Cardiovascular Therapeutics最新文献

Myocardial fibrosis is a common pathological feature in many cardiovascular diseases, yet effective targeted therapies remain elusive. Given the emerging potential of chimeric antigen receptor T (CAR-T) cell therapy in nononcological diseases and fibroblast activation protein (FAP) as a promising target, we engineered a second-generation FAP-targeted CAR construct incorporating the 4-1BB costimulatory domain to enhance therapeutic safety. Using two delivery approaches—lentiviral vectors and lipid nanoparticles (LNPs)—we generated FAP-CAR–engineered Jurkat cells as a preliminary screening model and evaluated their CAR expression, target recognition, and in vitro cytotoxic activity. These engineered cells selectively recognized and induced apoptosis in FAP-expressing cardiac myofibroblasts without triggering excessive IL-6 secretion, supporting their potential for fibrosis-selective cytotoxicity. Our findings provide key preliminary in vitro evidence supporting the design and target-specific functionality of FAP-targeted CAR constructs incorporating the 4-1BB domain, warranting further investigation in primary T cell models for cardiac fibrosis therapy.

Background: Calcific aortic valve disease (CAVD) is a prevalent valvular heart disease characterized by the fibrocalcific remodeling of the aortic valves, leading to significant health issues among the elderly population worldwide. The aberrant expression of long noncoding RNAs (lncRNAs) is closely associated with the pathogenesis of various diseases.

Methods and Results: A total of 241 differentially expressed lncRNAs were identified in calcified aortic valve tissues (fold change of ≥ 2 and p value < 0.05), including 65 upregulated and 176 downregulated lncRNAs. The expression of the Top 5 upregulated lncRNAs was monitored during the calcification of valvular interstitial cell (VIC). Notably, the expression of lnc-PRDM8-3 and lnc-COL6A1-6 in VICs increased significantly after calcification induction and was sustained at high levels. Inhibition of lnc-COL6A1-6, but not lnc-PRDM8-3, obviously alleviated the calcification of VICs, as evidenced by a marked reduction in calcium deposition, decreased alkaline phosphatase activity, and downregulated expression of Runx2 and OPN. Bioinformatic analysis predicted that lnc-COL6A1-6 might serve as a competing endogenous RNA for 11 miRNAs, potentially regulating the expression of 784 target genes. Among these, the Top 50 target genes were found to be significantly enriched in autophagy-related biological processes. Consistently, elevated levels of the autophagic markers Beclin 1 and LC3β were detected in calcified aortic valve tissues. Inhibition of lnc-COL6A1-6 significantly reduced autophagic flux in VICs under calcification-inducing conditions. Importantly, pharmacological inhibition of autophagy using chloroquine abolished the anticalcific effects of lnc-COL6A1-6 knockdown.

Conclusions: The present study identified a lnc-COL6A1-6-mediated miRNA–mRNA regulatory network in aortic valve calcification. Knockdown of lnc-COL6A1-6 could mitigate VIC calcification by attenuating autophagic activity, highlighting its potential as a therapeutic target for CAVD.

Objective: The CTI is increasingly recognized as a new marker for assessing inflammation and insulin resistance. However, the relationship between CTI and all-cause mortality risk in patients with CVD remains unclear.

Methods: We analyzed data from the NHANES from 1999 to 2010. The correlation between CTI and all-cause mortality risk in CVD patients was examined using Cox regression analysis. Nonlinear relationships between CTI and all-cause mortality risk were explored through restricted cubic splines and Cox proportional hazards regression. We employed six ML models, including RF, LightGBM, DT, XGBoost, LR, and KNN, to predict all-cause mortality risk in CVD patients based on CTI and SHAP for interpretability.

Results: A total of 1429 CVD patients were included, with 849 all-cause deaths recorded during the follow-up period. After adjusting for potential confounding factors, the highest quartile of CTI (Q4) significantly increased the risk of all-cause mortality compared to the lowest quartile (Q1) (HR = 1.38, 95% CI: 1.04–1.84, p = 0.03). Restricted cubic splines demonstrated a nonlinear relationship between CTI and all-cause mortality risk in CVD patients. Among the machine learning models, the LightGBM model exhibited the best predictive performance, with an ROC of 0.967, accuracy of 0.909, sensitivity of 0.906, specificity of 0.914, F1 score of 0.922, recall of 0.906, and PR of 0.979. SHAP analysis identified age, BU, and CTI as the primary predictive factors, with CTI positively correlated with all-cause mortality risk in CVD patients.

