Background Mutations of LDLR, APOB and PCSK9 have been well-established to cause hypercholesterolemia while the pathogenic effects of LPL has been confirmed by cohorts and functional studies in hypertriglyceridemia. However, these mutations do not fully account for all dyslipidemia, and it remains unexplained why some patients with dyslipidemia develop coronary heart disease (CHD) while others do not.Methods We enrolled 108 patients with lipid disturbances (67 with hypercholesterolemia and 41 with hypertriglyceridemia) and 414 controls from Tongji Hospital, Wuhan, China. Whole exome sequencing (WES) was performed, and candidate genes were assessed using the optimal sequence kernel association test (SKAT-O). Subgroup analysis compared genetic profiles between CHD and non-CHD patients.Results We identified 13 pathogenic or likely pathogenic (PP/LPP) variants in LDLR in hypercholesterolemia patients and four in LPL as well as two in APOA5 in hypertriglyceridemia patients. With exclusion of patients with PP/LPP variants, SKAT-O identified 192 and 184 additional genes associated with hypercholesterolemia and hypertriglyceridemia, respectively. In subgroup analysis, 119 genes showed relevance to CHD by comparison of patients with and without CHD in hypercholesterolemia cohort. Further enrichment analysis identified COL5A1, COL24A1, COL6A6, COL6A2, SLC3A1, ATP1A4 and SLC7A9 as candidate causal genes of CHD.Conclusions This study described the genetic landscape of dyslipidemia in Chinese Han population, and revealed novel susceptibility genes beyond canonical lipid pathways. Genes implicated in CHD suggests extracellular matrix remodeling may mediate atherosclerotic progression in hypercholesterolemia. These findings provide novel mechanistic insights into CHD development and highlight promising targets for functional validation.

Fulminant myocarditis (FM) is a lethal form of acute myocardial inflammation. To investigate this mechanism, we examined whether innate immunity trained by sequential exposure to lipopolysaccharide (LPS) and Coxsackievirus B3 (CVB3) could induce FM in CVB3-resistant C57BL/6J mice. Male 7–8-week-old C57BL/6J mice were used, and LPS + CVB3 double-hit treatment significantly increased mortality to 60

Vascular smooth muscle cell (VSMC)-derived foam cells critically drive atherosclerotic plaque progression, yet their regulatory mechanisms remain incompletely understood. This study aimed to elucidate the pathophysiological role of the VSMC-enriched factor axin interactor, dorsalization-associated (AIDA) in this process and evaluate its therapeutic potential. We utilized VSMC-specific AIDA knockout in male ApoE-/- mice and adenoviral shRNA silencing in oxLDL-stimulated murine aortic vascular smooth muscle cells (MOVAS), combined with co-immunoprecipitation (Co-IP), cholesterol flux assays, and ubiquitination profiling, which revealed that AIDA is selectively upregulated in VSMCs within human and murine atherosclerotic plaques. AIDA knockout attenuated aortic plaque burden, fibrosis, and elastic fiber fragmentation in vivo, and suppressed oxidized low-density lipoprotein (oxLDL) uptake and foam cell formation in vitro by specifically impairing CD36 membrane trafficking without affecting cholesterol efflux. Mechanistically, AIDA scaffolds HMG-CoA reductase degradation protein 1 (HRD1)-mediated K63-linked ubiquitination of vesicle-associated membrane protein 3 (VAMP3), resulting in the VAMP3-CD36 interaction and subsequent CD36 membrane translocation. These results demonstrate that AIDA promotes VSMC-derived foam cell formation by facilitating CD36 trafficking through the HRD1-VAMP3 ubiquitination axis, identifying the AIDA-HRD1-VAMP3-CD36 pathway as a potential novel strategy for the treatment of atherosclerosis.

