Erythromelalgia is a rare, debilitating chronic condition characterized by erythema, warmth, and recurrent burning pain typically in the feet. Despite numerous treatment options, management of erythromelalgia can be challenging. Sodium channel blockers are offered as treatment options for erythromelalgia; however, they are often nonselective, limiting their utility. Suzetrigine is a novel, selective Nav1.8 sodium channel inhibitor that appears to have promising antinociceptive potential.

Our clinical vignette describes the case of a 23-year-old woman with worsening burning pain in her bilateral feet and ankles, diagnosed as erythromelalgia. Various interventions were trialed without adequate relief, including nonpharmacological management, aspirin, lumbar sympathetic block, and various systemic medications. Suzetrigine was ultimately tried with significant pain relief, making this the first described case of suzetrigine alleviating erythromelalgia-associated pain.

Overall, our highlights suzetrigine's potentially wide applicability in various pain conditions, although additional clinical trials are still required to clarify the full extent.

Patients with multivessel disease (MVD) after acute myocardial infarction (AMI) have worse outcomes than those with single-vessel disease (SVD), but whether MVD is associated with diffuse myocardial injury beyond the infarct zone (IZ) remains unclear.

To characterize infarct-related and remote myocardial tissue properties using cardiac MRI in patients with MVD compared with SVD after AMI, and to explore differences according to revascularization completeness.

Retrospective.

Two hundred and twenty-four patients with AMI who underwent MRI within 31-90 days after percutaneous coronary intervention (90 SVD, 42 MVD with complete revascularization [CR], and 92 MVD with incomplete revascularization [IR]).

3.0 T; balanced steady-state free precession cine, phase-sensitive inversion recovery late gadolinium enhancement (LGE), modified Look-Locker (pre- and post-contrast T1-mapping), and gradient and spin echo (T2-mapping) sequences.

Left ventricular volumes and function (cine), infarct size (LGE), and myocardial tissue parameters (native T1 and extracellular volume [ECV], and T2) were quantified in IZ, peri-infarct zone (PIZ), and remote zone (RZ) using standardized methods.

Group comparisons used Student's t-test or Mann-Whitney U test for continuous variables and χ² or Fisher exact test for categorical variables. Adjusted comparisons of myocardial tissue parameters between coronary disease groups were performed using multivariable logistic regression models including relevant clinical covariates and infarct size. A p value < 0.05 was considered significant.

Compared with SVD, MVD showed larger infarct size (p < 0.001), and higher native T1, ECV, and T2 values in PIZ (p = 0.034, 0.004, 0.005) and RZ (p = 0.041, < 0.001, < 0.001). After adjustment for clinical covariates (age, diabetes, hyperlipidemia, BMI) and infarct size, these differences in RZ remained significant. Among patients with MVD, infarct size and ventricular function did not differ between CR and IR groups (p = 0.661, 0.494, 0.857). However, MVD-IR was associated with significantly higher ECV-PIZ (p = 0.023), ECV-RZ (p = 0.025) and T2-RZ (p = 0.003).

In AMI, MVD was associated with diffuse myocardial injury extending beyond the IZ. Differences related to revascularization completeness predominantly involved non-infarct myocardium.

Stage 2.

Although the maternal microbiome is recognized as a critical regulator of offspring physiology, its role in heart development and the pathogenesis of heart failure remains largely unclear. Using a germ-free (GF) mouse model, we demonstrated that maternal microbiota depletion leads to spontaneous heart failure with preserved ejection fraction (HFpEF) in adult female offspring, recapitulating the phenotypes of human diastolic dysfunction. Integrated transcriptomic and proteomic profiling of fetal hearts revealed impaired structural cardiomyocyte maturation in GF offspring, characterized by suppressed sarcomere assembly. Metabolomic analysis revealed that acetate was concurrently downregulated in maternal serum and fetal cardiomyocytes. Importantly, prenatal acetate supplementation and fecal microbiota transplantation rescued fetal cardiomyocyte maturation defects and prevented the onset of HFpEF in adult female offspring. Mechanistically, maternal microbe-derived acetate regulates fetal cardiomyocyte maturation by enhancing the levels of H3K9ac and H3K27ac in the MYL2 promoter region, thereby promoting the transcriptional enhancement of MYL2. This developmental reprogramming provides lifelong protection against diastolic dysfunction. In addition, the concentration of acetate in pregnant women's serum was positively correlated with myocardial thickness in the left ventricle of the fetus. Our findings establish maternal microbial metabolites as determinants of cardiac maturation and suggest prenatal acetate supplementation as a novel preventive intervention for developmental diastolic dysfunction.

