Citations

Giant cell arteritis (GCA) is the most common primary systemic vasculitis of older adults and has traditionally been framed as an ophthalmologic emergency. Its most serious consequences, however, occur in the cardiovascular system, often years after inflammatory markers have normalized. In contemporary matched population cohorts, patients with GCA carry an approximately two-fold excess risk of aortic aneurysm; the historical Olmsted County cohort reported a 17-fold excess of thoracic aortic aneurysm with wide confidence limits, and the characteristic latency to aneurysm is five to ten years. Patients also face elevated risks of aortic dissection, myocardial infarction, stroke, venous thromboembolism, and heart failure that cluster within the first year of diagnosis, when vascular inflammation is most active. This narrative review, based on a structured search of PubMed/MEDLINE and Google Scholar through September 2026 with independent verification of every cited estimate, synthesizes current evidence on the full spectrum of cardiac and aortic complications of GCA, including aortitis, aneurysm and dissection, coronary arteritis, valvular disease, pericarditis, myocarditis, and conduction disease. We trace their common origin to the immunopathology of the arterial wall, where dendritic cell activation, Th1/Th17 polarization, and maladaptive vascular remodeling produce occlusion in medium-sized arteries and dilation in the aorta. We examine current diagnostic modalities, from the ultrasound-based fast-track clinic, which has reduced permanent visual loss by half or more in observational cohorts, to FDG-PET/CT, in which aortic uptake at diagnosis is associated with subsequent aortic dilation. We review treatment after the GiACTA and SELECT-GCA trials in the light of the 2025 European Alliance of Associations for Rheumatology (EULAR) recommendations, the unresolved role of antiplatelet and statin therapy, and the surgical and endovascular management of GCA-related aortopathy. We suggest that the organization of care, as well as the limitations of drug therapy, may contribute to the residual mortality of GCA, a hypothesis that has not been tested; distinguish recommendations that are supported by current guidelines from those that are our own proposals; and outline a cardio-rheumatology pathway in which baseline vascular phenotyping informs individualized aortic surveillance. GCA is a disease whose natural history often begins in the rheumatology clinic and ends in the cardiac operating room without prior surveillance.

Hyperglycemia in prediabetes is accompanied by increased amino acid (AA) concentrations and impaired suppression of glucagon secretion by glucose. It is unknown whether an abnormal response to AA contributes or hepatic steatosis exacerbates α-cell dysfunction. Therefore, lean participants and participants with obesity (with and without hepatic steatosis) were studied on two occasions in random order using a graded glucose infusion. Saline or an AA mixture was infused. The glucagon secretion rate (GSR) was derived from peripheral glucagon concentrations, and the change in glucose required to reduce GSR by 50% (G50) was calculated for each participant. AAs were measured during the experiment. On both occasions, experimental conditions produced a progressive rise in insulin secretion and an inverse exponential suppression of glucagon. G50 did not differ between groups in response to glucose alone. AA infusion did not change G50 in lean participants. G50 increased during AA infusion in participants with obesity with and without hepatic steatosis, leading us to report these participants as a single group. The relative change in AA concentrations across study days was generally similar between groups. We conclude that despite a normal response to glucose, obesity increases α-cell responses to AA in humans. Article Highlights The aim of this study was to understand the pathogenesis of α-cell dysfunction in prediabetes. The primary hypothesis was that α-cell responsivity to glucose (reduction of the glucagon secretion rate by 50%) is impaired by amino acid (AA) infusion. A secondary hypothesis was that this abnormal response is exacerbated by hepatic steatosis. AA infusion impaired α-cell suppression in response to rising glucose in participants with obesity, but not in lean participants, despite a normal response to glucose alone. This abnormal response was unaffected by the presence or absence of hepatic steatosis. It seems likely that an abnormal α-cell response to AAs precedes an abnormal response to glucose alone.

Introduction Advancements in transplant care have led to an increasing number of women with solid organ transplantation (SOT) living through peri- and postmenopause. Menopause can significantly impact quality of life, and the added burden of SOT may exacerbate symptoms. Few studies have evaluated the menopausal experience in this population, and existing data rarely use validated questionnaires. Research Question This study aimed to characterize menopausal symptoms and menopausal hormone therapy (MHT) use in peri- and postmenopausal SOT recipients using validated measures. Design A cross-sectional survey study of female patients ≥18 years who underwent SOT between 2018 and 2023 was conducted at a tertiary transplant center. A reproductive and sexual health questionnaire incorporating validated instruments, including the Menopause Rating Scale (MRS), was administered. Results Among peri- and postmenopausal SOT recipients ( n = 192), 8.9% reported use of MHT. The median MRS total score was 8.0, consistent with mild-to-moderate symptom severity overall. Symptom severity differed by menopausal status for vasomotor symptoms ( P =.03), sleep disturbances ( P = .04), depressive mood ( P = .04), and anxiety ( P <.001), with perimenopausal participants generally reporting more symptoms in these domains than postmenopausal participants. Despite these differences, overall symptom severity remained mild to moderate in both groups. Conclusion Menopausal symptoms among female SOT recipients are common but generally mild to moderate, with low utilization of MHT. The lack of increased vasomotor burden compared to prior literature may reflect under-recognition or misattribution of symptoms to transplant-related factors. Incorporating menopause-specific screening into transplant care may improve symptom recognition, quality of life, and long-term health outcomes.

