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Background: Heart failure (HF) is a leading cause of morbidity and mortality worldwide. RNA-binding proteins are identified as regulators of cardiac disease; DDX5 (dead-box helicase 5) is a master regulator of many RNA processes, although its function in heart physiology remains unclear., Methods: We assessed DDX5 expression in human failing hearts and a mouse HF model. To study the function of DDX5 in heart, we engineered cardiomyocyte-specific Ddx5 knockout mice. We overexpressed DDX5 in cardiomyocytes using adeno-associated virus serotype 9 and performed transverse aortic constriction to establish the murine HF model. The mechanisms underlined were subsequently investigated using immunoprecipitation-mass spectrometry, RNA-sequencing, alternative splicing analysis, and RNA immunoprecipitation sequencing., Results: We screened transcriptome databases of murine HF and human dilated cardiomyopathy samples and found that DDX5 was significantly downregulated in both. Cardiomyocyte-specific deletion of Ddx5 resulted in HF with reduced cardiac function, an enlarged heart chamber, and increased fibrosis in mice. DDX5 overexpression improved cardiac function and protected against adverse cardiac remodeling in mice with transverse aortic constriction-induced HF. Furthermore, proteomics revealed that DDX5 is involved in RNA splicing in cardiomyocytes. We found that DDX5 regulated the aberrant splicing of Ca 2+ /calmodulin-dependent protein kinase IIδ ( CamkIIδ ), thus preventing the production of CaMKIIδA, which phosphorylates L-type calcium channel by serine residues of Cacna1c, leading to impaired Ca 2+ homeostasis. In line with this, we found increased intracellular Ca 2+ transients and increased sarcoplasmic reticulum Ca 2+ content in DDX5-depleted cardiomyocytes. Using adeno-associated virus serotype 9 knockdown of CaMKIIδA partially rescued the cardiac dysfunction and HF in Ddx5 knockout mice., Conclusions: These findings reveal a role for DDX5 in maintaining calcium homeostasis and cardiac function by regulating alternative splicing in cardiomyocytes, identifying the DDX5 as a potential target for therapeutic intervention in HF., Competing Interests: None.

Introduction: Heart failure with preserved ejection fraction (HFpEF) is a prevalent comorbidity among patients with end-stage kidney disease. Although sodium-glucose cotransporter 2 inhibitors are validated in treating heart failure and ameliorating left ventricular hypertrophy among non-dialysis patients, the effects on dialysis patients are unknown. We previously investigated the pharmacokinetics of henagliflozin in patients undergoing haemodialysis (HD) or peritoneal dialysis (PD) and clarified its safety., Methods and Analysis: This multicentre, randomised, double-blind, placebo-controlled trial is being conducted at three hospitals in Shanghai, China. A target of 108 HD or PD patients with HFpEF are randomly allocated to treatment group (henagliflozin 5 mg/day in addition to standard therapy) or control group (placebo with standard therapy) at a ratio of 1:1. All subjects will be followed up for 24 weeks. The primary outcome is change in echocardiography-measured left ventricular mass index. The secondary interests include changes in left atrial volume index, E/e', e' and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Intergroup comparisons of change in echocardiography-related outcomes from baseline to 24 weeks are based on a linear regression model adjusted for baseline values (analysis of covariance), and repeated measure analysis of variance with Bonferroni adjustment is employed for comparison of change in NT-proBNP. Subgroup analyses of the primary and secondary outcomes are conducted to determine whether the effect of henagliflozin varies according to dialysis modality. The χ 2 method is used to compare the occurrence of adverse events and severe adverse events., Ethics and Dissemination: This trial has been approved by the Ethics Committee of Renji Hospital, School of Medicine, Shanghai Jiao Tong University (LY2023-127-B). All participants provide written informed consent before screening. The results of the trial will be disclosed completely in international peer-reviewed journals. Both positive and negative results will be reported., Trial Registration Number: ChiCTR2300073169., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Heart failure (HF) is a significant global public health concern with a high readmission rate, posing a serious threat to the health of the elderly population. While several studies have used machine learning (ML) to develop all-cause readmission risk prediction models for elderly patients with HF, few have integrated ML-selected features with those chosen by human experts to assess HF patients readmission. A retrospective analysis of 8396 elderly HF patients hospitalized at the Affiliated Hospital of North Sichuan Medical College from January 1, 2018 to December 31, 2021 was conducted. Variables selected by XGBoost, LASSO regression, and random forest constituted the machine group, while the human expert group comprised variables chosen by two experienced cardiovascular professors. The variables selected by both groups were combined to form a human-machine collaboration group. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC). The SHapley Additive exPlanations (SHAP) method was used to elucidate the importance of each predictive feature, explain the impact of individual features on the model, and provide visual representation. A total of 73 features were included for model development. The human-machine collaboration model, utilizing CatBoost, achieved an AUC of 0.83617, an F1-score of 0.73521, and a Brier score of 0.16536 on the validation set. This model demonstrated superior predictive performance compared to those created solely by human experts or machine. The SHAP plot was then used to visually display the feature analysis of the human-machine collaboration model, revealing HGB, NT-proBNP, smoking history, NYHA classification, and LVEF as the 5 most important features. This study indicate that the human-machine collaboration model outperforms those relying solely on human expert selection or machine algorithm at predicting all-cause readmission in elderly HF patients. The application of the SHAP method enhanced the interpretability of the model outcomes, aiding clinicians in accurately pinpointing risk factors associated with HF readmission. This advancement enables the formulation of tailored treatment strategies, offering a more personalized approach to patient care., (© 2024. The Author(s).)