Sepsis-induced cardiomyopathy (SICM) has traditionally been viewed as pump-centered contractile failure, but this paradigm fails to explain the clinical spectrum and recovery patterns. This review presents an integrative framework where immunometabolic crosstalk and organelle dysfunction drive disease, including metabolic routing defects, mitochondrial fission, ER stress, and epigenetic regulation via m6A modification and lactylation. Clinically, it proposes a four-phenotype taxonomy (hyperdynamic, hypodynamic, right ventricular-predominant, Takotsubo-like) and advocates for strain imaging and MRI over ejection fraction. Diagnostic innovation includes liquid biopsy for mitochondrial DNA, extracellular vesicles, and metabolomics. Therapeutically, metabolic resuscitation and phenotype-guided vasopressors offer disease modification. The authors call for adaptive trials, biobanking, and organelle-targeted interventions, positioning SICM as a model for precision immunometabolic medicine.

Secondary neurodegeneration in brain regions remote from the primary infarct contributes substantially to long-term neurological dysfunction after ischemic stroke. Although pyroptosis has been implicated in acute ischemic injury, its contribution to delayed secondary thalamic degeneration remains poorly understood. This study investigated whether canonical inflammasome-mediated pyroptosis contributes to secondary thalamic injury following focal cerebral infarction.

A permanent distal middle cerebral artery electrocoagulation model was established in male C57BL/6 mice. Adeno-associated virus-mediated short hairpin RNA targeting caspase-1 was stereotactically delivered into the ipsilateral thalamus two weeks before ischemic injury. Behavioral assessments, histological analyses, immunofluorescence, and Western blotting were performed at predefined time points after infarction. Focal cortical ischemia induced marked activation of caspase-1 and downstream pyroptotic signaling within the ipsilateral thalamus, accompanied by progressive neuronal loss, astrocytic activation, and microglial polarization toward a pro-inflammatory phenotype. Targeted caspase-1 knockdown significantly improved sensory and cognitive performance, preserved thalamic neurons, reduced astrocyte proliferation, suppressed the expression of gasdermin D, interleukin-1β, and interleukin-18, and promoted polarization of Iba-1-positive cells toward an anti-inflammatory M2-like phenotype.

Canonical inflammasome-mediated pyroptosis plays an important role in secondary thalamic neurodegeneration after focal cerebral infarction. Targeted inhibition of caspase-1 attenuated remote neuroinflammation and neurodegeneration, supporting canonical inflammasome signaling as a promising therapeutic target for limiting delayed brain injury following ischemic stroke.

Optimal management of oral anticoagulation (OAC) after atrial fibrillation (AF) ablation remains uncertain. We evaluated thromboembolic and bleeding outcomes associated with OAC discontinuation versus continuation at a clinically relevant 6-month post-ablation landmark.

This target trial emulation used data from a multicentre prospective registry in China. Patients with CHA2DS2-VA scores ≥2, no prior thromboembolism, and no atrial arrhythmia recurrence within 6 months after ablation were classified according to OAC discontinuation or continuation at the 6-month landmark. The primary outcome was the composite of stroke, systemic embolism, and major bleeding. Inverse probability weighting was applied, with intention-to-treat as the primary analysis.