Dilated cardiomyopathy (DCM) is a leading cause of heart failure and heart transplantation and is characterized by marked clinical and etiological heterogeneity. Recent studies have expanded the understanding of DCM from a predominantly monogenic disorder to a multifactorial disease shaped by genetic susceptibility and acquired or environmental “second hits”. Beyond rare pathogenic variants, emerging evidence highlights the contribution of clonal hematopoiesis of indeterminate potential to inflammation-driven adverse cardiac remodeling and disease progression. These secondary modifiers interact with pre-existing genetic backgrounds to amplify shared downstream pathways. In parallel, advances in mechanism-informed therapies are increasingly translating these insights into clinical practice. Beyond guideline-directed medical and device therapy, emerging approaches targeting specific molecular pathways, including sarcomeric modulators, inflammatory signaling, and gene- or cell-based interventions, illustrate a shift toward more personalized and stage-specific management of DCM and heart failure. This review aims to provide an updated overview of recent advances in the molecular mechanisms and diagnosis underlying DCM and discuss their implications for current and emerging therapeutic strategies.

Background Conventional antiarrhythmic drugs that target cardiac ion channels carry proarrhythmic risks, highlighting the need for alternative therapeutic approaches. Cardiac nicotinic acetylcholine receptors (nAChRs) represent a novel electrophysiological target. Objectives The aim of this exploratory, proof-of-concept phase 2 trial was to evaluate the effect of varenicline, a partial nAChR agonist, on frequent premature ventricular complexes (PVCs) after myocardial infarction (MI) and to assess its short-term safety and biological target engagement. Methods In this multicenter, randomized, double-blind, placebo-controlled trial, adults with frequent PVCs (≥1,000/24 h) assessed using 72-hour ambulatory electrocardiographic monitoring at ≥4 weeks post-MI were randomly assigned (1:1) to varenicline 0.5 mg twice daily or matching placebo for 45 days, in addition to guideline-directed medical therapy. The primary endpoint was the percentage change in 24-hour PVC count from baseline to week 6. Key secondary endpoints included responder rate (≥50% reduction in PVC count) and the incidence of nonsustained ventricular tachycardia (VT). Results Among 118 randomized patients, varenicline produced a 60.1 percentage point greater reduction in PVC burden compared with placebo (95% CI: 21.3-98.8 percentage points; P = 0.001). The responder rate was higher with varenicline (67.8% vs 30.5%; RR: 2.22; 95% CI: 1.46-3.39; P < 0.0001), and nonsustained VT incidence was lower (20.3% vs 37.3%; RR: 0.49; 95% CI: 0.29-0.85; P = 0.007). No deaths or malignant ventricular arrhythmias occurred in the varenicline group, with comparable adverse event rates between groups. Conclusions In this phase 2 trial, varenicline significantly reduced PVC burden and nonsustained VT incidence in post-MI patients without evidence of a proarrhythmic effects. These findings support cardiac nAChRs as a potential antiarrhythmic target and justify further evaluation in larger outcome-driven trials. (Efficacy of Varenicline Tartrate in Treating Frequent Premature Ventricular Contractions: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial [Var-PVC]; NCT06780215)

Hepatitis B virus (HBV) infection represents a major global health burden. Elements play crucial roles in viral replication, immune response, and metabolic regulation, yet their systemic alterations and contributions to HBV pathogenesis remain insufficiently characterized. This study aimed to comprehensively investigate serum elementome changes associated with HBV infection. Using high‑throughput inductively coupled plasma mass spectrometry (ICP‑MS), we measured 70 elements in serum samples from 35 hepatitis B surface antigen (HBsAg) positive (+) patients and 70 matched HBsAg negative (-) controls. Seven elements including boron (B), sodium (Na), phosphorus (P), calcium (Ca), zinc (Zn), molybdenum (Mo), and barium (Ba) were significantly reduced in HBsAg (+) individuals compared to controls. Among these, Na, P, Ca, and Mo were identified as protective factors against HBV infection, while Zn exhibited a U‑shaped dose-response relationship with infection risk. Elemental levels were also correlated with renal function, hematological composition, and lipid profiles. Specifically, Mo influences HBV infection through regulating red blood cell and hemoglobin levels, whereas iodine (I) affects the disease with complete mediators such as cholesterol and low-density lipoprotein cholesterol (LDL-C). Our results defined a distinct serum elemental signature of HBV infection that links to hematopoietic and lipid metabolic pathways. This finding highlights the elementome as an integral modulator of host biochemical and immunological processes in HBV infection.