Conclusion: There is a nonlinear relationship between CTI and all-cause mortality risk in CVD patients, with elevated CTI levels significantly associated with increased mortality risk. Additionally, for the first time, this study constructed a machine learning model to predict all-cause mortality risk in cardiovascular disease using CTI, with LightGBM demonstrating the best predictive performance. SHAP analysis identified age, BUN, and CTI as critical factors in the prediction, providing valuable references for future related research.

Hypertension constitutes a major risk factor for cardiovascular diseases. Globally, the management and control of hypertension remain suboptimal. At present, pharmacological intervention is a critical strategy for patients with hypertension to achieve blood pressure regulation. Nevertheless, inadequate adherence to prescribed medication significantly impedes effective blood pressure control. Renal denervation (RDN) has emerged as a minimally invasive intervention that has the potential to achieve long-term reduction in blood pressure. Many preclinical and clinical trials have validated the effects of RDN. While trials such as SYMPLICITY HTN-3 raised questions about the efficacy of RDN, the majority of subsequent clinical trials have demonstrated benefits in patients with resistant hypertension. Presently, traditional RDN therapy is characterized by invasiveness and technical complexity, so the utilization of noninvasive high-intensity focused ultrasound (HIFU) has been incorporated into RDN procedures. This review is aimed at consolidating data on the efficacy and safety of various RDN modalities, examining the implementation of noninvasive HIFU in RDN practices, and suggesting potential avenues for future advancements and opportunities.

Background: Yes-associated protein (YAP) is a major downstream nuclear coactivator of the Hippo pathway and is activated during myocardial hypertrophy. Verteporfin, a YAP inhibitor, may serve as a potential treatment for myocardial hypertrophy.

Aim: This study was aimed at exploring the role and underlying mechanisms of verteporfin in isoproterenol (ISO)-induced myocardial hypertrophy both in vivo and in vitro.

Methods: GSE18801 directs our focus toward the Hippo pathway role in myocardial hypertrophy. Using an ISO-induced myocardial hypertrophy rat model, YAP expression and localization were observed through Western blot and immunofluorescence. Histopathological analysis was performed to evaluate cardiomyocyte cross-sectional area, and echocardiographic examinations were conducted to assess cardiac function. In vitro, primary neonatal rat cardiomyocytes (NRCMs) were cultured with conditioned medium from cardiac fibroblasts (CF-CM) treated with ISO to observe cell hypertrophy. Mechanistically, GSE203358 dataset analysis, enzyme-linked immunosorbent assay (ELISA), and Western blot were utilized to investigate the effects of ISO and verteporfin on IL-6, STAT3, and p-STAT3 levels in CFs. Subsequently, the changes in the IL-6/STAT3 pathway were evaluated in CFs treated with ISO and verteporfin. Additionally, recombinant IL-6 and IL-6 inhibitor were applied to CMs treated with CF-CM to observe changes in cardiomyocyte size.

Results: Verteporfin improved cardiac performance in rats receiving ISO. In cultured NRCM, both ISO and CF-CM treated with ISO could induce cardiomyocyte hypertrophy. Verteporfin did not attenuate ISO-induced cardiomyocyte hypertrophy. However, it could attenuate hypertrophy induced by the CF-CM treated with ISO. GSE203358 indicated the involvement of the IL-6/STAT3 pathway in the presence of verteporfin in CFs. Additionally, verteporfin reduces IL-6 production in cultured CFs subjected to ISO treatment. Notably, the effects of verteporfin on NRCM were reversed by IL-6.

Conclusions: Verteporfin protects the heart against ISO-induced myocardial hypertrophy by regulating IL-6/STAT3 in cardiac fibroblasts.

