The multifunctional enzyme transglutaminase 2 (TG2) primarily catalyzes cross-linking reactions of proteins via (γ-glutamyl) lysine bonds. Several recent findings indicate that altered regulation of intracellular TG2 levels affects renal cancer. Elevated TG2 expression is observed in renal cancer. However, the molecular mechanism underlying TG2 degradation is not completely understood. Carboxyl-terminus of Hsp70-interacting protein (CHIP) functions as an ubiquitin E3 ligase. Previous studies reveal that CHIP deficiency mice displayed a reduced life span with accelerated aging in kidney tissues. Here we show that CHIP promotes polyubiquitination of TG2 and its subsequent proteasomal degradation. In addition, TG2 upregulation contributes to enhanced kidney tumorigenesis. Furthermore, CHIP-mediated TG2 downregulation is critical for the suppression of kidney tumor growth and angiogenesis. Notably, our findings are further supported by decreased CHIP expression in human renal cancer tissues and renal cancer cells. The present work reveals that CHIP-mediated TG2 ubiquitination and proteasomal degradation represent a novel regulatory mechanism that controls intracellular TG2 levels. Alterations in this pathway result in TG2 hyperexpression and consequently contribute to renal cancer.

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Funding Acknowledgements Type of funding sources: None. Background Preventive therapy for atrial fibrillation (AF) is lacking, and association between hyperlipidemia and incident atrial fibrillation has been reported. We examined whether measured and genetically predicted low density lipoprotein cholesterol (LDL-C) can detect incident atrial fibrillation (AF) independent of clinical risk for AF. Methods A total of 339,023 individuals aged 39 to 73 without pre-existing ASCVD (coronary artery disease, ischemic stroke or transient ischemic attack, peripheral artery occlusive disease) and AF were included from the UK biobank. Clinical risk for AF was based on tertiles of CHARGE-AF (Cohorts for Heart and Aging Research in Genomic Epidemiology- Atrial Fibrillation) score. We calculated the risk of incident AF per SD increase in measured and genetic LDL, and its association with CHARGE-AF. Results Over a median 11.9 (11.2-12.6) years, the primary outcome occurred in 17,504 patients. Among those with low, moderate, and high CHARGE-AF, each SD increase in measured LDL-C was associated with hazard ratio of 1.09 (95% CI 0.85-1.38, p=0.502), 1.32 (95% CI 1.13-1.54, p<0.001), and 1.23 (95% CI 1.12-1.37, p<0.001). Among these same categories, each SD increase in genetic LDL-C was associated with hazard ratios of 1.10 (95% CI 1.04-1.16, p<0.001), 1.07 (95% CI 1.03-1.11, p<0.001), and 1.05 (95% CI 1.03-1.07, p<0.001). Among those with normal LDL, untreated hyperlipidemia, and treated hyperlipidemia, each SD increase in genetic LDL-C was associated with hazard ratios of 1.11 (95% CI 1.04-1.18, p=0.001), 1.07 (95% CI 1.05-1.09, p<0.001), and 1.02 (0.99-1.05, p=0.25). Conclusion LDL cholesterol polygenic risk score may augment identification of individuals at heightened AF risk, including those with low CHARGE-AF or normal LDL-C. Whether it may also guide antilipidemic initiation or intensification requires further study.

Funding Acknowledgements Type of funding sources: None. Purpose We compared the efficacy, safety, and heart rate variability (HRV) after cryo-balloon (Cryo-PVI), high-power short-duration (HPSD-PVI) or conventional radiofrequency pulmonary vein isolation (conventional-PVI) in patients with atrial fibrillation (AF). Methods In this retrospective analysis of single-center cohort, we included 2,975 patients who underwent AF catheter ablation (74.1% male, median 60 years old, 74.1% paroxysmal AF). We compared the procedural factors, rhythm outcomes, complication rates, and post-procedural heart rate variability (HRV) between the Cryo-PVI (n=493), HPSD-PVI (n=638), and conventional-PVI (n=1,844). Results In spite of significantly shorter procedural time in the Cryo-PVI group (73 min for Cryo-PVI vs 110 min for HPSD-PVI vs 153 min for conventional-PVI, p<0.001), major complication (2.8% for Cryo-PVI vs 2.4% for HPSD-PVI vs 2.5% for conventional-PVI, p=0.875) or freedom from late recurrence (log-rank, p=0.357) did not differ among the three ablation groups. Cryo-PVI showed significantly lower risk for AF recurrence in patients with paroxysmal AF (weighted hazard ratio [WHR] 0.62, 95% confidence interval [CI] 0.41-0.93), but worse rhythm outcome in those with non-paroxysmal AF (WHR 1.47, 95% CI 1.06-2.05, p for interaction=0.002) as compared with conventional-PVI. In the subgroup analysis for HRV (n=1,429), Cryo-PVI group showed significantly higher low-frequency to high-frequency ratio at post-procedure 3 month (p<0.001), 1-year (p<0.001), and 2-year (p=0.023). Conclusion Cryo-PVI showed better rhythm outcome in patients with paroxysmal AF, but worse outcome in those with non-paroxysmal AF with higher long-term post-procedural sympathetic nervous activity as compared with conventional-PVI.