Myocarditis, primarily induced by viral infection, lacks reliable non-invasive imaging for early diagnosis. We developed a novel PET probe, 68Ga-DOTA-linagliptin (abbreviated as 68Ga-linagliptin), which targets dipeptidyl peptidase-4 (DPP4), to assess its potential in detecting myocarditis. Western blotting and immunostaining showed an elevated cardiac DPP4 expression in mice with Coxsackievirus B3 (CVB3) myocarditis. Single-cell sequencing analysis and cardiac flow cytometry further revealed that the elevated DPP4 expression predominantly originated from infiltrating immune cells, including T cells, dendritic cells, and B cells. Molecular docking and dynamics simulations, together with a DPP4 enzyme inhibition assay, demonstrated high-affinity and direct binding between 68Ga-linagliptin and DPP4. 68Ga-linagliptin showed favorable pharmacokinetics in vivo and shows significantly higher probe uptake in DPP4-overexpressing cells in vitro and in vivo. PET/CT imaging revealed pronounced 68Ga-linagliptin accumulation within the inflamed myocardium of mice with myocarditis, with minimal uptake in control animals. The PET/CT signal distribution closely matched histologically identified inflammatory regions. Moreover, pretreatment with the unlabeled precursor drug linagliptin effectively attenuated inflammation and improved cardiac function in CVB3-infected mice. These findings indicate that 68Ga-linagliptin enables sensitive and non-invasive visualization of cardiac inflammation and may offer combined diagnostic and therapeutic benefits for viral myocarditis.

Mitochondrial distress signaling provides a mechanistic link between local organelle dysfunction and systemic cardio-hepatic remodeling. In metabolic dysfunction-associated steatotic liver disease (MASLD) and heart failure (HF), hepatic nutrient overload and cardiac energy-demand mismatch generate distinct but convergent disturbances in oxidative metabolism, mitochondrial dynamics, mitophagy, and redox control. These changes alter the production, localization, and release of mitochondria-linked metabolites, mitochondrial damage-associated molecular patterns, and extracellular vesicle-associated mitochondrial cargo, enabling stressed tissues to influence distant organs. This review examines how stage-dependent bioenergetic remodeling and defective mitochondrial quality control shape distress-signal generation in MASLD and HF. We further discuss the context-dependent roles of succinate, β-hydroxybutyrate, mitochondrial DNA-dependent innate immune signaling, and extracellular vesicle-mediated cargo transport in heart–liver communication. Finally, we summarize established cardiometabolic therapies and emerging mitochondria-centered strategies that reduce substrate overload, restore organelle resilience, or limit inflammatory signal propagation. Integrating these mechanisms positions mitochondrial distress signaling as a unifying framework for understanding the bidirectional relationship between MASLD and HF and for identifying biomarkers and therapeutic targets at the heart-liver interface.

Background:Ticagrelor is recommended as the preferred antiplatelet agent for patients with acute coronary syndrome (ACS), which is controversial in East Asians, Chinese patients in particular. This study aimed to compare the efficacy and safety of ticagrelor vs. clopidogrel in Chinese ACS patients following coronary stenting. Methods:Between August 2014 and October 2020, COSTIC recruited 9,040 patients prescribed with ticagrelor or clopidogrel. Applying propensity score matching, ticagrelor was compared with clopidogrel for 1-year risks of the primary efficacy endpoint (a composite of cardiovascular (CV) death, myocardial infarction and stroke) and bleeding endpoint. Results:The risk of the primary efficacy endpoint was comparable between the two groups but numerically higher after clopidogrel at 6 months (HR, 1.33 [95 % CI, 0.98-1.80]; P = 0.07). Clopidogrel was associated with high incidences of CV death (HR, 1.49 [95 % CI, 1.04-2.15]; P = 0.03 at 6 months; HR, 1.42 [95 % CI, 1.04-1.93]; P = 0.02 at 12 months) and all-cause death (HR, 1.43 [95 % CI, 1.02-1.99]; P = 0.04 at 6 months). BARC type 3 or 5 bleeding (OR, 0.60 [95 % CI, 0.40-0.88]; P = 0.008 at 6 months; OR, 0.71 [95 % CI, 0.52-0.96]; P = 0.03 at 12 months) and BARC type 2 bleeding risks (OR, 0.47 [95 % CI, 0.34-0.66] at 1 month, OR, 0.41 [95 % CI, 0.32-0.52] at 6 months, OR, 0.43 [95 % CI, 0.35-0.53] at 12 months, P < 0.001 at 1, 6 and 12 months) were higher with ticagrelor, as compared to clopidogrel. In terms of the net clinical benefit events, clopidogrel was comparable to ticagrelor in the total cohort. Conclusions:Among Chinese ACS patients with successful PCI, ticagrelor did not significantly reduce the risk of major ischemic events; instead, it was associated with a significant elevation bleeding risk.

