attractive strategy to counter ischemic cardiomyopathy.

Trehalose is a naturally occurring disaccharide with versatile commercial applications and health benefits, including promise as a therapeutic for obesity and diabetes. Although numerous previous reports purport the therapeutic uses of orally ingested trehalose, the abundance of glycosidases in the gastrointestinal tract suggest the potential for significant limitations of oral trehalose that have not been addressed. We first fed mice a high-fat diet (HFD) while providing trehalose by both oral and intraperitoneal routes. This combined strategy was broadly efficacious in reversing HFD-induced weight gain, fat mass, insulin resistance, and the development of hepatosteatosis. In contrast, oral-only trehalose failed to improve HFD-induced obesity and insulin resistance. This was due to trehalase (Treh)-mediated metabolism as blood trehalose levels remained low despite a significant rise in glucose. We next developed systemically deficient Trehalase (Treh-KO) mice to enhance the efficacy of trehalose. Surprisingly, oral trehalose therapy could not be facilitated resulting in neither an increase in serum trehalose levels nor metabolic benefits. Parenteral trehalose resulted in higher trehalose levels with lower serum glucose in Treh-KO mice, yet no additive metabolic benefits were observed. Overall, our findings still support a therapeutic role for trehalose in obesity and metabolic disease but with practical limitations in its delivery by oral route.