Effects of RBT-1 on preconditioning response biomarkers in patients undergoing coronary artery bypass graft or heart valve surgery: a multicentre, double-blind, randomised, placebo-controlled phase 2 trial.

Background: RBT-1 is a combination drug of stannic protoporfin (SnPP) and iron sucrose (FeS) that elicits a preconditioning response through activation of antioxidant, anti-inflammatory, and iron-scavenging pathways, as measured by heme oxygenase-1 (HO-1), interleukin-10 (IL-10), and ferritin, respectively. Our primary aim was to determine whether RBT-1 administered before surgery would safely and effectively elicit a preconditioning response in patients undergoing cardiac surgery. Methods: This phase 2, double-blind, randomised, placebo-controlled, parallel-group, adaptive trial, conducted in 19 centres across the USA, Canada, and Australia, enrolled patients scheduled to undergo non-emergent coronary artery bypass graft (CABG) and/or heart valve surgery with cardiopulmonary bypass. Patients were randomised (1:1:1) to receive either a single intravenous infusion of high-dose RBT-1 (90 mg SnPP/240 mg FeS), low-dose RBT-1 (45 mg SnPP/240 mg FeS), or placebo within 24-48 h before surgery. The primary outcome was a preoperative preconditioning response, measured by a composite of plasma HO-1, IL-10, and ferritin. Safety was assessed by adverse events and laboratory parameters. Prespecified adaptive criteria permitted early stopping and enrichment. This trial is registered with ClinicalTrials.gov, NCT04564833. Findings: Between Aug 4, 2021, and Nov 9, 2022, of 135 patients who were enrolled and randomly allocated to a study group (46 high-dose, 45 low-dose, 44 placebo), 132 (98%) were included in the primary analysis (46 high-dose, 42 low-dose, 44 placebo). At interim, the trial proceeded to full enrollment without enrichment. RBT-1 led to a greater preconditioning response than did placebo at high-dose (geometric least squares mean [GLSM] ratio, 3.58; 95% CI, 2.91-4.41; p < 0.0001) and low-dose (GLSM ratio, 2.62; 95% CI, 2.11-3.24; p < 0.0001). RBT-1 was generally well tolerated by patients. The primary drug-related adverse event was dose-dependent photosensitivity, observed in 12 (26%) of 46 patients treated with high-dose RBT-1 and in six (13%) of 45 patients treated with low-dose RBT-1 (safety population). Interpretation: RBT-1 demonstrated a statistically significant cytoprotective preconditioning response and a manageable safety profile. Further research is needed. A phase 3 trial is planned. Funding: Renibus Therapeutics, Inc.

Sex differences in patients with asymptomatic carotid atherosclerotic plaque: in vivo 3.0-T magnetic resonance study.

BACKGROUND AND PURPOSE: Stroke prevention with carotid endarterectomy in asymptomatic men with carotid stenosis is greater than in women. Men have a higher incidence of stroke <75 years of age. Sex differences in plaque characteristics may help explain this, because several plaque features, including a thin/ruptured fibrous cap, larger lipid-rich/necrotic core, and hemorrhage, are associated with increased risk of stroke. We hypothesize that MRI carotid plaque features will demonstrate sex differences indicative of higher-risk plaque in men. METHODS: One hundred thirty-one patients (men, 67; women, 64) with >or=50% asymptomatic carotid stenosis on duplex ultrasound were included. Two blinded reviewers interpreted multicontrast MRI. Presence of a thin/ruptured fibrous cap, plaque components (lipid-rich/necrotic core, hemorrhage, and calcification), and percent component volume were documented. The associations between sex and individual plaque characteristics were examined using logistic and linear regression models (2-part models) controlling for demographic characteristics and MR angiographic findings. RESULTS: Presence of a thin/ruptured fibrous cap (48% versus 17%, adjusted OR=4.41, P<0.01) and lipid-rich/necrotic core (73% versus 50%, adjusted OR=3.66, P=0.01) were more common in men. There was a trend for more highly prevalent hemorrhage (33% versus, 17%, adjusted OR=2.15, P=0.07) in men. Calcification was not significantly associated with sex. Men demonstrated larger volumes of percent lipid-rich/necrotic core (median, 7.7% versus 3.2%, P=0.01), and percent hemorrhage (median, 6.1% versus 1.5%, P<0.01). CONCLUSIONS: In patients with asymptomatic >or=50% carotid stenosis by duplex ultrasound, men had higher-risk plaque features compared with women after controlling for potential confounders. These findings may help explain sex differences in stroke incidence and prevention.

Carotid intraplaque hemorrhage imaging at 3.0-T MR imaging: comparison of the diagnostic performance of three T1-weighted sequences.

PURPOSE: To compare the diagnostic performances of three T1-weighted 3.0-T magnetic resonance (MR) sequences at carotid intraplaque hemorrhage (IPH) imaging, with histo logic analysis as the reference standard. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained for this HIPAA-compliant study. Twenty patients scheduled for carotid endarterectomy underwent 3.0-T carotid MR imaging, including two-dimensional fast spin-echo, three-dimensional time-of-flight (TOF), and three-dimensional magnetization-prepared rapid acquisition gradient-echo (RAGE) sequences. Two reviewers blinded to the histologic findings assessed the presence, area, and signal intensity of IPH with each sequence. Detection statistics (sensitivity, specificity, and Cohen kappa values) and agreement between area measurements (Pearson correlation coefficient [r] values) were calculated for each sequence. RESULTS: When all 231 available MR sections were included for analysis, the magnetization-prepared RAGE (kappa = 0.53) and fast spin-echo (kappa = 0.42) sequences yielded moderate agreement between MR and histologic measurements, while the TOF sequence yielded fair agreement (k = 0.33). However, when 47 sections with either small IPHs or heavily calcified IPHs were excluded, sensitivity, specificity, and kappa values, respectively, were 80%, 97%, and 0.80 for magnetization-prepared RAGE imaging; 70%, 92%, and 0.63 for fast spin-echo imaging; and 56%, 96%, and 0.57 for TOF imaging. MR imaging-histologic analysis correlation for IPH area was highest with magnetization-prepared RAGE imaging (r = 0.813), followed by TOF (r = 0.745) and fast spin-echo (r = 0.497) imaging. The capability of these three sequences for IPH detection appeared to be in good agreement with the quantitative contrast of IPH versus background plaque tissue. CONCLUSION: The magnetization-prepared RAGE sequence, as compared with the fast spin-echo and TOF sequences, demonstrated higher diagnostic capability for the detection and quantification of IPH. Potential limitations of 3.0-T IPH MR imaging are related to hemorrhage size and coexisting calcification.