Citations

Variants in the Glucokinase Regulator ( GCKR ) gene are increasingly being detected with growing applications of genomic sequencing technologies. Despite the crucial roles of the GCKR gene in energy homeostasis, the clinical applications of GCKR variants are currently limited. We observed that a large proportion of GCKR variants that are available in gnomAD database ( https://gnomad.broadinstitute.org/ ) lacked adequate evidence of pathogenicity or benign impact. We highlight the clinical need for an improved understanding of GCKR variants by presenting 2 compelling cases of unrelated families (3 individuals in total) who harbor rare GCKR variants in the context of cornea arcus and hyperlipidemia. Our observations underscore the burgeoning need for functional as well as family segregation studies to facilitate the clinical applications of GCKR variants.

Background Coronary flow reserve reflects microvascular function, whereas filling pressure indicates myocardial hemodynamic burden. In angina with nonobstructive coronary arteries, abnormalities in either could contribute to a supply–demand mismatch; however, their combined prognostic significance remains unclear. Methods Patients with angina with nonobstructive coronary arteries who underwent invasive coronary reactivity tests were studied retrospectively. Coronary microvascular dysfunction (CMD) was coronary flow reserve <2.5. An artificial intelligence–enabled ECG marker of elevated filling pressure (AIEFP) was applied as a scalable prognostic marker of myocardial hemodynamic stress. Associations with major adverse cardiovascular events were evaluated using Cox regression and propensity score overlap weighting. Results Among 1957 patients with angina with nonobstructive coronary arteries (median age, 51.8 years; 67.2% women), CMD+ was identified in 26.4% and AIEFP+ in 6.6%. Over 8 years, 204 patients (10.4%) experienced major adverse cardiovascular events. In nested models, both CMD (hazard ratio [HR]=1.42 [95% CI=1.13–1.78]; P =0.002) and AIEFP (HR=2.28 [95% CI=1.67–3.11]; P <0.001) remained associated with major adverse cardiovascular events after adjustment. Adding AIEFP to the base model improved model fitness (Δχ 2 =23.65, P <0.001; ΔAkaike Information Criterion=−21.7) and modestly improved discrimination (ΔHarrell concordance index=0.02, P =0.02). In a 4‐group model, adjusted risks increased in a graded manner. Overlap‐weighted analysis after covariate balance demonstrated distinct temporal risk trajectories: CMD+/AIEFP+ had the highest 1‐year risk (12.7%), and AIEFP+ had the highest cumulative 8‐year risk (57% in CMD− and 51.8% in CMD+). Conclusions CMD and AIEFP provide complementary prognostic information, with AIEFP remaining significantly associated with outcomes after multivariable adjustment. A dual‐axis framework integrating myocardial hemodynamic stress (AIEFP) and microvascular function (coronary flow reserve) may enhance risk stratification and enable identification of clinically distinct angina with nonobstructive coronary arteries phenotypes with divergent trajectories.

Background Female sex is associated with lower incidence of myocardial infarction, especially at younger ages. However, sex differences in mortality and coronary artery disease patterns among young patients with ST‐segment–elevation myocardial infarction are not well established. This study evaluated sex differences in in‐hospital and 1‐year all‐cause death and in the extent of coronary artery disease in patients aged ≤45 years with ST‐segment–elevation myocardial infarction. Methods A systematic review (December 9, 2025) was conducted using PubMed, Cochrane, Embase, major cardiology conference proceedings, and ClinicalTrials.gov . Studies comparing sexes for outcomes were included. Non‐English publications, abstracts without full text, and studies published before 2010 were excluded. A random‐effects meta‐analysis was performed, with results presented as relative risks (RR) and 95% CIs. Heterogeneity was assessed using τ and I 2 , risk of bias using the Risk of Bias in Nonrandomized Studies of Interventions tool. The study was registered on the International Prospective Register of Systematic Reviews. Results Eleven studies including 738 029 patients with ST‐segment–elevation myocardial infarction (22% women) were analyzed. Female sex was associated with higher unadjusted in‐hospital (RR, 1.56 [95% CI, 1.40–1.74]; τ=0.04; I 2 =0%) and 1‐year mortality rate (RR, 1.78 [95% CI, 1.50–2.12]; τ=0.00; I 2 =0%). Women more frequently had single‐vessel disease (73% versus 60%; RR, 1.13 [95% CI, 1.03–1.23]; τ=0.07; I 2 =67%), while men had 2‐vessel (23% versus 18%; RR, 0.76 [95% CI, 0.68–0.85]; τ=0.00; I 2 =0%;) and 3‐vessel disease (16% versus 9%; RR, 0.49 [95% CI, 0.27–0.86]; τ=0.41; I 2 =33%). Conclusions In young patients with ST‐segment–elevation myocardial infarction, female sex is associated with higher unadjusted in‐hospital and 1‐year death despite less extensive CAD. Further studies adjusting for comorbidities and standardizing CAD definitions are needed.