BACKGROUND AND AIMS:Fulminant myocarditis (FM) is a life-threatening inflammatory cardiomyopathy with high mortality. Soluble ST2 (sST2), traditionally regarded as a decoy receptor for interleukin-33 (IL-33), is markedly elevated in FM, yet its mechanistic and translational roles remain unclear. METHODS:A Coxsackievirus B3-induced FM mouse model was used to define the cellular source and function of sST2 through histological, molecular, and integrated single-cell and single-nucleus transcriptomic analyses. Cardiomyocyte responses were assessed in neonatal murine cardiomyocytes and human engineered heart tissues. The therapeutic efficacy and safety of sST2-neutralizing antibodies were evaluated in vivo, with clinical relevance examined in a cohort of FM patients. RESULTS:sST2 originated predominantly from infiltrating CCR2+ macrophages in FM hearts and aggravated cardiac damage by amplifying inflammation, mitochondrial dysfunction, and contractile failure. Mechanistically, sST2 acted independently of IL-33. It entered cardiomyocytes via IGF2R and bound the transcription factor YY1, preventing its nuclear translocation and repressing mitochondrial electron transport chain gene expression, thereby reducing ATP synthesis. Neutralizing antibodies targeting sST2 effectively restored mitochondrial function, improved hemodynamics, and reduced mortality without evident short-term systemic toxicity. Integrated single-cell and single-nucleus transcriptomic analyses revealed broad therapeutic effects across cardiomyocytes, fibroblasts, endothelial cells, and macrophages. Combined glucocorticoid and anti-sST2 therapy provided additive benefit. Clinically, elevated plasma sST2 independently predicted 30-day mortality or extracorporeal membrane oxygenation requirement in FM patients, outperforming N-terminal pro-B-type natriuretic peptide and cardiac troponin I for prognostic discrimination. CONCLUSIONS:sST2 drives FM by disrupting cardiomyocyte mitochondrial homeostasis independently of IL-33 and represents both a clinically prognostic biomarker and a therapeutic target.

