Background: Heart failure with reduced ejection fraction (HFrEF) is a chronic disease with substantial mortality. Management of HFrEF has seen significant breakthrough after the launch of neprilysin inhibitor. The PARADIGM‐HF (Prospective Comparison of ARNI with ACEI to Determine Impacton Global Mortality and Morbidity in Heart Failure) trial showed that sacubitril/valsartan significantly reduces HFrEF mortality and the heart failure hospitalization rate. However, in patients with advanced kidney disease, who have the highest prevalence of heart failure, the efficacy and safety of sacubitril/valsartan remains uncertain. We aim to study the efficiency of sacubitril/valsartan in patients with end‐stage kidney disease. Methods and Results: Heart function was screened by echocardiogram among all patients with end‐stage kidney disease in 2 hospitals. Patients with HFrEF received either sacubitril/valsartan or conventional treatment. Fifteen echocardiographic parameters were compared before and after treatment. After 1‐year sacubitril/valsartan treatment, parameters of systolic (left ventricular ejection fraction 31.3% to 45.1%, P <0.0001; left ventricular end‐systolic volume 95.7 to 70.1 mL, P =0.006; left ventricular internal diameter at end‐systole phase 47.2 to 40.1 mm, P =0.005), and diastolic (E/A ratio 1.3 to 0.8, P =0.009; E/Med e' ratio 25.3 to 18.8, P =0.010) function improved in patients with HFrEF and end‐stage kidney disease. These parameters were unchanged in the conventional treatment group. Serum potassium did not increase in the sacubitril/valsartan group. Conclusions: Sacubitril/valsartan improves left ventricular systolic and diastolic function in patients with HFrEF and end‐stage kidney disease.

Key Points: METTL3 was upregulated in CKD, leading to increased m ⁶ A modification levels. M ⁶ A modifications were enriched in genes related to the cyclic guanosine monophosphate–AMP synthase-stimulator of IFN genes pathway in CKD. Normalizing heightened METTL3 and m ⁶ A modification levels showed promise as a strategy to combat kidney disease. Background: Chemical modifications on RNA profoundly affect RNA function and regulation. m ⁶ A, the most abundant RNA modification in eukaryotes, plays a pivotal role in diverse cellular processes and disease mechanisms. However, its importance is understudied in human CKD samples regarding its influence on pathological mechanisms. Methods: Liquid chromatography–tandem mass spectrometry and methylated RNA immunoprecipitation sequencing were used to examine alterations in m ⁶ A levels and patterns in CKD samples. Overexpression of the m ⁶ A writer METTL3 in cultured kidney tubular cells was performed to confirm the effect of m ⁶ A in tubular cells and explore the biological functions of m ⁶ A modification on target genes. In addition, tubule-specific deletion of Mettl3 (Ksp-Cre Mettl3 ^f/f ) mice and antisense oligonucleotides inhibiting Mettl3 expression were used to reduce m ⁶ A modification in an animal kidney disease model. Results: By examining 127 human CKD samples, we observed a significant increase in m ⁶ A modification and METTL3 expression in diseased kidneys. Epitranscriptomic analysis unveiled an enrichment of m ⁶ A modifications in transcripts associated with the activation of inflammatory signaling pathways, particularly the cyclic guanosine monophosphate–AMP synthase (cGAS)-stimulator of IFN genes (STING) pathway. m ⁶ A hypermethylation increased mRNA stability in cGAS and STING1 as well as elevated the expression of key proteins within the cGAS-STING pathway. Both the tubule-specific deletion of Mettl3 and the use of antisense oligonucleotides to inhibit Mettl3 expression protected mice from inflammation, reduced cytokine expression, decreased immune cell recruitment, and attenuated kidney fibrosis. Conclusions: Our research revealed heightened METTL3-mediated m ⁶ A modification in fibrotic kidneys, particularly enriching the cGAS-STING pathway. This hypermethylation increased mRNA stability for cGAS and STING1, leading to sterile inflammation and fibrosis.

Proprotein convertase subtilisin/kexin-6 (PCSK6) is a secretory protein that activates corin in the heart. Higher circulating levels of corin are associated with improved cardiovascular outcomes in patients with acute myocardial infarction. This study aimed to determine the role of serum PCSK6 and corin levels in predicting cardiovascular outcomes in patients with suspected coronary artery disease (CAD). In total, 565 patients who had undergone coronary angiography were enrolled. Serum PCSK6 and corin levels were determined before the administration of contrast media. In this study, coronary revascularization, acute myocardial infarction, acute stroke, and death were defined as cardiovascular outcomes. All patients were followed up for at least one year after coronary angiography or until the occurrence of death. During a median follow-up of 691 days, 67 patients (15.7%) developed composite cardiovascular outcomes after coronary angiography, including 51 incidents of coronary revascularization, 7 instances of acute myocardial infarction, 2 acute strokes, and 15 deaths. After adjustment for demographic characteristics and all significant variables in the univariate analysis, serum levels of neither PCSK6 nor corin were associated with increased risk for cardiovascular outcomes. This correlation remained insignificant in patients with underlying hypertension, diabetes mellitus, CAD, heart failure, or chronic kidney disease (CKD). However, in patients without CKD, higher serum PCSK6 levels were associated with increased risk for cardiovascular outcomes (hazard ratio 1.380; 95% confidence interval 1.023–1.862). We found no association between cardiovascular outcomes and pre-procedural serum levels of PCSK6 or corin in patients undergoing coronary angiography. However, an increased risk was seen in non-CKD patients with higher PCSK6 levels. Further studies are needed to verify these results.

