Citations

Background: Lower (worse) left atrial (LA) function is associated with higher dementia risk. It is unclear whether lower LA function is associated with vascular brain injury on brain MRI, an established correlate for higher dementia risk. Using data from the Atherosclerosis Risk in Communities (ARIC) study, we assessed the cross-sectional association between LA function measures and brain MRI markers of vascular brain injury (cerebral microbleeds, brain infarcts). Hypothesis: Participants with lower LA function will be more likely to have presence of > 1 cerebral microbleed or brain infarct. Methods: ARIC participants who had both an echocardiogram and brain MRI at visit 5 (2011-13) were included. We excluded those with prevalent dementia, stroke, or atrial fibrillation. LA function measures were obtained from 2D-echocardiograms and assessed in quartiles (highest quartile was the reference). Brain MRI measures were assessed as the presence or absence of > 1 cerebral microbleed or brain infarct. Logistic regression was used. Results: Of the 1502 participants (mean [SD] age 76 [5], 60% female, 27% Black) in this analysis, 345 (23%) and 351 (23%) had > 1 cerebral microbleed or brain infarct present. Compared to the highest quartile, lower LA reservoir and conduit strain quartiles were associated with higher odds of cerebral microbleeds. LA contractile strain was not associated with cerebral microbleeds. Compared to the highest quartile, the lowest LA conduit strain quartile, but not reservoir strain, was associated with higher odds of brain infarcts. LA contractile strain was inversely associated with brain infarcts. Conclusion: In this community-based cohort, lower LA function was cross-sectionally associated with cerebral microbleeds and brain infarcts. The inverse relationship with LA contractile strain may be due to contractile function compensating for a decrease in early diastolic filling. Prospective studies are needed to confirm these findings.

Introduction: Rilonacept treatment in RHAPSODY resolved active pericarditis recurrences, and long-term treatment led to sustained risk reduction. Prior analysis linked greater baseline Late Gadolinium Enhancement (LGE), with more rapid recurrence upon rilonacept suspension after 12 weeks of treatment. Serial cardiac magnetic resonance (CMR) imaging (T2-STIR, LGE) enabled longitudinal assessment for tracking clinical improvement, guiding decision-making, and predicting patient outcomes after treatment cessation. Methods: At the long-term extension (LTE) 18-month decision milestone (18MDM), investigators chose, based on clinical status, to continue rilonacept, suspend rilonacept/observe, or discontinue the LTE. An imaging core lab blinded to clinical data measured pericardial thickness and graded pericardial edema (T2-STIR) and LGE at baseline and 18MDM. Pericarditis recurrence was assessed clinically following rilonacept suspension. Results: Baseline and 18MDM CMRs were available for 13 patients. Reductions in pericardial thickness, T2-STIR, and LGE from baseline to 18MDM while on treatment are provided in Figure . CMRs were obtained in 7/8 patients suspending rilonacept at 18MDM: LGE was none/trace, and T2-STIR was negative; yet, 5/7 (71%) had pericarditis recurrence within 1-4 months of rilonacept suspension despite prophylactic colchicine (n=2). Conclusions: Continued clinical improvement during prolonged rilonacept treatment corresponded with improvement on CMR, including reduced pericardial thickness, resolution of pericardial edema on T2-STIR, and resolution of LGE. Negative/trace LGE at 18MDM while on treatment did not predict absence of pericarditis recurrence upon subsequent rilonacept suspension in this size-limited subgroup. Larger prospective studies examining CMR parameters in guiding RP treatment duration decisions and informing associated clinical outcomes are warranted.

Patients with cholangiocarcinoma have poor clinical outcomes due to late diagnoses, poor prognoses, and limited treatment strategies. To identify drug combinations for this disease, we have conducted a genome-wide CRISPR screen anchored on the bromodomain and extraterminal domain (BET) PROTAC degrader ARV825, from which we identified anticancer synergy when combined with genetic ablation of members of the mTOR pathway. This combination effect was validated using multiple pharmacological BET and mTOR inhibitors, accompanied by increased levels of apoptosis and cell cycle arrest. In a xenograft model, combined BET degradation and mTOR inhibition induced tumor regression. Mechanistically, the 2 inhibitor classes converged on H3K27ac-marked epigenetic suppression of the serine glycine one carbon (SGOC) metabolism pathway, including the key enzymes PHGDH and PSAT1. Knockdown of PSAT1 was sufficient to replicate synergy with single-agent inhibition of either BET or mTOR. Our results tie together epigenetic regulation, metabolism, and apoptosis induction as key therapeutic targets for further exploration in this underserved disease.