Aim: To examine the association between intravenous immunoglobulin (IVIG) use and in-hospital outcomes in adults with fulminant myocarditis (FM). Methods: This two-center retrospective cohort study included 316 adults hospitalized with FM between January 2020 and January 2025; 184 received IVIG, and 132 did not. The primary outcome was all-cause in-hospital mortality. Secondary outcomes were a composite of acute liver injury (ALI) or Kidney Disease: Improving Global Outcomes-defined acute kidney injury (AKI) and successful extracorporeal membrane oxygenation (ECMO) weaning with survival to discharge. We evaluated associations using multivariable and time-dependent Cox models, an analysis restricted to methylprednisolone-treated patients, propensity-score overlap weighting, Aalen-Johansen cumulative-incidence analyses, and Fine-Gray competing-risk models. Dose- and timing-related analyses were exploratory. Results: In-hospital death occurred in 17 of 184 IVIG-treated patients (9.2%) and 51 of 132 non-IVIG-treated patients (38.6%). IVIG use was associated with lower mortality across multiple models, including the multivariable Cox model (hazard ratio [HR], 0.23; 95% confidence interval [95%CI]: 0.14-0.40; P < 0.001), the time-dependent model (HR, 0.15; 95%CI: 0.08-0.29), the methylprednisolone-treated cohort (HR, 0.15; 95%CI: 0.08-0.27), and the overlap-weighted analysis (HR, 0.24; 95%CI: 0.07-0.87). ALI/AKI occurred in 53 of 184 IVIG-treated patients (28.8%) and 72 of 132 non-IVIG-treated patients (54.5%; adjusted HR, 0.43; 95%CI: 0.30-0.61; P < 0.001). Among ECMO-supported patients, successful weaning with survival to discharge occurred in 50 of 61 IVIG-treated patients and 6 of 18 non-IVIG-treated patients (subdistribution HR, 5.89; 95%CI: 2.96-11.73; P < 0.001). Exploratory dose- and timing-related estimates did not establish an optimal IVIG regimen. Conclusions: In this two-center retrospective cohort, IVIG use within a corticosteroid-containing care pathway was associated with lower in-hospital mortality, less ALI/AKI, and a greater likelihood of successful ECMO weaning with survival. Residual and unmeasured confounding preclude causal inference; prospective multicenter validation is required.

BACKGROUND:Premature atrial contractions (PACs) are independently associated with atrial fibrillation, stroke, and heart failure, yet no pharmacological therapy is approved for PAC suppression. Experimental studies have identified a functional cardiac glutamatergic system in which N-methyl-D-aspartate receptors regulate atrial electrophysiology. Preclinical studies show that pharmacological antagonism of N-methyl-D-aspartate receptors with memantine suppresses atrial arrhythmias. METHODS:We conducted an investigator-initiated, phase 2, multicenter, randomized, double-blind, placebo-controlled trial. Symptomatic adults with frequent PACs (≥1000/24 h) were randomly assigned to receive memantine or placebo for 6 weeks. The primary end point was the percentage change in mean 24-hour PAC count from baseline to the end of treatment. The primary analysis was performed in the intention-to-treat population. Prespecified secondary end points included the responder rate (≥50% PAC reduction), percentage change in nonsustained atrial tachycardia burden, and cumulative incidence of new-onset atrial fibrillation. RESULTS:Among 241 patients included in the efficacy analysis, memantine resulted in a greater reduction in PAC count than placebo (between-group difference, 47.1 percentage points; P=0.0045). The responder rate was higher with memantine than with placebo (52.4% versus 23.1%; P<0.0001). Memantine also reduced nonsustained atrial tachycardia burden (between-group difference, 30.98 percentage points; P=0.0043) and was associated with a lower cumulative incidence of new-onset atrial fibrillation (4.8% versus 23.9%; P<0.0001). No clinically meaningful differences were observed in electrocardiographic intervals or left ventricular function, and no drug-related serious adverse events occurred. CONCLUSIONS:In patients with frequent symptomatic PACs, memantine reduced atrial ectopy and atrial tachyarrhythmia burden and demonstrated a favorable safety profile. These findings provide proof of concept for a novel, non-ion channel-based therapeutic strategy targeting the cardiac glutamatergic system. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT06501638.

BACKGROUND AND AIMS:An overactive inflammatory response and immune cell infiltration following myocardial infarction (MI) impair cardiac tissue repair. This study investigates the mechanistic role of the arachidonic acid (AA) metabolic cascade in mediating post-MI inflammation. METHODS:Single-cell RNA-sequencing analysis was performed to characterize cardiac macrophage heterogeneity in post-MI mice. Metabolomic analyses were conducted to profile polyunsaturated fatty acid metabolites in both plasma from MI patients and cardiac tissue from infarcted mice to identify key factors influencing MI progression. RESULTS:Leukotriene B4 (LTB4), an AA metabolite, was consistently elevated in MI patients and mouse models, demonstrating significantly higher plasma concentrations in recurrent MI cases. Mechanistically, AA promotes nuclear translocation of protein phosphatase 5 (PP5), which subsequently dephosphorylates 5-lipoxygenase at Thr218, driving sustained LTB4 production. This process enhances CXCL13-mediated B-cell recruitment and amplifies inflammation through macrophage-B-cell crosstalk. Disruption of PP5 in mouse macrophages prevents these adverse changes. CONCLUSIONS:The findings elucidate the conserved role of 5-lipoxygenase phosphorylation regulated LTB4 levels in MI and identify PP5 as a potential therapeutic target for the treatment of MI.

