Hyperhomocysteinemia, an elevation of plasma homocysteine levels, has been implicated in multiple diseases, yet its causal role remains debated. This umbrella review systematically evaluated and graded the evidence from published systematic reviews and meta-analyses on associations between hyperhomocysteinemia and diverse health outcomes.

We searched Medline, Embase, and Web of Science up to March 5, 2025. Eligible studies were systematic reviews and meta-analyses of observational studies reporting associations between hyperhomocysteinemia and any health outcome. Methodological quality was assessed using AMSTAR-2, and the certainty of evidence was graded using GRADE.

A total of 104 meta-analyses including 2,110 studies and 953,793 participants were analyzed, covering 126 outcomes. Eighty-three percent of outcomes showed significant associations with hyperhomocysteinemia. Nine outcomes were supported by high, 18 by moderate, 73 by low, and 26 by very low certainty of evidence. High-certainty evidence supported associations between hyperhomocysteinemia and increased risks of stroke, intracerebral haemorrhage, fracture (hip and total), and chronic kidney disease. Moderate-certainty evidence linked hyperhomocysteinemia to dementia, Alzheimer's disease, mortality, and selected cardiovascular and pregnancy outcomes. Most meta-analyses were of low or critically low methodological quality.

Across nearly one million participants, hyperhomocysteinemia was consistently associated with adverse health outcomes, particularly vascular, neurological, skeletal, and renal conditions. While causality cannot be inferred, the evidence supports hyperhomocysteinemia as a potentially modifiable risk factor meriting targeted preventive and interventional research.

https://osf.io/dezms.

Glycogen storage diseases (GSDs) are a heterogeneous group of rare and often under-recognized causes of inherited cardiomyopathy characterized by pathological glycogen or autophagic vacuole accumulation of debris within various tissues, including the heart. These diseases often present as phenocopies of sarcomeric hypertrophic cardiomyopathy, though they may also manifest with dilated or mixed phenotypes. Key GSDs with cardiomyopathy include Pompe disease (GSD IIa), Danon disease (IIb), Cori/Forbes disease (GSD III), Andersen disease (GSD IV), Tarui disease (GSD VII), phosphorylase kinase deficiency (GSD IX), glycogenin-1 deficiency (GSD XV), and PRKAG2 syndrome, each presenting unique clinical trajectories. Accurate diagnosis requires integration of clinical red flags, multimodality cardiac imaging, and electrocardiography, alongside definitive diagnostic tools like enzyme screening, genetic testing, and endomyocardial biopsy. There is a dearth of evidence regarding specific treatment of each unique GSD cardiomyopathy, but emerging therapeutics across the spectrum of GSDs aim to address this need. This review covers current knowledge on the spectrum of GSD-related cardiomyopathies, discussing pathophysiology, diagnosis, and evolving treatment strategies.

The cardiovascular-renal-liver-metabolic (CKLM) syndrome integrates dysmetabolically driven heart, vascular, kidney, and liver diseases through a shared pathophysiological substrate. In obesity, upregulation of the clearance natriuretic peptide receptor C (NPR-C) in adipose tissue creates a "NP deficiency," undermining the protective cardiovascular and metabolic actions of endogenous NPs. Recent preclinical data demonstrates that NPR-C functions beyond simple peptide clearance. Through interactions with ligands like CNP, musclin, and osteocrin, NPR-C triggers context-dependent intracellular signaling. In experimental models, independent of systemic NP levels, NPR-C directly modulates cardiac remodeling, podocyte injury, hepatic steatosis, vascular inflammation, and adipocyte function. This review synthesizes NPR-C biology within the CKLM framework. While human validation remains limited, targeting tissue-specific NPR-C pathways represents a promising therapeutic frontier for restoring cardiometabolic homeostasis.

Mitochondrial dysfunction contributes to numerous human diseases. Voltage‑dependent anion channel 2 (VDAC2) is an essential outer mitochondrial membrane porin with distinct structural and functional properties that are non-redundant with those of VDAC1 and VDAC3. VDAC2 precisely controls ATP, ADP, NADPH and Ca²⁺ transport, thereby acting as a key hub for energy metabolism, calcium homeostasis, redox balance and cell fate. It directly binds BAX/BAK to differentially regulate apoptosis and is also involved in ferroptosis, necroptosis, Parkin‑dependent mitophagy, and lipid transport through protein interactions and post‑translational modifications. Aberrant expression or dysfunction of VDAC2 promotes tumorigenesis, neurodegenerative diseases, and cardiovascular disorders through metabolic reprogramming, apoptotic imbalance, immune evasion, and impaired mitochondrial quality control. Several small‑molecule compounds and peptides targeting VDAC2 have been developed, providing valuable tools for mechanistic studies and potential therapies for mitochondrial dysfunction‑related diseases. Several major challenges remain, including poor isoform selectivity, a lack of tissue‑specific conditional knockout models, and unclear cross‑species conservation. This review systematically summarizes the structure of VDAC2, its versatile roles in mitochondrial function, disease mechanisms, and advances in pharmacological targeting. We also highlight current limitations and future directions, with the aim of providing a theoretical basis for VDAC2‑targeted drug development and clinical translation.