Among 8,339 patients (mean age 68 years; 40.5% women), 4,406 discontinued and 3,933 continued OAC. The risk of the primary outcome did not differ significantly between groups (weighted HR 0.93; 95% CI 0.67-1.29). Thromboembolic risk was similarly comparable (HR 0.96; 95% CI 0.69-1.35). Clinically relevant non-major bleeding occurred less frequently after OAC discontinuation (HR 0.68; 95% CI 0.47-0.97). Findings were consistent in sensitivity analyses. Annualized thromboembolic rates after discontinuation were <1% in patients with CHA2DS2-VA scores 2-3 but 1.52% in those with scores ≥4.

Among patients without prior thromboembolism who remained arrhythmia-free at 6 months after AF ablation, OAC discontinuation was not associated with a difference in the composite outcome of stroke, systemic embolism and major bleeding, compared with OAC continuation. Residual risk remained low in patients with CHA2DS2-VA scores 2-3 but exceeded conventional thresholds in those with scores ≥4.

Hypertension is a major risk factor for cardiovascular diseases, with changes in gut microbiota composition and function being closely associated with its onset and progression. However, the high inter-individual variability in gut microbiota complicates the identification of pathogenic mechanisms using traditional methods. In contrast, the smaller variability in gut microbial metabolites offers a more reliable and consistent basis for cross-individual comparisons. Parsimonious flux balance analysis (pFBA), integrated with double machine learning (DoubleML), identified 17 metabolites significantly associated with hypertension (P < 0.05, robustness value [RV] >0.1). These included meso-2,6-diaminoheptanedioate, p-hydroxyphenylacetic acid, cellobiose, dextran 40 (1,6-α-D-glucan), L-glutamic acid, and kestopentaose, among others. Differential microbial correlation network analysis identified a key microbial subnetwork, termed the FERM guild, consisting of 19 species, with prominent genera including Faecalibacterium, Enterobacter, Roseburia, and Methanobrevibacter. Using Gene Set Enrichment Analysis (GSEA), the dysregulation of this guild was found to be strongly associated with a set of 17 hypertension-related metabolites (P = 0.017). Further analysis revealed that the contribution of FERM genera to key metabolites is significantly associated with blood pressure (P < 0.05), even without significant differences in their abundance; additionally, an imbalance exists between FERM genera and other species. Our findings reveal that hypertension is associated with a disruption of gut microbial diversity, structure, and metabolic function. Seventeen key metabolites related to blood pressure regulation were identified, exhibiting pro- or anti-hypertensive potential and linked to functional microbial modules. These results highlight the gut microbiota and its metabolites as promising targets for therapeutic intervention in hypertension.

Hypertension remains a major global public health burden; however, most studies on its relationship with the gut microbiota rely on traditional species-abundance analyses, which are limited by substantial inter-individual variability. In contrast, microbial metabolites show greater stability across individuals and thus offer a more reliable entry point for mechanistic research. By integrating metabolic modeling, causal inference, and network analysis, this study identified 17 key metabolites significantly associated with blood pressure and uncovered a functionally coordinated microbial community (FERM) whose contribution to critical metabolic fluxes (rather than its taxonomic abundance) was closely linked to hypertension. These findings reveal a metabolite-centered mechanism connecting microbial functions to host blood pressure regulation and provide new potential targets for microbiome-based interventions.

Atherosclerosis is considered one of the main causes of cardiovascular diseases (CVDs). Both innate and adaptive immune responses are crucial in their development. In recent years, various immunotherapies have emerged, involving mechanisms such as inflammatory cell recruitment, efferocytosis, extracellular traps, and adaptive immune vaccines. However, immunotherapeutic agents often have inherent limitations, resulting in suboptimal effectiveness or severe adverse effects. Therefore, designing nanomaterials for targeted delivery of immunotherapeutic drugs is an effective strategy to improve efficacy and reduce toxicity. This review discusses the immune features and immunotherapeutic strategies involved in atherosclerosis progression. It introduces different nanomaterial delivery systems for atherosclerosis and their applications in immune-based therapies. Additionally, this article explores future directions for nanomaterials in immunotherapy, helping researchers address clinical challenges beyond current treatments.