The 2025 American College of Cardiology/American Heart Association/American College of Emergency Physicians/National Association of Emergency Medical Services Physicians/Society for Cardiovascular Angiography & Interventions acute coronary syndrome guideline focuses on strategies to reduce bleeding risk with antiplatelet therapy yet lacks any recommendation related to CYP2C19 genotyping. The impact of CYP2C19 loss‐of‐function alleles on the effectiveness of clopidogrel is well documented, and although prasugrel and ticagrelor more effectively reduce the risk for atherothrombotic events compared with clopidogrel in patients with a CYP2C19 loss‐of‐function allele, clopidogrel reduces bleeding risk without an increase in atherothrombotic events compared with prasugrel or ticagrelor in those without a loss‐of‐function allele. Accordingly, an American Heart Association Scientific Statement supports CYP2C19 genetic testing before oral P2Y 12 inhibitors are prescribed. This commentary summarizes the evidence in support of CYP2C19 ‐guided P2Y 12 inhibitor selection in the context of other 2025 acute coronary syndrome guideline recommendations and urges future guidelines to incorporate recommendations for CYP2C19 genotyping, especially for those at high bleeding risk.

Background COVID‐19 and other respiratory viral infections can cause cardiovascular complications. SARS‐CoV‐2 virions are found in the blood, and circulating viral RNA levels are associated with death. We hypothesized that viremia can induce thrombotic endotheliopathy that contributes to death and studied this relationship in patients hospitalized for COVID‐19 and enrolled in the ACTIV‐4a (Accelerating COVID‐19 Therapeutic Interventions and Vaccines) randomized trial of antithrombotic therapy. Methods We quantified SARS‐CoV‐2 nucleocapsid RNA and protein in plasma and measured their associations with clinical outcomes and biomarkers of thromboinflammation and endotheliopathy. We used Cox regression and Fine–Gray competing risk models to analyze survival and thrombosis. We conducted causal mediation analysis to explore whether thrombotic endotheliopathy mediates the relationship between viral RNA and death. Results In 93 patients, SARS‐CoV‐2 RNA and N‐antigen were higher in nonsurvivors. Baseline viral RNA levels were associated with increased 90‐day death (hazard ratio [HR], 1.31 [95% CI, 1.17–1.46]) and thrombosis (HR, 1.35 [95% CI, 1.24–1.47]). Viral RNA more effectively predicted survivorship than N‐antigen levels. Soluble thrombomodulin, a biomarker of thrombotic endotheliopathy, positively correlated with viral RNA levels. Mediation analysis revealed that soluble thrombomodulin accounts for 12.2% (95% CI, 0.1%–32.3%; P =0.048) after adjustment for age and sex of the relationship between viral RNA and the 90‐day mortality rate. Conclusions Elevated plasma SARS‐CoV‐2 RNA levels are associated with death in ACTIV‐4a, which is causally mediated in part by soluble thrombomodulin. We propose that lung–blood viral dissemination is a potential mechanism for cardiovascular complications of respiratory viruses. Registration URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT04505774.

Abstract Background and aims Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent thunderclap headaches and reversible multifocal cerebral arterial narrowing. Although prognosis is generally favorable, a subset of patients develops cerebrovascular complications that may drive long-term disability; this study aims to identify factors associated with these complications. Methods We retrospectively reviewed 348 patients with probable or definite RCVS evaluated at Mayo Clinic between 2010-2023. Diagnostic criteria were adapted from RCVS2 and ICHD-3. The primary outcome was a composite of ischemic stroke, non-aneurysmal subarachnoid hemorrhage, and intracerebral hemorrhage; secondary outcome was poor functional status (modified Rankin Scale ≥2 within one year). Univariable and multivariable logistic regression identified predictors of these outcomes. Results Cerebrovascular complications occurred in 37.6% of patients and were the strongest determinant of poor functional outcome (aOR 5.05, 95% CI 2.04–12.51). On multivariable analysis, older age (aOR per year 1.02, 95% CI 1.00–1.04) and angiographically visible vasoconstriction (aOR 3.14, 95% CI 1.85–5.33) were independently associated with higher risk of cerebrovascular complications, whereas male sex (aOR 0.55, 95% CI 0.30–0.99), thunderclap headache at presentation (aOR 0.30, 95% CI 0.11–0.86), and sexual activity as a trigger (aOR 0.19, 95% CI 0.08–0.42) were associated with lower risk of these complications. Conclusions Cerebrovascular complications are common and strongly predict disability. Angiographic vasoconstriction and older age identify patients at higher risk, whereas thunderclap headache and sexual activity as a trigger mark a more benign phenotype. These findings may guide early risk stratification and help tailored monitoring strategies. Conflict of interest Name of author: nothing to disclose.

