Coronary microvascular disease (CMVD) is an important contributor to ischemic heart disease. Symptomatic patients without obstructive coronary lesions may still have microvascular ischemia, which is associated with an increased risk of major adverse cardiovascular events. The diagnosis of CMVD relies on coronary function testing or noninvasive imaging techniques, which are not universally available and may limit routine clinical implementation.

Growing evidence supports the notion that biological processes such as inflammation and oxidative stress drive vascular aging and contribute to microvascular dysfunction. The systemic immune-inflammation index (SII) is a marker used to assess immune-inflammatory and thrombotic status and has shown prognostic value in chronic heart failure, and acute myocardial infarction. However, its role in CMVD remains underexplored.

To address this gap, we retrospectively analyzed 180 patients with angina who underwent myocardial contrast stress echocardiography between January and November 2022 at the First Affiliated Hospital of Harbin Medical University.

Based on coronary microcirculatory function, patients were divided into two groups: 91 with normal function and 89 with microcirculatory disorders. Clinical data and lab indicators were compared.

SII was significantly higher in the CMVD group (722.96 ± 354.10 vs 618.51 ± 324.50; p < 0.05). Logistic regression identified SII, LDL cholesterol as independent CMVD predictors. Pearson correlation demonstrated an inverse relationship between SII and coronary flow reserve, supporting its link with impaired microvascular function. Receiver operating characteristic analysis further showed that the combined SII and LDL model provided improved discriminatory performance compared with either marker alone, achieving an area under the curve of 0.76 with a sensitivity of 77.5% and specificity of 69.2%.

SII is independently associated with CMVD and improved discriminatory performance when combined with LDL.

Ventriculoperitoneal (VP) shunting is the standard surgical treatment for hydrocephalus, yet it is associated with a wide range of complications. Distal catheter migration into the pericardial cavity is exceedingly rare and poses an immediate life-threatening risk due to potential cardiac tamponade.

A 1-year-old male infant, who had undergone VP shunt insertion for congenital communicating hydrocephalus at 3 months of age, presented with acute respiratory distress. Neuroimaging revealed a right-sided subdural hygroma. Chest imaging demonstrated a right pleural effusion and a large pericardial effusion, with the distal tip of the VP shunt catheter visualized within the pericardial sac. Urgent multidisciplinary intervention involving neurosurgery, pediatric surgery, and cardiothoracic surgery was undertaken. The migrated catheter was removed; the pericardial defect was repaired, and a new distal catheter was repositioned into the peritoneal cavity. Temporary ligation of the shunt was performed to manage the subdural hygroma, followed by gradual reopening after clinical and radiological resolution.

Pericardial migration of a VP shunt is a rare but potentially fatal complication. Early recognition through appropriate imaging and prompt multidisciplinary surgical management are crucial to achieving favorable outcomes and preventing mortality.

Lung ischemia-reperfusion injury (IRI), a significant factor contributing to early mortality following lung transplantation (LTx), is driven by molecular mechanisms that are not yet fully understood. In this study, we elucidate a crucial signaling pathway initiated by extracellular histones (ex-His), which connects mitochondrial damage to inflammatory cell death. Through the use of a murine model of lung IRI and in vitro experiments with alveolar macrophages, we demonstrate that ex-His facilitate Drp1-dependent mitochondrial fission, resulting in the release of oxidized mitochondrial DNA (ox-mtDNA) into the cytosol. Our mechanistic analysis reveals that cytosolic ox-mtDNA is detected by the transcription factor IRF1, which subsequently upregulates NLRC5 at the transcriptional level. Additionally, we identify NLRC5 as a non-canonical scaffold that is essential for the assembly of the PANoptosome, a multi-protein complex that mediates PANoptosis, an inflammatory cell death pathway that aggravates tissue damage. The clinical relevance of this pathway was then examined in lung transplant recipients. An analysis of their peripheral blood mononuclear cells (PBMCs) revealed that patients who developed primary graft dysfunction (PGD) exhibited markedly elevated levels of circulating histones and cytosolic ox-mtDNA. This was associated with hyperactivation of the core signaling axis, characterized by increased Drp1 phosphorylation and elevated expression of IRF1 and NLRC5. Collectively, our study elucidates a comprehensive pathogenic cascade from an extracellular danger signal to a specific cell death program, identifying the ex-His-mitochondria-IRF1-NLRC5 axis as a critical driver of macrophage PANoptosis and a promising therapeutic target for alleviating lung IRI.

Vascular aging profoundly impacts on cardiovascular disease. Sirtuin 3 (SIRT3) is a key regulator of metabolic homeostasis whose expression declines with age; however, the mechanisms linking SIRT3 deficiency to age-associated vascular impairment remain unclear. Here, we investigated whether SIRT3 deficiency drives age-associated vascular impairment by inducing mitochondrial dysfunction and initiating endothelial-to-mesenchymal transition (EndMT).