Background: Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular disease. Corin converts proatrial natriuretic peptide into its active form after being activated by PCSK6 (proprotein convertase subtilisin/kexin type 6) protease. It remains unknown whether the PCSK6/corin/atrial natriuretic peptide pathway plays a role in CKD‐induced cardiomyopathy. Methods and Results: Serum corin, left ventricular mass index, and corin–left ventricular mass index correlation were compared between outpatients with versus without CKD. Cardiac corin expression and activity as well as serum corin were compared between 5/6 nephrectomy CKD animal models and sham controls. The effects of indoxyl sulfate, a uremic toxin, on cardiomyocytes were examined in vitro in H9c2 cells. A total of 543 patients were enrolled in this study. Serum corin levels were elevated in patients with CKD compared with levels in patients without CKD. Serum corin levels correlated negatively with left ventricular mass index in participants without CKD, but not in patients with CKD. Compared with sham controls, CKD mice had higher serum corin levels and increased cardiac expression of corin but reduced cardiac corin conversion activity. Indoxyl sulfate stimulated corin expression while suppressing serine protease activity in H9c2 cardiomyoblasts. Lower PCSK6 expression in CKD mouse hearts and indoxyl sulfate–treated H9c2 cardiomyoblasts may explain, at least partly, the observed CKD‐associated reduction in corin activity. Conclusions: In CKD, cardiac and serum levels of corin are increased, yet corin activity is suppressed. The latter may be attributable to reduced PCSK6 expression. These findings suggest that corin dysfunction may play a significant role in the pathogenesis of CKD‐associated cardiomyopathy.

Background: Early fluid resuscitation is a key aspect in the successful management of critically ill patients, but the optimal goal for volume control after the acute stage of critical illness remains unclear. This study aimed to evaluate the prognostic value of bioimpedance spectrometry for fluid management in critically ill patients. Methods: In this prospective observational study, patients who consented to participate were screened within the first 24 hours of admission to a medical intensive care unit (ICU) from February 4, 2015, to January 31, 2016. Information on demographics, comorbidities, primary reasons for admission, baseline laboratory data, and ventilator or inotropic use were documented. Data of fluid intake, fluid output, and body weight were recorded for the first 3 days of ICU admission. Bioimpedance spectrometry was performed on the first and third days after ICU admission. All participants were followed until death or hospital discharge. Results: Of the 140 enrolled patients (median age: 70 years, interquartile range: 60-77 years), 23 (16.4%) patients died during hospitalization. Independent predictors of hospital mortality were Acute Physiology and Chronic Health Evaluation II scores (per 1 point increase, odds ratio [OR]: 1.101) and overhydration (OH) volume on the first day (per 1 L increase, OR: 1.216). Compared to normal OH status (OH volume between −1 and 1 L), hyper OH status (OH volume < −1 L) on the third day after ICU admission was an independent predictor of hospital death (OR: 7.609). Normal OH status on the third day was associated with greater numbers of ICU-free and ventilator-free days. Conclusion: Bioimpedance spectrometry can be used to predict outcomes in critically ill patients. Increased OH volume on day 1 and hyper OH volume on day 3 of ICU admission are associated with a greater risk of hospital mortality. Volume status on day 3 is associated with durations of ventilator use and ICU stay.

Cardiac remodeling is implicated in numerous physiologic and pathologic conditions, including scar formation, heart failure, and cardiac arrhythmias. Nuclear factor-activated T-cell cytoplasmic (NFATc) is a crucial transcription factor that regulates cardiac remodeling. MicroRNA (miR)-424/322 has pathophysiological roles in the cardiovascular and respiratory systems by modulating hypoxia and inflammatory pathways. The role of miR-424/322 in regulating cardiac remodeling is under investigation. We identified several cardiac hypertrophy and fibrosis-related molecules as putative targets of miR-424/322. We propose that miR-424/322 could have crucial roles in cardiac remodeling by modulating several key molecules for cardiac fibrosis and hypertrophy. Human cardiac fibroblasts (HCFs) and a myogenic cell line H9c2 cells were used for in vitro experiments. A murine model of angiotensin II (AngII)-induced cardiac remodeling was used to assess the roles of miR-322 on cardiac hypertrophy and fibrosis in vivo. Immunoblotting, immunofluorescence, real-time polymerase chain reaction and cell proliferation, Sirius Red, and dual-luciferase reporter assays were used to decipher the molecular mechanism. We found that miR-322 knockout mice were susceptible to AngII-induced cardiac fibrosis and hypertrophy in vivo. Administration of miR-424/322 inhibitors aggravated AngII-induced overexpression of NFATc3, furin, natriuretic peptides and collagen 1A1 in H9c2 cells and HCFs. miR-424/322 mimics reversed the AngII-induced fibrosis, hypertrophy, and proliferation by targeting NFATc3 and furin in vitro. miR-424/322 could be transactivated by NFATc3. Exogenous miR-322 ameliorated AngII-induced hypertrophy and cardiac fibrosis in vivo. The NFATc3/miR-424/322/furin axis is crucial for developing cardiac remodeling, and exogenous miR-322 mimics could have therapeutic potential in cardiac remodeling.