Background: The goal was to explore the aberrant human epididymal protein 4 (HE4) in chronic heart failure (CHF) patients and its association with C-reactive protein (CRP), uric acid (UA), and homocysteine (HCY)., Methods: Analysis of serum HE4 and its relevance with associated indexes in 117 CHF patients was implemented., Results: Serum HE4 in CHF patients was linked with the disease's severity and CRP, UA, and HCY. An assessment value was provided for it (p < 0.05)., Conclusions: HE4 is aberrant in CHF patients' serum and is associated with the disease's severity and CRP, UA, and HCY's indexes.

Background: The cardiac-protective role of GSNOR (S-nitrosoglutathione reductase) in the cytoplasm, as a denitrosylase enzyme of S-nitrosylation, has been reported in cardiac remodeling, but whether GSNOR is localized in other organelles and exerts novel effects remains unknown. We aimed to elucidate the effects of mitochondrial GSNOR, a novel subcellular localization of GSNOR, on cardiac remodeling and heart failure (HF)., Methods: GSNOR subcellular localization was observed by cellular fractionation assay, immunofluorescent staining, and colloidal gold particle staining. Overexpression of GSNOR in mitochondria was achieved by mitochondria-targeting sequence-directed adeno-associated virus 9. Cardiac-specific knockout of GSNOR mice was used to examine the role of GSNOR in HF. S-nitrosylation sites of ANT1 (adenine nucleotide translocase 1) were identified using biotin-switch and liquid chromatography-tandem mass spectrometry., Results: GSNOR expression was suppressed in cardiac tissues of patients with HF. Consistently, cardiac-specific knockout mice showed aggravated pathological remodeling induced by transverse aortic constriction. We found that GSNOR is also localized in mitochondria. In the angiotensin II-induced hypertrophic cardiomyocytes, mitochondrial GSNOR levels significantly decreased along with mitochondrial functional impairment. Restoration of mitochondrial GSNOR levels in cardiac-specific knockout mice significantly improved mitochondrial function and cardiac performance in transverse aortic constriction-induced HF mice. Mechanistically, we identified ANT1 as a direct target of GSNOR. A decrease in mitochondrial GSNOR under HF leads to an elevation of S-nitrosylation ANT1 at cysteine 160 (C160). In accordance with these findings, overexpression of either mitochondrial GSNOR or ANT1 C160A, non-nitrosylated mutant, significantly improved mitochondrial function, maintained the mitochondrial membrane potential, and upregulated mitophagy., Conclusions: We identified a novel species of GSNOR localized in mitochondria and found mitochondrial GSNOR plays an essential role in maintaining mitochondrial homeostasis through ANT1 denitrosylation, which provides a potential novel therapeutic target for HF., Competing Interests: Disclosures None.

Background: In a large randomized controlled trial (PARADIGM-HF), ARNI has been shown to significantly reduce cardiovascular mortality and hospitalization for patients with reduced ejection fraction in heart failure. This study analyzed the efficacy and safety of ARNI on the basis of various types of heart failure patients in southwestern Sichuan Province., Methods: This study included patients with heart failure who were treated at the Affiliated Hospital of North Sichuan Medical College from July 2017 to June 2021. This study analyzed the efficacy and safety of ARNI in the treatment of heart failure, and analyzed the risk factors for readmission after ARNI treatment., Results: After propensity score matching, a total of 778 patients were included in the study. The readmission rate for heart failure in patients treated with ARNI (8.7%) was significantly lower than that in the standard treatment group (14.5%) (P = 0.023). Both the proportion of patients with increased LVEF and with decreased LVEF were higher in the ARNI treatment group than in the conventional therapy group. Compared with receiving standard medical treatment, combined ARNI treatment resulted in a greater reduction in SBP (-10.00, 95%CI: -24.00-1.50 vs. -7.00, 95%CI: -20.00-4.14; P = 0.016) in HF patients. Combination ARNI therapy did not increase the risk of adverse events. The study found that age (> 65 vs. ≤65 years) (OR = 4.038, 95%CI: 1.360-13.641, P = 0.013) and HFrEF (OR = 3.162, 95%CI: 1.028-9.724, P = 0.045) were independent predictors of readmission in HF patients treated with ARNI., Conclusion: Patients with heart failure treated with ARNI can improve clinical symptoms and reduce the risk of readmitted hospital admission. Age > ~ 65 years and HFrEF were independent predictors of readmission in HF patients treated in ARNI group., (© 2023. The Author(s).)