Abstract Background and aims Patient foramen ovale (PFO) is a stroke risk factor evaluated using transthoracic echocardiogram (TTE), transesophageal echocardiogram (TEE), transcranial Doppler ultrasound (TCD), and cardiac computed tomography (CCT). TCD is non-invasive, but its diagnostic performance relative to other modalities is unclear. We hypothesized that TCD has high sensitivity but low specificity for PFO detection. Methods We conducted an IRB-approved, single-center retrospective study of patients undergoing TCD for right-to-left shunt (RLS) detection between January 2024 and April 2025. Patients were identified from the Neurosonology Laboratory Quality Database. Records were reviewed for demographics, comorbidities, and TTE, TEE, and CCT findings. Sensitivity, specificity, and positive and negative predictive values were calculated for TCD, TTE, and CCT relative to TEE, the gold standard. The sensitivity and specificity of TCD versus TTE were compared using McNemar test. Results Ninety-two patients were included. Mean age was 52.66 ± 15.78 years, and 51% were female; qualifying events included ischemic stroke or transient ischemic attack. RLS was detected in 53 patients (57.6%) by TCD, 17 (30%) by TTE, 18 (28.5%) by TEE, and 3 (21%) by CCT. TCD demonstrated 94% sensitivity and 53% specificity, (PPV 66%, NPV 89%). TTE showed 50% sensitivity and 82% specificity (PPV: 75%, NPV 61%), while CCT showed 33% sensitivity and 100% specificity (PPV 100%, NPV 33.3%). TCD had significantly higher sensitivity than TTE for RLS detection (p=0.039) with a non-significant difference in specificity (p=0.062), using TEE as the reference. Conclusions TCD has high sensitivity for RLS detection in patients with ischemic stroke or transient ischemic attack. Conflict of interest Rachel Knopp: nothing to disclose; Kelly Flemming: nothing to disclose; Eugene Scharf: nothing to disclose; Zafer Keser: nothing to disclose; Jessica Prink: nothing to disclose; Shari Johnson: nothing to disclose; Guy Reeder: nothing to disclose; Robert Brown: nothing to disclose; William Harmsen: nothing to disclose; Muhib Khan: nothing to disclose Table 1 - belongs to Results

Abstract Background and aims Carotid calcification features are readily quantifiable by CTA, yet their relationship with plaque vulnerability and rupture remains controversial. We investigated whether calcium score, volume, density, and residual (volume-normalized) calcium density are associated with carotid plaque vulnerability, symptomatic status, and recurrent ipsilateral ischemic stroke and transient ischemic attack (TIA). Methods Patients with recent TIA or ischemic stroke and ≥2mm carotid plaque with &lt;70% stenosis underwent baseline CTA and MRI. Carotid calcifications were segmented on CTA (≥130 Hounsfield units), yielding calcium score, volume, and density. Volume-normalized residual calcium density was calculated as the standardized residuals from a log-transformed calcium density-volume model (Figure 1). Vulnerable plaque features (intraplaque hemorrhage, thin-or-ruptured fibrous cap, and lipid-rich necrotic core, and ulceration) were linked to calcium metrics. Associations between calcium metrics and recurrent ipsilateral TIA or ischemic stroke were assessed using Cox regression and adjusted for age, sex, stenosis. Results Among 193 patients (mean age 67.8±8.5 years, 144 (75%) men), 26 experienced ipsilateral ischemic stroke or TIA over median 5-year follow-up. Lower calcium density and residual calcium density were independently associated with vulnerable plaques (adjusted ORs: 0.40-0.60; Figure 2). Residual calcium density remained independently associated with symptomatic side (adjusted OR: 0.64, 95%CI: 0.47-0.88) and with recurrent TIA/stroke (adjusted HR: 0.53, 95%CI: 0.29-0.95). Calcium score, volume, and density were not independently associated with symptomatic side or recurrent events (Figure 3). Conclusions Residual calcium density is a robust, independent marker of carotid plaque vulnerability and ipsilateral ischemic stroke and TIA risk in patients with symptomatic carotid artery disease. Conflict of interest Juul Bierens: nothing to disclose; Daniel Bos: nothing to disclose; Paul J. Nederkoorn: nothing to disclose; Pim A. de Jong: nothing to disclose; Robert J. van Oostenbrugge: nothing to disclose; Luc J.M. Smits: nothing to disclose; Jae W. Song: nothing to disclose; Giuseppe Lanzino: nothing to disclose; M. Eline Kooi: nothing to disclose; Luca Saba: nothing to disclose. Figure 1 - belongs to Methods Figure 2 - belongs to Results Figure 3 - belongs to Conclusions