Abstract Glioblastoma (GBM) remains the most lethal primary brain cancer due to its remarkable metabolic plasticity and therapeutic resistance. Here, we identify cholesterol dependency as a therapeutically exploitable vulnerability in GBM using two FDA-approved drugs: the H1 histamine antagonist clemastine and the retinoid X receptor agonist bexarotene. Combined treatment induces potent synergistic anti-tumor activity across patient-derived glioma models, suppressing proliferation, stemness, and survival at sub-IC50 concentrations. Mechanistically, this therapy disrupts cholesterol biosynthesis, transport, and homeostasis, triggering endoplasmic reticulum stress and activation of the unfolded protein response, ultimately leading to autophagy and apoptotic cell death. Orthotopic patient-derived glioma models recapitulate these mechanisms in vivo, where local intracranial administration significantly reduces tumor progression and prolongs survival using fourfold lower doses than systemic intraperitoneal delivery. Single-cell RNA sequencing revealed activation of regeneration and plasticity programs, accompanied by immune microenvironment remodeling and enhanced inflammatory signaling. Importantly, syngeneic models preserved immune cell composition, supporting future integration with immunotherapeutic strategies. Together, these findings establish cholesterol dysregulation–induced metabolic collapse as a promising therapeutic approach for GBM.

ABSTRACT Background Genetic testing for cardiomyopathy and arrhythmia (CM/ARRH) provides diagnostic information and informs screening for at-risk relatives. Clinical guidelines recommend genetic testing for these conditions; however, data on how genetic test results influence clinical management recommendations are limited. Here, we determined the frequency of cardiologist-recommended management changes for patients following CM/ARRH genetic testing. Methods This was a retrospective cross-sectional study of patients referred for multigene panel testing between April 2016 and April 2024. Genetically-experienced cardiologists at multicenter academic clinical practices were recruited for participation to complete surveys indicating clinical decision making on patients who had genetic testing. Cases for review were randomly selected to have both positive and non-positive results. Results Among 249 patients (138 positive, 111 non-positive), 136 (54.6%) received clinical management recommendations for their own or their at-risk relatives’ care. Of these, 75 (55.1%) received recommendations for the patient’s own care, most frequently additional diagnostic tests/procedures (n=33). Compared to non-positive results, patients with positive results were more likely to receive recommendations for their own management (66/138, 47.8% vs 9/111, 8.1%; P<0.00001). Patients with positive results in arrhythmogenic cardiomyopathy genes had 263% higher odds of recommended management changes compared to those with TTN (OR=3.63, CI:1.40-9.84, P=0.009). Conclusions The results from CM/ARRH genetic testing on affected patients influenced cardiologists’ medical decision making and management recommendations. Additional research is needed to evaluate how genetic testing for CM/ARRH impact health outcomes.

Abstract Insulin autoimmune syndrome (IAS), also known as Hirata disease, is a rare cause of spontaneous hypoglycemia due to circulating insulin autoantibodies, most commonly described in East Asian individuals and those exposed to sulfhydryl-containing drugs. We describe a 58-year-old South Asian man with type 2 diabetes mellitus who presented with recurrent fasting and postprandial hypoglycemia despite cessation of all glucose-lowering medications. A spontaneous episode confirmed Whipple triad: plasma glucose 38 mg/dL (SI: 2.1 mmol/L; reference range, 70-99 mg/dL [SI: 3.9-5.5 mmol/L]), markedly elevated serum insulin at 156 µIU/mL (SI: 1083 pmol/L; reference range, 2.6-24.9 µIU/mL [SI: 18-173 pmol/L]), and C-peptide of 5.8 ng/mL (SI: 1.9 nmol/L; reference range, 0.5-2.0 ng/mL [SI: 0.17-0.66 nmol/L]), with a negative sulfonylurea screen and markedly elevated insulin autoantibody titers. Polyethylene glycol precipitation confirmed antibody-bound insulin sequestration. Workup identified IgG-kappa monoclonal gammopathy of undetermined significance as the probable precipitant. Dietary modification, oral glucocorticoids, and acarbose achieved near-complete resolution of hypoglycemia with declining autoantibody titers over 4 weeks. This case highlights the importance of considering IAS in unexplained hyperinsulinemic hypoglycemia and the need to screen for plasma cell dyscrasias in atypical presentations.