Background: Myocardial T1 and extracellular volume (ECV) fraction values have important roles in the prognostication of heart failure with preserved ejection fraction (HFpEF). However, the traditional mean quantification of intensity levels is not sufficient., Purpose: To evaluate a T1 map-based radiomic nomogram as a long-term prognosticator for HFpEF in systemic lupus erythematosus (SLE) patients., Study Type: Prospective., Population: A total of 115 SLE patients and 50 age- and gender-matched controls., Field Strength/sequence: A 3.0 T scanner; cine imaging, precontrast and post-contrast T1 mapping and T2 mapping sequences., Assessment: A radiomic nomogram was developed based on precontrast T1 mapping. Three independent readers assessed and compared the ECV value and the value of the radiomic nomogram for predicting HFpEF in SLE patients., Statistical Test: Cox proportional hazard models, Youden index for determining cut-off values for high HFpEF risk vs. low HFpEF risk classification, Kaplan-Meier analysis, intraclass correlation (ICC), and Uno C statistic test., Results: During a median follow-up of 27 (interquartile range, 19-37) months, 31 SLE patients developed HFpEF. Patients with elevated ECV (≥31%) and a higher output (≥42.7) from the radiomic feature "S&#95;33&#95;sum average" of the precontrast T1 map had a significantly higher risk of developing HFpEF than those who had lower ECV (<31%) and an output <42.7. Patients with a higher "S&#95;33&#95;sum average" value on precontrast T1 map had a significantly increased risk for HFpEF (hazard ratio, 1.363, 95% CI, 1.130-1.645), after adjusting for covariates including ECV and LVEF. Finally, "S&#95;33&#95;sum average" from precontrast T1 mapping had modest but significantly incremental prognostic value over the mean ECV value (Uno C statistic comparing models, 0.860 vs. 0.835)., Data Conclusion: The precontrast T1 map-based radiomic nomogram, as a measure of diffuse myocardial fibrosis was associated with HFpEF and provided modest prognostic value for predicting HFpEF in SLE patients., Evidence Level: 1 TECHNICAL EFFICACY: Stage 2., (© 2022 International Society for Magnetic Resonance in Medicine.)