Vascular morphology, aging-related protein expression, and endothelium-dependent vasorelaxation were evaluated in young (5-month-old) and aged (21-month-old) wild-type mice, alongside Sirt3 knockout (KO) mice. EndMT was assessed using immunofluorescence and immunoblotting. Mitochondrial function was examined by assessing mitochondrial morphology, determining the protein expression of mitochondrial biogenesis-related factors and superoxide dismutase 2, and measuring mitochondrial reactive oxygen species levels. In vitro, human umbilical vein endothelial cells (HUVECs) were transfected with SIRT3-targeting siRNA and treated with H₂O₂ to induce premature senescence, after which mitochondrial function and EndMT marker levels were analyzed.

Vascular aging was characterized by increased expression of aging-related proteins, endothelial dysfunction, and medial calcification and fibrosis, which were linked to EndMT and mitochondrial dysfunction in aged endothelial cells (ECs). SIRT3 expression was downregulated in aging vascular ECs. Sirt3 KO mice exhibited exacerbated vascular calcification and fibrosis, associated with the promotion of aging-induced EndMT and the aggravation of mitochondrial dysfunction. Silencing SIRT3 in prematurely senescent HUVECs confirmed its role in driving EndMT and mitochondrial dysfunction.

SIRT3 deficiency promotes age-related vascular impairment potentially by mediating EndMT and mitochondrial dysfunction, Thus, SIRT3 represents a potential therapeutic target for delaying vascular aging and associated cardiovascular diseases.

Methylmalonic acidemia (MMA)-induced pulmonary hypertension (PH) is a rare but treatable cause of pediatric PH, often misdiagnosed as idiopathic pulmonary arterial hypertension (IPAH).

We conducted a 10-year, multicenter retrospective study of children with clinically unexplained PH. Thirteen patients with MMA-PH were compared to 113 with idiopathic or hereditary PAH (IPAH/HPAH) regarding clinical features, hemodynamics, and outcomes.

MMA-PH accounted for 2.7% of pediatric PH cases. Patients presented younger (7±4 vs. 11±5 years, p=0.008) and exhibited higher rates of growth failure (84.6% vs. 15.9%, p<0.001), anorexia/malnutrition (76.9% vs. 14.2%, p<0.001), recurrent pneumonia (46.2% vs. 13.3%, p=0.003), microscopic hematuria (84.6% vs. 1.8%, p<0.001), and proteinuria (31% vs. 4.4%, p=0.007) than IPAH/HPAH. All had the combined MMA subtype with markedly elevated homocysteine (median 87 µmol/L vs. 18 µmol/L, p<0.001). With metabolic therapy (hydroxocobalamin, betaine, etc.) and short-term pulmonary vasodilators, all achieved complete clinical and hemodynamic remission within one year. Median follow-up was 7.0 years; no relapse occurred.

Elevated total homocysteine and multisystem involvement should prompt metabolic screening in children with unexplained PH. Early diagnosis and metabolite-targeted treatment can lead to sustained, nearly-curative outcomes, distinguishing MMA-PH from IPAH/HPAH. Routine homocysteine testing is recommended in the diagnostic workup of pediatric PH.

Adults with congenital heart disease (CHD) experience earlier and higher cardiovascular morbidity and mortality than the general population. Serious illness conversations (SICs) can help align care with patients' values and preferences but are underused, partly because clinicians lack guidance on when to initiate them.

This study aimed to develop consensus-based clinical criteria that should prompt SICs in adults with CHD, incorporating perspectives from clinical experts, people with lived experience (PWLE), and advocacy group representatives.

In a modified Delphi study, an international panel of 39 health care professionals rated 67 potential SIC trigger criteria over 3 rounds. Consensus was predefined as ≥70% agreement. A second panel of 4 PWLEs and 4 advocacy group representatives rated the Round 1 consensus triggers for appropriateness. Triggers deemed sufficient on their own were labeled as "major," those requiring at least one additional criterion were labeled as "minor."

Forty-one clinical experts were invited, of which 39 agreed to participate. Response rates were 94.9% in Rounds 1 and 2, and 92.3% in Round 3. Fifty of 67 criteria (74.6%) reached consensus in Round 1, and all were judged appropriate by PWLE and advocacy group representatives. Eighteen criteria were classified as major, spanning "patient needs," "CHD-defect characteristics," "lifetime events," "preintervention" triggers, "disease progression," and the surprise question.

This international consensus identified 18 major trigger criteria to support timely SIC initiation in adults with CHD. These criteria span diverse clinical scenarios and provide a practical framework for integrating SICs into routine care for adults with CHD.

EP4 is a G protein-coupled receptor for prostaglandin E2 (PGE2) that drives the key pathological processes involved in inflammation, immune suppression, and carcinogenesis, making it a promising drug target for treating various human diseases. Pharmacological blockade of EP4 neutralizes the deleterious effects of PGE2 without impairing the biosynthesis of other protective prostaglandins, thus circumventing the dose-limiting gastrointestinal and cardiovascular adverse events associated with effects characteristic of cyclooxygenase inhibitors, including traditional nonsteroidal anti-inflammatory drugs (NSAIDs). Since the discovery of EP4 as a drug target, rapid innovation has led to multiple potent and EP4-selective antagonists advancing to clinical trials. This article comprehensively reviews the medicinal chemistry of EP4 antagonists, analyzes the latest clinical advancements, summarizes recent breakthroughs in dual and triple prostanoid receptor antagonists, and critically evaluates future challenges and opportunities, thereby providing valuable insights and guidance for the development of next-generation EP4 antagonists.

