Aim: To investigate the association between fluid input volume and long-term outcomes, including all-cause mortality, cardiac mortality, and in-hospital hypotension, in patients with right ventricular myocardial infarction (RVMI).

Methods: This retrospective multicenter study included 1,561 patients with RVMI from four hospitals between 1 January 2013 and 30 June 2021. Fluid input volume was assessed on the first day and as the average over 3 and 7 days. Cox proportional hazards models were used to evaluate associations with all-cause mortality, cardiac mortality, and in-hospital hypotension.

Results: The median follow-up was 4.8 years (interquartile range: 2.7-6.4). We found a significantly lower all-cause mortality risk with higher first-day fluid input (median tertile hazard ratio (HR): 0.64, 95% confidence interval (CI): 0.44-0.94; highest tertile HR: 0.66, 95%CI: 0.44-0.99) compared with the lowest input tertile. Similar reductions were observed for cardiac mortality (median tertile HR: 0.52, 95%CI: 0.31-0.85; highest tertile HR: 0.50, 95%CI: 0.30-0.85). However, average fluid input over three or seven days was not associated with long-term mortality risk. Higher first-day input was associated with reduced in-hospital hypotension risk (HR: 0.68, 95%CI: 0.46-1.00; P = 0.049) after confounder adjustment.

Conclusion: Sufficient early fluid input is associated with improved long-term outcomes (all-cause and cardiac mortality) and lower in-hospital hypotension risk in patients with RVMI.

Aim: This study aimed to evaluate the bidirectional association between coronary artery disease (CAD) and epilepsy and to examine the modifying effect of genetic susceptibility.

Methods: Using data from the UK Biobank, we conducted cross-sectional and longitudinal analyses. In the cross-sectional analysis (n = 502,359), logistic regression estimated odds ratios for the association between CAD and epilepsy. In Cohort 1 (n = 496,921 without baseline epilepsy), stratified Cox models assessed the risk of incident epilepsy by CAD status. In Cohort 2 (n = 475,130 without baseline CAD), the risk of incident CAD by epilepsy status was similarly evaluated. Polygenic risk scores for CAD and epilepsy were incorporated to assess genetic modification.

Results: The median baseline age was 58.0 years, and 45.6% were male. Over a median follow-up of 13.8 years, 3,590 participants developed epilepsy and 39,223 developed CAD. CAD was significantly associated with epilepsy both cross-sectionally and longitudinally (hazard ratio (HR) 1.32; 95% confidence interval (CI): 1.15-1.51; P < 0.001). Conversely, epilepsy increased CAD risk (HR 1.31; 95%CI: 1.12-1.54; P < 0.001). These associations were consistent across age, sex, and body mass index (BMI) strata. CAD predicted epilepsy only in participants with low genetic risk, while epilepsy predicted CAD mainly in those with high genetic risk.

Conclusions: Our findings indicate a bidirectional association between CAD and epilepsy. Additionally, this association exhibits heterogeneity across subgroups and may be influenced by genetic susceptibility. These results underscore the need for further studies to elucidate the underlying mechanisms and clinical implications.

Aim: The protective effects of inorganic nitrate in hypertensive patients remain uncertain. Therefore, this study investigated the associations of urinary nitrate with blood pressure, the prevalence of cardiovascular disease (CVD), and cardiovascular mortality among the hypertensive population.

Methods: A total of 6,130 hypertensive adults from the 2005-2014 NHANES (The National Health and Nutrition Examination Survey) were included. Piecewise linear regression, logistic regression, and Cox proportional hazards regression models were performed to evaluate the associations of urinary nitrate with blood pressure, CVD prevalence, and cardiovascular mortality, respectively. Mediation and subgroup analyses were further conducted to explore the potential mechanisms and the consistency of the association between urinary nitrate and cardiovascular mortality.

Results: Within the range of 0-4.40 mg/dL, an inverse linear correlation between urinary nitrate and systolic blood pressure (SBP) was observed [β = -0.60; 95% confidence interval (95%CI): -0.99 to -0.21; P < 0.001]. Higher urinary nitrate levels were associated with a reduced prevalence of heart failure [odds ratio (OR): 0.942; 95%CI: 0.905 to 0.981; P = 0.004] and lower cardiovascular mortality [hazard ratio (HR): 0.921; 95%CI, 0.867 to 0.977; P = 0.006]. Mediation analyses indicated that neither SBP nor baseline heart failure mediated the association between urinary nitrate and cardiovascular mortality. Subgroup analyses showed that the inverse association between urinary nitrate and cardiovascular mortality was modified by the presence of coronary heart disease.

Conclusion: Among hypertensive individuals, higher urinary nitrate levels were associated with lower SBP, heart failure prevalence, and cardiovascular mortality. These findings suggest that urinary nitrate may serve as a potential biomarker for cardiovascular risk stratification.

Aim: This study aimed to identify key ubiquitin-regulating molecules involved in cardiomyocyte survival under ischemic injury and to investigate the role of Josephin domain-containing protein 2 (JOSD2) in ischemic stress-induced cardiomyocyte death after myocardial infarction (MI).

Methods: A ubiquitin-related single-guide RNA (sgRNA) library targeting 903 genes was screened in AC16 cells under oxygen-glucose deprivation (OGD), followed by sgRNA sequencing. Integrated analysis of multiple transcriptomic datasets was performed to identify JOSD2 as a candidate. Stable JOSD2 knockdown and overexpression cell models were established. Reverse transcription quantitative polymerase chain reaction (RT-qPCR), Western blot, flow cytometry, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, and Cell Counting Kit-8 (CCK-8) assays were performed to evaluate OGD-induced cardiomyocyte apoptosis and survival. Transcriptomic analysis, co-immunoprecipitation (co-IP), and deubiquitination assays were performed to explore the underlying mechanism. Adeno-associated virus 9 (AAV9)-mediated cardiomyocyte-specific JOSD2-overexpressing mice were used to evaluate cardiac remodeling and function after MI.

Results: The CRISPR-Cas9 screen identified a series of ubiquitin-regulating candidate genes associated with cardiomyocyte survival under ischemic stress. Combined transcriptomic and experimental analyses showed that JOSD2 was significantly upregulated in cardiomyocytes and mouse hearts after ischemic injury. JOSD2 knockdown attenuated OGD-induced cardiomyocyte apoptosis, whereas JOSD2 overexpression increased apoptosis. Mechanistically, JOSD2 reduced K27-, K29-, K33-, and K63-linked polyubiquitin chains on liver kinase B1 (LKB1), suppressed its activity, and inhibited downstream AMPK (AMP-activated protein kinase) phosphorylation. In vivo, cardiomyocyte-specific JOSD2 overexpression promoted cardiomyocyte death and aggravated cardiac remodeling and dysfunction after MI.

Conclusion: JOSD2 is upregulated in cardiomyocytes after MI and may promote post-infarction cell death and cardiac remodeling by suppressing the LKB1-AMPK pathway. Targeting JOSD2 may represent a potential therapeutic strategy for MI.