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors lowered the risk of cardiovascular events in patients with diabetes or heart failure (HF) with reduced ejection fraction, whether they directly promote cardiac function remains unclear. Therefore, we sought to determine whether SGLT2 inhibitors could improve left ventricular (LV) function in these patients., Methods: A literature search was conducted using MEDLINE, EMBASE, and Cochrane Library databases from their inception to July 9, 2021. Randomized clinical trials and cohort studies that reported LV function-related variables were included., Results: Thirteen studies comprising 1437 patients (830 SGLT2 inhibitor-treated and 607 non-SGLT2 inhibitor-treated patients) and representing 7 randomized controlled trials with 640 individuals and 6 cohort studies with 797 individuals were included in this meta-analysis. LV regression [LV mass (LVM)], LV ejection fractions (LVEF), LV volumes [LV end-diastolic volumes and systolic volumes (LVEDV and LVESV, respectively], and LV diastolic function [mitral inflow E velocity to tissue Doppler e' ratio, E/e' and left atrial volume index (LAVI)] were all significantly improved in patients treated with SGLT2 inhibitors (weighted mean differences, 95% CI, LVM: -6.319 g, -10.850 to -1.789; LVEF: 2.458%, 0.693 to 4.224; LVEDV: -9.134 mL, -15.808 to -2.460; LVESV: -8.440 mL, -15.093 to -1.787; LAVI: -2.791 mL/m2, -.554 to -1.027; E/e': -1.567, -2.440 to -0.698). Subgroup analysis further confirmed the improvement of LV function mainly in patients with HF or those receiving empagliflozin treatment., Conclusions: Treatment with SGLT2 inhibitors can significantly improve LV function in patients with or without diabetes (especially those with HF or undergoing empagliflozin treatment)., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Elevated homocysteine (Hcy) levels showed increasing significance as the predisposing factor for the pathogenesis of atherosclerotic sequelae, including cardiovascular mortality, coronary artery disease, and stroke. There is increasing evidence linking plasma Hcy levels and heart failure (HF). The association between the elevated level of plasma Hcy and HF was examined by meta-analysis and systematic review in this study., Methods: The PubMed and ScienceDirect databases until April 2020 were utilized to collect previous literature on plasma Hcy levels and the potential relation to HF. The pooled effects were evaluated depending on standardized mean differences (SMDs) with 95% confidence intervals (CIs), and the calculation was performed using Stata 12 software. Potential sources of heterogeneity were assessed with subgroup analysis and sensitivity analysis., Results: A total of 12 research projects including 5506 subjects were selected. For pooled effect, the results confirmed that patients with HF had higher Hcy levels than the control subjects (SMD,1.148 and 95%CI, [0.715, 1.581]). Based on the classification of New York Heart Association (NYHA), the Hcy levels for the group of NYHA I or II (SMD, 1.484 and 95% CI, [0.442, 2.527]) and the group of NYHA III or IV (SMD, 3.361 and 95% CI, [1.902, 4.820]) were significantly increased compared to controls, while the increase was more intensive for the group of NYHA III or IV. Subgroup analyses revealed similar results., Conclusion: Our meta-analysis identified that plasma Hcy levels were significantly elevated in HF patients compared to control subjects, which is positively related to the advancement of NYHA class., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The presence of late gadolinium enhanced (LGE), which may enable better evaluation of myocardial impairment, would help predict the occurrence of life-threatening arrhythmias and major adverse cardiovascular events (MACE) in patients suffering from ischemic cardiomyopathy (ICM) and nonischemic cardiomyopathy (NICM) patients and who underwent a process of implantable cardioverter-defibrillator (ICD)., Purpose: To evaluate the prognostic value of cardiac MR-LGE for ICM and NICM patients with ICD., Study Type: Systematic review and meta-analysis., Population: A total of 33 studies of 3457 patients were included., Field Strength: 1. 5T and 3.0T, LGE., Assessment: PubMed, Cochrane Library, EMBASE, and Web of Science were systematically searched for studies reporting LGE in ICM or NICM patients with ICD implantation with several kinds of endpoints: MACE, life-threatening arrhythmia, cardiovascular mortality, and all-cause mortality., Statistical Tests: A meta-analysis was performed using a random-effects model to calculate odds ratios or standard mean differences (SMDs) for binary and continuous data., Results: MR-LGE was positive in 1923 (55.6%) of ICM and NICM patients. LGE-present patients were more likely to have life-threatening arrhythmia (odds ratio [OR]: 5.1; 95% confidence interval [CI]: 3.8-6.8), MACE (OR: 5.2; 95% CI: 3.8-6.9), cardiovascular mortality (OR: 2.4; 95% CI: 1.2-4.6), and all-cause mortality (OR: 2.1; 95% CI: 1.3-3.4) compared with those without LGE. Moreover, ICM and NICM patients with LGE both had increased life-threatening arrhythmia (OR: 4.6; 95% CI: 2.7-8.0; OR: 5.2; 95% CI: 3.6-7.8, respectively) and MACE (OR: 4.7; 95% CI: 2.8-7.9; OR: 4.7; 95% CI: 2.7-8.1, respectively)., Data Conclusion: The presence of MR-LGE may worsen the prognosis for adverse cardiovascular events in both ICM and NIMC patients who benefit more from ICDs., Level of Evidence: 3 Technical Efficacy Stage: 3 J. Magn. Reson. Imaging 2020;51:1422-1439., (© 2019 International Society for Magnetic Resonance in Medicine.)

Ubiquitin-specific protease 18 (USP18), a USP family member, is involved in antiviral activity and cancer inhibition. Although USP18 is expressed in heart, the role of USP18 in the heart and in cardiac diseases remains unknown. Here, we show that USP18 expression is elevated in both human dilated hearts and hypertrophic murine models. Cardiomyocyte-specific overexpression of USP18 in mice significantly blunted cardiac remodeling as evidenced by mitigated myocardial hypertrophy, fibrosis, ventricular dilation, and preserved ejection function, whereas USP18-deficient mice displayed exacerbated cardiac remodeling under the same pathological stimuli. Similar results were observed for in vitro angiotensin II-induced neonatal rat cardiomyocyte hypertrophy. The antihypertrophic effects of USP18 under hypertrophic stimuli were associated with the blockage of the transforming growth factor-β-activated kinase 1-p38/c-Jun N-terminal kinase 1/2 signaling cascade. Blocking transforming growth factor-β-activated kinase 1-p38/c-Jun N-terminal kinase 1/2 signaling with a pharmacological inhibitor (5Z-7-oxozeaenol) greatly reversed the detrimental effects observed in USP18-knockout mice subjected to aortic banding. Our data indicate that USP18 inhibits cardiac hypertrophy and postpones cardiac dysfunction during the remodeling process, which is dependent on its modulation of the transforming growth factor-β-activated kinase 1-p38/c-Jun N-terminal kinase 1/2 signaling axis. Thus, USP18 is a potent therapeutic target for heart failure treatment., (© 2016 American Heart Association, Inc.)