Atherosclerosis significantly contributes to global cardiovascular mortality. Macrophage polarization and foam cell formation via oxidized low-density lipoprotein uptake are key drivers of plaque progression and instability. Targeting these processes may offer a promising therapeutic approach. This study aimed to investigate the potential therapeutic effects of Shanhuang Jiangzhi tablets (SHJZT) using apolipoprotein E-deficient mice and RAW264.7 macrophage-based experimental models.

Key assays, including oxidized low-density lipoprotein-induced foam cell formation and lipopolysaccharide (LPS)-induced macrophage polarization, were performed to elucidate the regulatory effects of SHJZT, with a particular focus on the reactive oxygen species (ROS)/Toll-like receptor 4 (TLR4)/NF-κB signaling pathway.

In vivo, SHJZT treatment significantly attenuated atherosclerotic lesion development, improved lipid metabolism, and enhanced reverse cholesterol transport by regulating ABCA1 and ABCG1 expression, thereby suppressing foam cell formation. Furthermore, SHJZT promoted macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Mechanistic investigations revealed that SHJZT mitigated LPS-induced ROS production and inhibited the activation of the TLR4/NF-κB signaling cascade in vitro. Specifically, SHJZT downregulated key pathway components, including TLR4, MYD88, and phosphorylated NF-κB p65, in high-fat diet-induced atherosclerosis.

SHJZT exerts anti-atherosclerotic effects by modulating macrophage polarization and inhibiting foam cell formation through the suppression of ROS/TLR4/NF-κB signaling pathway.

Guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) is well established, but data on differences between men and women in real-world use, tolerability, and outcomes are limited. We examined these differences in contemporary HFrEF patients.

TITRATE-HF is a prospective registry across 48 Dutch hospitals (inclusion June 2022-February 2024), enrolling patients with de novo, chronic, and worsening heart failure (HF). This analysis studied 3,367 HFrEF patients and compared men and women regarding GDMT implementation, side effects, change in left ventricular ejection fraction (LVEF), and clinical outcomes (composite endpoint: first HF hospitalization or all-cause death). The cohort included 2,408 men (71.5%; 71 years [IQR 63-77]) and 959 women (28.5%; 72 years [IQR 64-79]). At 12-month follow-up, 59.0% of men and 59.7% of women received quadruple therapy (p=0.729). Men more often achieved quadruple therapy at ≥50% of target doses (16.2% versus 11.9%, p=0.004). Compared to men, women experienced more downgrades of ARB (11.6% versus 6.9%, p=0.040) and MRA (13.2% versus 10.4%, p=0.038) due to side effects. In de novo HFrEF, women showed greater LVEF improvement than men (15% versus 13%, p=0.005). In chronic HFrEF, women had lower risk of the composite endpoint compared to men (aHR 0.64, 95% CI 0.45-0.91; p=0.015).

GDMT initiation and sequencing were comparable between men and women, but differences were observed in dose achievement, treatment tolerability, and clinical outcomes. These findings underscore the need for implementation and dosing strategies that account for differences between men and women.

Chronic kidney disease-mineral bone disorder (CKD-MBD) concerns more than 50% of patients with moderate/severe CKD, increasing their risk for fractures and cardiovascular events.

To present its pathogenesis, clinical presentation and management.

A Pubmed search for CKD-MBD until December 2025 was conducted using combinations of relevant terms.

Total-body positive phosphate balance, increased levels of fibroblast-growth factor 23 (FGF-23) and sclerostin, and bone resistance to parathyroid hormone (PTH) are the earliest detected abnormalities, followed by calcitriol deficiency, secondary hyperparathyroidism, and bone minerals derangement. High bone turnover and adynamic bone disease stem from PTH excess and deficiency/resistance respectively, with the latter being prevalent in early CKD, peritoneal dialysis and post-kidney transplantation. Osteomalacia is rare, while mixed uremic osteodystrophy is rather common. Fracture risk assessment is based on fracture risk assessment tool, bone mineral density testing and vertebral morphometry, while bone biopsy remains the gold standard for renal osteodystrophy evaluation. Cardiovascular manifestations include vascular calcifications and left ventricular hypertrophy induced by mineral stress in the setting of disrupted buffering system, osteoblastic differentiation of vascular smooth cells and direct FGF-23 effects in myocardium. In severe secondary hyperparathyroidism, active vitamin D and analogues, calcimimetics, and, in refractory cases, parathyroidectomy effectively lower PTH. In mild/moderate CKD, the efficacy of all anti-osteoporotic agents is mainly proven in post-menopausal women without biochemical evidence of CKD-MBD. In dialysis patients, denosumab is the best-studied agent, while recent data highlight pronounced therapeutic benefit of romosozumab. Finally, teriparatide has demonstrated utility in treating adynamic bone disease.

Fracture risk prevention in CKD-MBD should be prioritized. Dedicated research and validation of CKD-specific bone turnover markers may assist towards this direction.