Myocardial ischemia-reperfusion (MIR) injury compromises therapeutic effects of revascularization and leads to functional impairment and exacerbation of structural damage in the heart. Limiting the damage caused by MIR is crucial but is still an unmet clinical need because of the complexity of the underlying mechanisms. Increasing evidence suggests that lysosomal autophagy plays a significant regulatory role in MIR injury. The specific mechanisms involved remain to be fully understood.

We here systematically analyzed the murine MIR model database to screen the potentially protective lysosome-localized proteins against MIR injury. The positive hits were further functionally screened and validated for their capability on autophagy and hypoxia/reoxygenation insults of cardiomyocytes. After exploring the detailed molecular mechanism underlying the protective effects of the target protein, we generated target gene cardiac-specific knockout mice and overexpression mice to verify its function in mouse MIR injury models.

LAPTM4A (lysosome-associated protein transmembrane 4 alpha) stood out as a significant protective lysosome-localized protein from the screening. LAPTM4A deficiency significantly heightened the inflammatory response and cell death both in primary cardiomyocytes and in a MIR-induced mouse model. Conversely, LAPTM4A overexpression exerted protective effects on cell viability and myocardial damage. Mechanistically, LAPTM4A interacts with Rubicon (Run domain Beclin1-interacting and cysteine-rich domain-containing protein), hindering its engagement within the Beclin1 complex, resulting in a robust augmentation of autophagic flux and thereby mitigating cardiac damage during reperfusion. It is important to note that Rubicon knockdown markedly reversed the aggravated injury induced by LAPTM4A knockdown, further verifying the effects of LAPTM4A depend on Rubicon.

Our findings screened out and validated that LAPTM4A is a lysosome-localized protein exerting protective effects against MIR injury by facilitating autophagic flux. Targeting LAPTM4A represents a promising therapeutic strategy for mitigating MIR injury.

Chronic transplant arteriosclerosis is the primary cause of long-term graft failure. Selectively targeting specific inflammatory macrophage subpopulations is essential for inhibiting the primary triggers of inflammatory and immune responses. Therefore, elucidating the origins and regulatory mechanisms of these macrophages in allograft arteriosclerosis is key for the development of targeted therapies.

We performed single-cell RNA sequencing and spatial transcriptomics or integrated transcriptomic data from human chronic allograft vasculopathy specimens and mouse vascular allograft models. Flow cytometry and immunofluorescence staining were used to characterize macrophage subpopulations within remodeled allograft arteries. To determine cellular origins, CD34⁺ lineage tracing and depletion strategies were used. The interactions among COL1A1 (collagen type 1 α1), CD44, and SLC7A11 (solute carrier family 7 member 11) were analyzed using proximity ligation assays and coimmunoprecipitation. Furthermore, metabolic profiles were investigated with ultraperformance liquid chromatography coupled with high-resolution mass spectrometry. To validate the role of cystine transport in macrophage differentiation, we used pharmacologic inhibitors and a genetic approach using myeloid-specific Slc7a11 knockout mice (Lysm-Slc7a11-KO). The mechanisms identified in vivo were further corroborated through in vitro experiments.

We identified a novel proinflammatory foam-like macrophage phenotype in allograft arterial adventitia. These macrophages primarily originated from bone marrow-derived CD34⁺ lineage cells and exhibit heightened de novo lipogenesis and proinflammatory activity. Their lipogenesis is driven by increased cystine uptake, facilitated by enhanced membrane expression of the CD44-SLC7A11 complex, which activates mTORC1 (mechanistic target of rapamycin complex 1)-HIF-1α (hypoxia-inducible factor 1α) signaling. We also revealed that fibroblast-secreted COL1A1 is essential for anchoring the complex to the cell membrane through its direct interaction with CD44. Blocking COL1A1, CD44, or SLC7A11 effectively attenuated mTORC1-HIF-1α signaling, inflammation, and lipogenesis in macrophages as well as accumulation of foam-like cells and intimal hyperplasia in allograft arteries.

This study has revealed previously uncharacterized foam-like macrophages in transplant arteriosclerosis, with COL1A1-enhanced amino acid metabolism modulating lipogenesis and foamy macrophage formation. This study offers potential therapeutic targets to modulate immune response and enhance transplant outcomes.