Instruction and Objectives . Noninvasive positive pressure ventilation (NPPV) alleviates sleep-disordered breathing (SDB) and it may improve cardiac function in SDB patients. Because large randomized controlled trials directly evaluating the impact of NPPV on cardiac function are lacking, we conducted a meta-analysis of published data on effectiveness of NPPV in improving cardiac function in patients with chronic heart failure regardless of SDB presence. Methods . Controlled trials were identified in PubMed, OVID, and EMBASE databases. Both fixed and randomized models were used in meta-analysis with primary outcomes of left ventricular ejection fraction (LVEF). Results . Nineteen studies were included with a total of 843 patients. Compared to standard medical treatment (SMT) plus sham-NPPV or SMT only, NPPV plus SMT was associated with improvement in LVEF (weighted mean difference 5.34, 95% CI, [3.85,6.82]; P < 0.00001) and plasma brain natriuretic peptide (BNP) level (weighted mean difference -117.37, 95% CI, [-227.22, -7.52]; P = 0.04) and no influence on overall mortality (RR 1.00, 95% CI, [0.96,1.04]; P = 0.95). Conclusions . In the present meta-analysis, use of NPPV plus SMT improved LVEF and reduced plasma BNP level but did not improve overall mortality in patients with chronic heart failure., Competing Interests: The authors have no financial disclosures or competing interests to declare.

Background: Although left ventricular pacing (LVP) leads to a greater acute hemodynamic response than does biventricular pacing (BVP), the long-term effects are diverse. We aimed to assess the efficacy of LVP and BVP in patients undergoing cardiac resynchronization therapy and determine which patients would benefit more from LVP or BVP., Methods: Randomized controlled trials that compared left and biventricular pacing were retrieved from MEDLINE and analyzed for changes in cardiac function and dimensions, cardiac resynchronization therapy response, and electromechanical effects., Results: A total of 811 patients were included from 9 trials. After a mean follow-up, a shorter QRS duration (-40.92 milliseconds; 95% confidence interval [CI], -64.50 to -17.34; P = 0.0007), and improved left ventricular dimensions were observed in the BVP group compared with the LVP group. Moreover, the BVP group had a longer 6-minute hall walk (6MHW) test (37.19 m; 95% CI, 4.72 to 69.67; P = 0.02)., Conclusion: Our results indicate that BVP results in a better electromechanical effect and leads to a better 6MHW test. For all other test criteria, LVP showed a benefit equal to that of BVP. Thus, there is currently insufficient evidence to advocate for LV-only pacing., (Copyright © 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Aims: Malignant ventricular arrhythmias can arise in a subset of congestive heart failure (CHF) patients after they undergo cardiac resynchronization therapy (CRT), thus counteracting the haemodynamic benefits typically associated with biventricular pacing. This study seeks to assess whether alteration of the ventricular transmural repolarization and conduction due to reversal of the depolarization sequence during epicardial or biventricular pacing facilitate the development of ventricular arrhythmias., Methods and Results: ECGs and monophasic action potential (MAP) were recorded during programmed stimulation from right ventricle (RV) endocardium (RV-Endo), left ventricle (LV) epicardium (LV-Epi), or both (biventricular, Bi-V) in 15 individuals without structural heart diseases. In patients with severe CHF and CRT (n=21), ECGs were collected during RV-Endo, LV-Epi, and Bi-V pacing. MAP duration on intracardiac electrogram, the QT, JT, and T(peak)-T(end) intervals on ECGs at different pacing sites were measured and compared. In subjects with or without structural heart disease, compared with RV-Endo pacing, LV-Epi and Bi-V pacing resulted in a longer JT (341.78+/-61.97 ms with LV-Epi, 325.86+/-59.69 ms with Bi-V vs. 286.14+/-38.68 ms with RV-Endo in CHF individuals, P<0.0001) or T(peak)-T(end) interval (121.55+/-19.88 ms with LV-Epi, 117.71+/-42.63 ms with Bi-V vs. 102.28+/-12.62 ms with RV-Endo in normal-heart subjects, P<0.0001; 199.70+/-62.44 ms with LV-Epi, 184.89+/-74.08 ms with Bi-V vs. 146.41+/-31.06 ms with RV-Endo in CHF patients, P<0.0001), in addition to prolonged myocardial repolarization time and delayed endocardial activation. During follow-up, sudden death and arrhythmia storm occurred in two CHF patients after CRT., Conclusion: Epicardial and biventricular pacing prolong the time and increase the dispersion of myocardial repolarization and delay the transmural conduction. All of these should be considered as potential arrhythmogenic factors in CHF patients who receive CRT.