Cyclooxygenase-2 (COX-2), a key enzyme to catalyzes the formation of prostanoids from arachidonic acid, is involved in inflammatory events. Furthermore, the calpain/PARP/NF-κB inflammatory pathway has been implicated in the damage to the neurovascular unit (NVU) following ischemic stroke. This study investigated the effects of parecoxib, a specific COX-2 inhibitor, on calpain, PARP, NF-κB inflammatory signaling, and NVU damage in the rat model of ischemic stroke. Male Sprague-Dawley rats (n = 107) were subjected to 90 min of ischemia, followed by reperfusion. Parecoxib was administered intraperitoneally 5 min post-ischemia, and the activation of calpain, PARP, and NF-κB-inflammatory signaling, and the NVU damage were evaluated 24 h post-ischemia. It was found that parecoxib alleviated neurological deficits, brain swelling and apoptotic cell death, and decreased infarct volumes 24 h post-ischemia. It decreased the levels of calpain 1 and 2, enhanced the levels of calpastatin, and repressed the activities of calpain in penumbra and core. Meanwhile, it reduced the levels of cytosolic PARP and HMGB1, elevated the level of cytosolic IκBα, lowered the levels of nuclear PARP, poly(ADP-ribose) and NF-κB p65, lessened the levels of cytosolic ICAM-1, IL-1β, MMP-2, and MMP-9, and suppressed the MPO activities in penumbra and core. Additionally, it attenuated the NVU and blood-brain barrier damage in penumbra and core. These data demonstrated that parecoxib exerts its protective effects on the NVU by blocking the over-activation of calpain and PARP, as well as by suppressing NF-κB-mediated inflammatory response during ischemic stroke. Moreover, the findings suggest that COX-2 contributes to NVU damage by up-regulating the calpain/PARP/NF-κB inflammatory pathway during brain ischemia.

To externally validate and compare CUORE and SCORE2 for 10-year prediction of first fatal or non-fatal myocardial infarction or stroke in an Italian primary care cohort, and to quantify the impact of administrative endpoint definition and model recalibration.

We studied 38,101 adults in ATS Milan (baseline 2007-2009) with primary care risk factors linked to hospital discharge and mortality registries for 10-year follow-up. The endpoint was first fatal or non-fatal myocardial infarction or stroke, ascertained using a strict (primary diagnosis/procedure fields) and a broad (any diagnosis/procedure field) administrative definition. Discrimination was assessed with IPCW time-dependent AUC and calibration with decile plots, calibration-in-the-large and calibration slope, comparing uncalibrated and recalibrated implementations. SCORE2 AUC ranged 0.713-0.720, whereas CUORE ranged 0.730-0.741. Broad ascertainment increased event rates (SCORE2: 5.6% vs 4.4%; CUORE: 6.8% vs 5.0%) without materially changing AUC. SCORE2 showed more stable calibration, whereas CUORE showed calibration slopes <1.

In this real-world Italian cohort, CUORE and SCORE2 provided robust ordinal risk stratification and moderate discrimination at 10 years. Absolute risk estimates were sensitive to administrative endpoint mapping and recalibration strategy, supporting transparent endpoint reporting and local calibration assessment before applying risk thresholds in practice.

Obesity and diabetes are widely recognized risk factors for cardiovascular disease, and their increase among Indigenous populations has been documented in the medical literature. Given the regional differences in the prevalence of metabolic disorders, this study aimed to evaluate the prevalence of obesity, diabetes, and other metabolic conditions in the Bororo population of the Central-West region of Brazil.

In this cross-sectional study, 152 Bororo individuals from the Meruri Reservation in Mato Grosso, Brazil, underwent clinical, anthropometric, and laboratory assessments.

Women presented a worse metabolic profile than men, demonstrating significantly higher body mass index, waist circumference, total cholesterol, LDL-c, and 2-hour glucose levels, whereas men exhibited higher systolic blood pressure. Obesity was observed in 30.2% of the participants, with a higher prevalence among women (40.0% vs. 21.9%, p = 0.02). Prediabetes affected 51.3% of the participants, showing a higher prevalence in older men than in younger men (70.6% vs. 43.7%, p = 0.02). Diabetes was diagnosed in 9.2% of the participants, exclusively among women (20.0%), and rose to 38.7% in women aged ≥40 years. Hypertension was present in 23.0% of the participants and was positively associated with age. Central obesity was highly prevalent in this study cohort (72.3%).

Our findings revealed an unfavorable metabolic profile among the Bororo Indigenous population, particularly in older women. This underscores the critical need for sexand age-specific preventive measures and management strategies for metabolic diseases in this population.

11β-hydroxylasedeficiency (11β-OHD) is a rare form of congenital adrenal hyperplasia caused by biallelic pathogenic variants in the CYP11B1 gene. It leads to impaired cortisol synthesis, resulting in increased adrenocorticotropic hormone stimulation and consequent accumulation of steroid precursors, which are diverted to androgen synthesis. In addition, the accumulation of 11-deoxycorticosterone, which is a potent mineralocorticoid, causes hyporeninemic hypokalemic hypertension. We report the clinical, hormonal, and genetic profiles of five children with 11β-OHD, emphasising phenotypic variability, a median 2-year diagnostic delay, the crucial role of hormonal profile in diagnosis, and management challenges, including post-treatment central precocious puberty. Two novel CYP11B1 variants were identified in two unrelated patients. Hydrocortisone replacement resolved hypertension in only one of the three hypertensive patients; others required spironolactone. Early differentiation of 11β-OHD from 21-hydroxylase deficiency is critical to prevent hypertension-related morbidity.

Cerebral venous sinus thrombosis (CVST) is an uncommon cause of stroke. This case report describes a 47-year-old man who developed concurrent sigmoid sinus thrombosis and bilateral cephalic vein thrombosis following traumatic brain injury and surgical evacuation of an epidural hematoma. The patient presented with a new headache on postoperative day 5. Diagnosis was confirmed by CT angiography and Doppler ultrasound. He was successfully treated with subcutaneous enoxaparin, resulting in symptom resolution and radiologic improvement. This case highlights that CVST can co-occur with peripheral thrombosis post-trauma, indicating a systemic hypercoagulable state. Early recognition and anticoagulation are crucial for management, even in a postoperative setting, underscoring the need for vigilance in these complex patients.