Abstract Since its introduction in 2002, left atrial appendage closure (LAAC) has rapidly expanded as an alternative to anticoagulation in patients with atrial fibrillation at high risk of stroke. Harmonized processes for data collection, analysis, and reporting in LAAC trials are essential to enhance research quality and improve clinical practice. The Left Atrial Appendage Academic Research Consortium (LAARC) initiative is an independent collaboration of academic research organizations, cardiology and neurology experts, clinical trialists, and regulatory authorities from the USA, Europe, and Asia. The consortium engaged clinical experts, regulators—including the US Food and Drug Administration (FDA), European Notified Bodies, and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA)—and industry leaders to define standardized study elements and endpoints for LAAC trials. Key considerations included alignment with prior Academic Research Consortium initiatives, procedural and mechanistic insights, and clinical relevance. Consensus definitions were proposed for mortality, stroke, bleeding, and device performance, along with composite endpoints for safety and effectiveness. The proposed LAARC consensus definitions aim to standardize endpoint reporting, improve comparability across studies, and support regulatory and clinical trial applications for this evolving therapy through broad dissemination in the peer-reviewed literature.

BACKGROUND: Some symptomatic patients manifest pulmonary hypertension (PH), despite normal pulmonary vascular resistance and pulmonary artery wedge pressure—a condition termed unclassified PH. Although hypothesized to reflect increased flow as seen in congenital heart disease, broader clinical implications remain unknown. METHODS: The current analysis included pulmonary vascular disease phenomics participants with either no PH or unclassified PH who underwent dynamic right heart catheterization and transpulmonary metabolomics. In a validation cohort, patients with no PH or unclassified PH underwent exercise right heart catheterization. In exploratory cohorts to understand the impact of increased flow, the prevalence of unclassified PH was assessed in (1) adult congenital heart disease and (2) high output heart failure. RESULTS: The overall prevalence of unclassified PH in pulmonary vascular disease phenomics (n=1046) and the validation cohort (n=1202) was 7.8% (175/2248), which was comparable to the 6.6% (66/1005) prevalence in adult congenital heart disease (n=1005), and lower than high output heart failure (n=159, prevalence 14.5% [23/159]; P =0.006). Increased flow occurred in a minority of unclassified PH from both pulmonary vascular disease phenomics (28%; 15/53) and the validation cohort (11%; 13/122). Unclassified PH (n=53) was associated with greater adiposity, higher heart failure with preserved ejection fraction (HFpEF)–age, body mass index, atrial fibrillation score probability, and more left heart remodeling compared with those with no PH (n=216). Metabolomics revealed lower glycine metabolites in unclassified PH indicative of metabolic dysfunction. Left heart remodeling, quality of life, exercise capacity, and glycine levels were all abnormal in unclassified PH relative to healthy controls (n=96). In the validation cohort, pulmonary artery wedge pressure, pulmonary vascular resistance, and pulmonary artery compliance were subtly abnormal at rest in unclassified PH (n=122) compared with no PH (n=312). With exercise testing, 59% (72/122) with unclassified PH had exertional pulmonary artery wedge pressure elevation consistent with undiagnosed HFpEF. CONCLUSIONS: The presence of PH without obvious cause most often reflects subclinical left heart and metabolic dysfunction consistent with unrecognized early-stage HFpEF. Dynamic provocation during right heart catheterization can unmask unrecognized HFpEF in over half of unclassified PH, which may help guide appropriate initiation of proven HFpEF therapies to improve symptoms and functional status. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02980887.

Objective Long COVID (LC) refers to the long-term symptoms occurring after SARS-CoV-2 infection and resolution of the initial disease prodrome. While LC is increasingly recognized, knowledge about its biomarkers is still limited. This study examines imaging findings in 18 F-FDG PET-CT scans in 40 patients with LC from an academic LC Clinic, for potential imaging biomarkers. Methods This study included patients aged 18 and older with confirmed positive SARS-CoV-2 PCR test and at least 28 days post-symptom onset. 18 F-FDG PET-CT scans were performed, and brain metabolic activity was compared to a control database to generate Z-scores. Participants were grouped based on their clinical phenotype and Z-scores of different brain regions were analyzed using t-tests. Results The study group was mainly female (70%), with a median age of 53 years, and predominantly non-Hispanic White (90%). Most had pre-existing conditions such as gastrointestinal, cardiovascular, endocrine, and psychiatric disorders. The findings showed significant cerebral hypometabolism in 29 patients with fatigue and post-exertional malaise (PEM), particularly in the left sensorimotor cortex (p=0.0253) and bilateral primary visual cortex (right: p=0.0096, left: p=0.0016), which persisted up to two years after infection. Conclusions In summary, this study identified persistent cerebral hypometabolism in LC patients, especially those with fatigue with PEM, up to two years post-infection. These results suggest that 18 F-FDG PET-CT could be a valuable tool for diagnosing and managing LC. Further research is essential to confirm these findings and improve treatment strategies for patients with LC.