In order to verify the hypothesis that left ventricular epicardial (LV-Epi) pacing and biventricular (BiV) pacing unavoidably influence the myocardial electrophysiological characters and may result in high risk of malignant ventricular arrhythmia, we calculated, in both normal mongrel dogs and dog models with rapid-right-ventricular-pacing induced dilated cardiomyopathy congestive heart failure (DCM-CHF), the monophasic action potential duration (MAPD) and the transmural dispersion of repolarization (TDR) in intracardiac electrogram together with the QT interval and T(peak)-T(end) (T(p(-T(e)) interval in surface electrocardiogram (ECG) during LV-Epi and BiV pacing, compared with those during right ventricular endocardial (RV-Endo) pacing. To prepare the DCM-CHF dog model, rapid right ventricular pacing (250 bpm) was performed for 23.6+/-2.57 days to the dog. All the normal and DCM-CHF dogs were given radio frequency catheter ablation (RFCA) to His bundle with the guide of X-ray fluoroscopy. After the RFCA procedures, the animals were under the situation of complete atrioventricular block so that the canine heart rates could be voluntarily controlled in the following experiments. After a thoracotomy, ECG and monophasic action potentials (MAP) of subendocardial, subepicardial and mid-layer myocardium were recorded synchronously in 8 normal and 5 DCM-CHF dogs during pacing from endocardium of RV apex (RV-Endo), epicardium of LV anterior wall (LV-Epi) and simultaneously both of the above (biventricular, BiV), the later was similar to the ventricular resynchronization therapy to congestive heart failure patients in clinic. The Tp-Te) meant the interval from the peak to the end of T wave, which was a representative index of TDR in surface ECG. The TDR was defined as the difference between the longest and the shortest MAPD of subendocardial, subepicardial and mid-layer myocardium. Our results showed that in normal dogs, pacing participating of LV (LV-Epi, BiV) prolonged MAPD of all the three layers of the myocardium (P<0.05) with the character that mid-layer MAPD was the longest and subepicardial MAPD was the shortest following subendocardial MAPD. At the same time, TDR prolonged from 26.75 ms at RV-Endo pacing to 37.54 ms at BiV pacing and to 47.16 ms at LV-Epi pacing (P<0.001). Meanwhile in surface ECG, BiV and LV-Epi pacing resulted in a longer Tp-Te) interval compared with RV-Endo pacing (P<0.01), without parallel QT interval prolongation. Furthermore, all the DCM-CHF model dogs showed manifestations of congestive heart failure and enlargement of left ventricles. Based on the lengthening of mid-layer MAPD from 257.35 ms to 276.30 ms (P<0.0001) and increase of TDR from 27.58 ms to 33.80 ms (P equals;0.002) in DCM-CHF model due to the structural disorders of myocardium compared with the normal dog, LV-Epi and BiV pacing also led to the effect of prolonging MAPD of three layers of the myocardium and enlarging TDR. From these results we make the conclusions that prolongation of MAPD of subendocardial, subepicardial and mid-layer myocardium and increase in TDR during pacing participating of LV (LV-Epi, BiV) may contribute to the formation of unidirectional block and reentry, which play roles or at least are the high risk factors in the development of malignant ventricular arrhythmia, especially in case of structural disorders of myocardium. These findings must be considered seriously when ventricular resynchronization therapy is performed to congestive heart failure patients.