Introduction: Comparative data on long-term outcomes (> 5 years) between fulminant myocarditis (FM) and non-fulminant myocarditis (NFM) remain limited, particularly under contemporary treatment strategies in China. Aim: To compare long-term clinical outcomes between FM and NFM patients and to evaluate the prognostic value of persistent troponin I elevation. Methods and Results: In this multicenter prospective cohort study, 355 patients with myocarditis confirmed by endomyocardial biopsy or cardiac magnetic resonance were enrolled (181 FM, 174 NFM). The primary composite endpoint included cardiovascular death, heart transplantation, chronic heart failure, or cardiac structural abnormalities. The secondary outcome was persistent troponin I elevation (> 34.2 pg/mL at 1 month). Directed acyclic graphs guided covariate selection in Cox regression models. In the unadjusted analysis, FM was associated with a higher risk of the primary outcome compared with NFM [hazard ratio (HR) 1.52, 95% confidence interval (CI) 1.10-2.11; P = 0.011]. After adjustment for age, sex, and time from symptom onset to hospitalization, this association was attenuated and no longer statistically significant (HR 1.38, 95%CI 0.98-1.94; P = 0.062). Findings were consistent in propensity score-matched and age ≥ 15 years subgroups. FM patients had a higher likelihood of persistent troponin elevation [odds ratio (OR) 3.44, 95%CI 2.01-6.03; P < 0.001]. Persistent troponin elevation was positively associated with increased risk of the primary outcome. Conclusion: Under current treatment strategies in China, FM was not associated with a significantly higher long-term risk compared with NFM. However, limited statistical power may influence this finding. Persistent troponin elevation is associated with a worse prognosis.

Endothelial dysfunction and inflammation are pivotal contributors to pathological cardiac remodeling and its progression toward heart failure (HF). Sphingosine-1-phosphate receptor 3 (S1PR3), a G protein-coupled receptor enriched in endothelial cells (ECs), is an important regulator of endothelial function, but its role in pressure overload-induced cardiac remodeling remains unclear. In this study, we observed a substantial reduction in S1PR3 levels in cardiac ECs following transverse aortic constriction (TAC). Endothelial-targeted S1PR3 knockdown aggravated TAC-induced cardiac remodeling, as evidenced by aggravated myocardial fibrosis, cardiac hypertrophy, microvascular rarefaction, and inflammatory cell infiltration. Mechanistically, both in vitro and in vivo analyses showed that S1PR3 deficiency promoted endothelial inflammatory activation and NF-κB-associated signaling, and altered endothelial paracrine communication with cardiac fibroblasts and cardiomyocytes, thereby contributing to fibroblast activation and cardiomyocyte hypertrophy under pathological stress. Conversely, endothelial S1PR3 overexpression alleviated TAC-induced cardiac remodeling. Importantly, pharmacological activation of S1PR3 with CYM-5541 also attenuated functional impairment, reduced fibrosis and hypertrophy, preserved myocardial microvascular density, and suppressed inflammatory responses after TAC. Collectively, our findings identify endothelial S1PR3 as a protective regulator in pressure overload-induced cardiac remodeling and support S1PR3 as a potential therapeutic target for limiting maladaptive cardiac remodeling.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and heart failure (HF) frequently coexist within a shared cardiometabolic environment, yet their mitochondrial abnormalities are stage- and phenotype-dependent rather than uniform. In MASLD, mitochondrial adaptation evolves from increased oxidative metabolism in early steatosis toward impaired respiratory flexibility, oxidative stress, and defective quality control with disease progression, whereas the failing myocardium develops reduced energetic reserve and altered substrate utilization. These organ-specific disturbances can modify mitochondria-linked metabolites, mitochondrial damage-associated molecular patterns, stress-responsive endocrine mediators, and extracellular vesicle-associated mitochondrial cargo. However, similar mitochondrial abnormalities or circulating signals in the liver and heart do not by themselves establish direct inter-organ communication. This review distinguishes shared systemic drivers and organ-intrinsic mitochondrial stress from source-resolved cardio-hepatic signaling, highlighting hepatic ketogenesis, fibroblast growth factor 21 (FGF21), mitochondrial DNA (mtDNA)-dependent inflammatory pathways, and extracellular vesicle-mediated cargo transfer as mechanistically distinct examples with different levels of evidence. We further discuss biomarker limitations, HF-related hemodynamic liver injury, and therapeutic strategies ranging from established cardiometabolic unloading to emerging mitochondria-centered interventions. A stage-, phenotype-, and source-resolved framework may improve interpretation of mitochondrial signals and guide future mechanistic and translational studies in the MASLD–HF overlap.