Abstract Background and aims Intravenous thrombolysis (IVT) is the most common acute ischemic stroke (AIS) treatment. This study compared the efficacy and safety of different IVT agents to determine the optimal option for AIS management. Methods A comprehensive search was conducted in PubMed, Scopus, Web of Science, and Cochrane CENTRAL until 23 March 2025. Randomized controlled trials (RCTs) on alteplase (tPA), tenecteplase (TNK), reteplase, and recombinant human pro-urokinase (rhPro-UK) of any dose in AIS were included. A frequentist network meta-analysis was conducted using R software to pool risk ratios (RRs) with 95% confidence intervals (CIs). Results Twenty-one RCTs (10,852 patients) were included. Compared with tPA 0.9 mg/kg, tPA 0.6 mg/kg showed a lower risk of symptomatic intracranial hemorrhage (RR, 95% CI: 0.48 [0.27–0.86]), whereas TNK 0.4 mg/kg showed a higher risk (RR, 95% CI: 1.88 [1.06–3.35]). Reteplase 18 + 18 mg (RR, 95% CI: 1.13 [1.05–1.21]) and TNK 0.25 mg/kg (RR, 95% CI: 1.05 [1.01–1.10]) were associated with higher rates of excellent functional outcome at 90 days (mRS 0–1) compared with tPA 0.9 mg/kg. No significant differences were observed among interventions in 90-day mortality and favorable function outcomes (mRS 0–2), or serious adverse events. Conclusions Thrombolytic efficacy and safety in AIS appear to be dose dependent. A lower tPA dose (0.6 mg/kg) improved safety; reteplase 18 + 18 mg and TNK 0.25 mg/kg favored functional recovery, whereas a higher TNK dose increased sICH risk, underscoring the importance of dose optimization in IVT selection. Conflict of interest Haneen Sabet: nothing to disclose, Moaz Elsayed Abouelmagd: nothing to disclose, Abdelrahman Shata: nothing to disclose, Mohamed El-Moslemani: nothing to disclose, Diana Kadi: nothing to disclose, Dina Essam Abo-elnour: nothing to disclose, Abdallah Abbas: nothing to disclose, Ramanathan Kadirvel: nothing to disclose, Sherief Ghozy: nothing to disclose Figure 1 - belongs to Results

Abstract Background and aims A substantial proportion of large vessel strokes remain untreated worldwide due to limited access to specialized neuroendovascular care. Remote robotic neuroendovascular thrombectomy performed by expert interventionalists from a distant hub has been proposed as one solution to address these disparities. In this study, we test the feasibility of remote robotic thrombectomy in a live animal model. Methods Two live porcine experiments were conducted, involving Mayo Clinic Arizona (MCA), University Hospital Zurich (USZ), and Inselspital—Bern University Hospital (USB), Switzerland. Aspiration thrombectomy at USB was performed remotely from USZ (regional hub, 95 km; two experiments) and MCA (international hub, one experiment). Five aspiration thrombectomies were completed using a proprietary robotic magnetic navigation system consisting of a mobile magnetic field generator, a three-axis robotic advancer, controlling an 80 cm 6f sheath, a 6f aspiration catheter and a 0.035″ magnetically trackable guidewire, and a teleoperated console. The primary endpoint was the feasibility of successful clot aspiration using the robotic magnetic navigation system. Results Five out of seven thrombectomy procedures were successfully completed, achieving full clot retrieval. In the remaining two procedures, more distal clots were targeted, which could not be reached due to the limited catheter length. Magnetic navigation was successful in all cases. Image quality was excellent to acceptable. Conclusions Remote robotic thrombectomy using robotic magnetic navigation technology is technically feasible over both regional and transcontinental distances. This first-in-vivo regional and transatlantic study establishes a potential model of stroke intervention that may one day bridge access to endovascular stroke treatment. Conflict of interest Patrick Thurner and Tilman Schubert have consulting agreements with Nanoflex Robotics.