Background: Diabetes mellitus (DM) and coronary microvascular dysfunction (CMD) increase the risk of adverse cardiac events in patients with non-ST-segment elevation myocardial infarction (NSTEMI). This study aimed to evaluate the combined risk estimates of DM and CMD, assessed by the angiography-derived index of microcirculatory resistance (angio-IMR), in patients with NSTEMI. Methods: A total of 2212 patients with NSTEMI who underwent successful percutaneous coronary intervention (PCI) were retrospectively enrolled from three centers. The primary outcome was a composite of cardiac death or readmission for heart failure at a 2-year follow-up. Results: Post-PCI angio-IMR did not significantly differ between the DM group and the non-DM group (20.13 [17.91–22.70] vs. 20.19 [18.14–22.77], P = 0.530). DM patients exhibited a notably higher risk of cardiac death or readmission for heart failure at 2 years compared to non-DM patients (9.5% vs. 5.4%, P < 0.001). NSTEMI patients with both DM and CMD experienced the highest cumulative incidence of cardiac death or readmission for heart failure at 2 years (24.0%, P < 0.001). The combination of DM and CMD in NSTEMI patients were identified as the most powerful independent predictor for cardiac death or readmission for heart failure at 2 years (adjusted HR: 7.894, [95% CI, 4.251–14.659], p < 0.001). Conclusions: In patients with NSTEMI, the combination of DM and CMD is an independent predictor of cardiac death or readmission for heart failure. Angio-IMR could be used as an additional evaluation tool for the management of NSTEMI patients with DM. Trial registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05696379. [ABSTRACT FROM AUTHOR]

Background: The impact of left ventricular mechanical dyssynchrony (LVMD) on the long‐term prognosis of ST‐segment elevation myocardial infarction (STEMI) is unclear. Hypothesis: MR uniformity ratio estimates (URE) can detect LVMD and assess STEMI prognosis. Study Type: Retrospective analysis of a prospective multicenter registry (EARLY‐MYO trial, NCT 03768453). Population: Overall, 450 patients (50 females) with first‐time STEMI were analyzed, as well as 40 participants without cardiovascular disease as controls. Field Strength/Sequence: 3.0‐T, balanced steady‐state free precession cine and late gadolinium enhancement imaging. Assessment: MRI data were acquired within 1 week of symptom onset. Major adverse cardiovascular events (MACEs), including cardiovascular death, nonfatal re‐infarction, hospitalization for heart failure, and stroke, were the primary clinical outcomes. LVMD was represented by circumferential URE (CURE) and radial URE (RURE) calculated using strain measurements. The patients were grouped according to clinical outcomes or URE values. Patients' clinical characteristics and MR indicators were compared. Statistical Tests: The Student's t‐test, Mann–Whitney U test, chi‐square test, Fisher's exact test, receiver operating characteristic curve analysis with area under the curve, Kaplan–Meier analysis, Cox regression, logistic regression, intraclass correlation coefficient, c‐index, and integrated discrimination improvement were used. P < 0.05 was considered statistically significant. Results: CURE and RURE were significantly lower in patients with STEMI than in controls. The median follow‐up was 60.5 months. Patients with both lower CURE and RURE values experienced a significantly higher incidence of MACEs by 3.525‐fold. Both CURE and RURE were independent risk factors for MACEs. The addition of UREs improved diagnostic efficacy and risk stratification based on infarct size and left ventricular ejection fraction (LVEF). The indicators associated with LVMD included male sex, serum biomarkers (peak creatine phosphokinase and cardiac troponin I), infarct size, and LVEF. Data Conclusion: CURE and RURE may be useful to evaluate long‐term prognosis after STEMI. Evidence Level: 4 Technical Efficacy: Stage 2 [ABSTRACT FROM AUTHOR]

This editorial discusses the prevalence of heart failure worldwide and the advancements in molecular and cellular biology that are transforming our understanding and treatment of the condition. The special issue includes nine papers that highlight recent advances in understanding the transcriptome profile in cardiovascular diseases and providing novel treatments for promoting cardiac repair. The papers cover topics such as the transcriptomic profile of endothelial cells in Duchenne muscular dystrophy, the impact of inflammation in remote zones after myocardial infarction, the effectiveness of manganese porphyrin compound for cardiac arrest, the role of HIF2α and ARNT signaling in endothelial cells, strategies to induce cardiomyocyte proliferation, the characterization of the common marmoset as a primate model for cardiovascular disease, and the link between heart failure and cognitive impairment. The authors express their gratitude to the contributors and reviewers of the special issue. [Extracted from the article]