Pulmonary arterial hypertension (PAH) has a poor prognosis despite available treatments. TPN171H, structurally modified from traditional Chinese medicine (Epimedium), was reported to have a high affinity for phosphodiesterase type 5 and exhibited anti-inflammatory and vasodilatory effects in preclinical studies. This phase 2a randomized trial (NCT04483115) evaluated the hemodynamic effects and safety of TPN171H in PAH. Sixty patients with PAH were randomly assigned to receive placebo, TPN171H (2.5, 5, or 10 mg) or tadalafil (20 or 40 mg) and evaluated for hemodynamic changes for 24 h. The primary endpoint was the maximum change (%) in pulmonary vascular resistance (PVR) from baseline. The key secondary endpoint was the change (%) in PVR to systemic vascular resistance (SVR) ratio at each observation point from baseline. Compared to the placebo group, the least square mean differences in the maximum change in PVR were -16.8% (95% CI, -29.1 to -4.5, p = 0.008) in TPN171H 5 mg, -15.4% (95% CI, -28.2 to -2.7, p = 0.019) in tadalafil 20 mg, and -13.3% (95% CI, -25.6 to -0.9, p = 0.036) in the tadalafil 40 mg group. Moreover, TPN171H 5 mg, but none of the tadalafil doses, showed a significant reduction in PVR/SVR ratio at 2 h (p = 0.026), 3 h (p = 0.030), and 5 h (p = 0.046) compared to the placebo group. No serious adverse events occurred. TPN171H 5 mg demonstrated favorable acute hemodynamic effects and an acceptable short-term safety profile in this exploratory trial, supporting further evaluation in adequately powered trials.

Sodium-Glucose Transport Protein 2 inhibitors (SGLT2i), initially developed as antidiabetic agents and now established as foundational therapies for heart failure, have also shown antihypertensive effects in clinical trials involving patients with diabetes and heart failure. However, the underlying mechanisms remain incompletely understood. Given the diverse roles of arachidonic acid (AA) and its metabolites in blood pressure regulation, we investigated the antihypertensive effects of SGLT2i in hypertensive patients and an animal model, and explored whether modulation of AA metabolism contributes to these effects. We first confirmed the antihypertensive effects of SGLT2i in a retrospective cohort study and spontaneously hypertensive rats (SHRs). Targeted metabolomic analysis of plasma and tissues from SHRs identified 20-hydroxyeicosatetraenoic acid (20-HETE) originating from the renal cortex as a key metabolite modulated by SGLT2i. Among the enzymes responsible for 20-HETE production, CYP4A but not CYP4F was found to be downregulated by dapagliflozin at both mRNA and protein levels. Immunofluorescence colocalization further localized this effect to proximal tubular epithelial cells, where SGLT2i reduced CYP4A expression and subsequent 20-HETE production, leading to attenuated renal inflammation, fibrosis and blood pressure elevation. Together, these findings not only confirm the antihypertensive effects of SGLT2i but also delineate a novel antihypertensive mechanism by which lower blood pressure, demonstrating that modulation of arachidonic acid metabolism contributes partially to blood pressure-lowering effects.