It remains unclear whether adults with metabolically healthy obesity (MHO) have altered myocardial tissue-level characteristics. This study aims to assess the subclinical myocardial tissue-level characteristics of adults with MHO. The EARLY-MYO-OBESITY (EARLY Assessment of MYOcardial Tissue Characteristics in OBESITY; NCT05277779) registry was a prospective, 3-center, cardiac imaging study of obese nondiabetic individuals without cardiac symptoms who underwent cardiac magnetic resonance. Myocardial tissue-level characteristics, including extracellular volume fraction (ECV) and native T2 values, were measured as indicators of myocardial fibrosis and edema. Global longitudinal peak systolic strain and early diastolic longitudinal strain rate were assessed by tissue tracking analysis to detect subclinical systolic and diastolic dysfunction. A total of 120 participants were included: MHO (n = 32; mean age, 38 years; 41% men), metabolically healthy controls without obesity (n = 32; mean age: 37 years; 41% men), and metabolically unhealthy obesity (MUHO) (n = 56; mean age: 37 years; 55% men). The MHO group had higher ECV and native T2 values than healthy controls (both P < 0.001); furthermore, the ECV was higher in the MUHO group than in the MHO group (P = 0.002). The prevalence of myocardial fibrosis was 44% (14 of 32) in the MHO group and 71% (40 of 56) in the MUHO group. Although there was no intergroup difference in left ventricular ejection fraction, the MHO group had reduced global longitudinal peak systolic and early diastolic longitudinal strain rates, indicating subclinical systolic and diastolic dysfunction. Multivariate regression analysis identified increased body mass index to be an independent risk factor for myocardial fibrosis (OR: 6.28 [95% CI: 3.17-12.47]; P < 0.001). This study provides the first evidence of subclinical myocardial tissue-level remodeling in adults with obesity, regardless of metabolic health. Early identification of cardiac impairment may facilitate preventive strategies against heart failure in the MHO population. (EARLY Assessment of MYOcardial Tissue Characteristics in OBESITY [EARLY-MYO-OBESITY]; NCT05277779) [Display omitted] [ABSTRACT FROM AUTHOR]

Dysregulation of the ubiquitin proteasome system components ubiquitin ligases and proteasome plays an important role in the pathogenesis of cardiac hypertrophy. However, little is known about the role of another ubiquitin proteasome system component, the deubiquitinating enzymes, in cardiac hypertrophy. Here, we revealed a crucial role of ubiquitin specific protease 4 (USP4), a deubiquitinating enzyme prominently expressed in the heart, in attenuating pathological cardiac hypertrophy and dysfunction. USP4 levels were consistently decreased in human failing hearts and in murine hypertrophied hearts. Adenovirus-mediated gain- and loss-of-function approaches indicated that deficiency of endogenous USP4 promoted myocyte hypertrophy induced by angiotensin II in vitro, whereas restoration of USP4 significantly attenuated the prohypertrophic effect of angiotensin II. To corroborate the role of USP4 in vivo, we generated USP4 global knockout mice and mice with cardiac-specific overexpression of USP4. Consistent with the in vitro study, USP4 depletion exacerbated the hypertrophic phenotype and cardiac dysfunction in mice subjected to pressure overload, whereas USP4 transgenic mice presented ameliorated pathological cardiac hypertrophy compared with their control littermates. Molecular analysis revealed that USP4 deficiency augmented the activation of the transforming growth factor β-activated kinase 1 (TAK1)-(JNK1/2)/P38 signaling in response to hypertrophic stress, and blockage of TAK1 activation abolished the pathological effects of USP4 deficiency in vivo. These findings provide the first evidence for the involvement of USP4 in cardiac hypertrophy, and shed light on the therapeutic potential of targeting USP4 in the treatment of cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

Objectives: We proposed that the severity of ST-segment elevation myocardial infarction (STEMI) could be classified based on pathophysiological changes. Methods: First-STEMI patients were classified within hospitalization. Grade 0: no detectable myocardial necrosis; Grade 1: myocardial necrosis without functional and morphological abnormalities; Grade 2: myocardial necrosis with reduced LVEF; Grade 3: reduced LVEF on the basis of cardiac remodeling; Grade 4: mitral regurgitation additional to the Grade-3 criteria. Results: Of 180 patients, 1.7, 43.9, 26.1, 23.9 and 4.4% patients were classified as Grade 0 to 4, respectively. The classification is an independent predicator of 90-day MACEs (any death, resuscitated cardiac arrest, acute heart failure and stroke): the rate was 0, 5.1, 8.5, 48.8 and 75% from Grade 0 to 4 (p<0.001), respectively. The Grade-2 patients were more likely to have recovered left ventricular ejection fraction than the Grade-3/4 patients did after 90 days (48.9% vs. 19.1%, p<0.001). Avoiding complicated quantification, the classification served as a good reflection of infarction size as measured by cardiac magnetic resonance imaging (0±0, 15.68±8.48, 23.68±9.32, 36.12±11.35 and 40.66±14.33% of the left ventricular mass by Grade 0 to 4, P<0.001), and with a comparable prognostic value (AUC 0.819 vs. 0.813 for infarction size, p = 0.876 by C-statistics) for MACEs. Conclusions: The new classification represents an easy and objective method to scale the cardiac detriments for STEMI patients. [ABSTRACT FROM AUTHOR]