This study explores the predictive utility of brain natriuretic peptide (BNP) levels in assessing outcomes for patients with chronic left heart failure (LHF). A cohort of 59 patients diagnosed with chronic LHF was compared to 59 healthy controls. BNP levels, alongside other cardiac function parameters, such as left ventricular ejection fraction (LVEF) and left ventricular end-systolic dimension (LVESD), were evaluated. Results revealed that BNP levels were positively correlated with worsening cardiac function and negatively correlated with LVEF. In individuals with obesity or Type 2 diabetes mellitus, BNP levels were unexpectedly lower, whereas patients with chronic kidney disease or atrial fibrillation exhibited elevated BNP levels. A BNP cut-off value of 98.9 was identified, demonstrating high diagnostic sensitivity (91.53%), specificity (83.05%), and accuracy (88.14%). The area under the ROC curve (AUC) indicated strong diagnostic performance for BNP in predicting adverse cardiovascular events. The findings underscore BNP’s value not only as a biomarker for diagnosing LHF but also in prognostication and tailoring patient-specific interventions. Future studies should validate these findings across diverse populations to enhance clinical application.

Trial Registration: Chinese Clinical Trial Registry identifier: ChiCTR2500101966

Background: Chronic heart failure (CHF) involves changes in cardiac structure and function, along with extensive neuroendocrine adaptations and metabolic abnormalities. Heart rate variability (HRV) is a noninvasive measure of autonomic nervous system function and is associated with mortality in CHF. However, the significance of HRV in predicting major adverse cardiovascular events (MACEs) in CHF patients has not been fully explored. This study was aimed at investigating the predictive value of HRV parameters assessed by 24-h Holter monitoring for MACEs in CHF patients.

Methods: This prospective cohort study included 906 CHF patients from five centers in Xinjiang, China, who underwent Holter monitoring and were followed up. Cox proportional hazards regression models were used to assess the independent associations between HRV parameters and the incidence of MACEs. Receiver operating characteristic (ROC) curve analysis was conducted to determine the predictive accuracy of each HRV parameter, and the incremental predictive value of HRV parameters was evaluated using coherence index (C-index), net reclassification improvement (NRI), and integrated discrimination improvement (IDI).

Results: During a median follow-up of 16 months, 211 (23.3%) MACEs occurred. Cox regression analysis indicated that SDNN (HR: 0.976, 95% CI: 0.970~0.981), triangular index (HR: 0.963, 95% CI: 0.953~0.973), SDNN index (HR: 0.983, 95% CI: 0.974~0.992), SDANN index (HR: 0.974, 95% CI: 0.967~0.981), NN50 (HR: 0.859, 95% CI: 0.787~0.937), rMSSD (HR: 0.980, 95% CI: 0.970~0.989), TP (HR: 0.890, 95% CI: 0.816~0.971), VLF (HR: 0.889, 95% CI: 0.815~0.969), LF (HR: 0.817, 95% CI: 0.743~0.898), and HF (HR: 0.806, 95% CI: 0.728~0.893) were independently associated with MACEs. ROC analysis revealed that the triangular index and SDNN had the highest area under the curve (AUC) for predicting MACEs, with values of 0.699 (95% CI: 0.655~0.743) and 0.711 (95% CI: 0.668~0.753), respectively. Incorporation of HRV parameters into traditional risk models improves the C-index, NRI, and IDI of the model’s predictive ability for MACE and cardiovascular mortality to varying degrees.

Conclusion: SDNN and triangular index demonstrated the strongest predictive abilities; other time–domain and frequency–domain parameters also showed certain predictive values for MACEs.

Aims: This prospective cohort study was aimed at evaluating the association of galectin-3 (Gal-3) and other prognostic factors with atrial fibrillation (AF) recurrence in patients with nonvalvular AF undergoing radiofrequency catheter ablation (RFCA).

Methods and Results: Overall, 92 patients were included, with the AF group comprising 70 patients and the control group comprising 20 (supraventricular tachycardic) patients. Preablation parameters were recorded, including baseline Gal-3 levels. Patients were followed up for 6 months post-RFCA. AF recurrence was defined as AF episodes lasting > 30 s after the blanking period. Univariate and multivariate logistic regression analyses revealed patients with AF were older and significantly hypertensive (p < 0.05) when compared to control. Gal-3 levels were significantly higher in the paAF (13.81 ± 2.56) and peAF (15.92 ± 3.67) groups than in the control group (12.04 ± 3.28). Recurrence occurred in 28 patients (40%) with AF. Baseline Gal-3 levels were higher in the recurrence group than in the nonrecurrence group. Univariate analysis revealed left atrial diameter (LAD), left atrial volume (LAV), high-sensitivity C-reactive protein (hs-CRP), Gal-3, and LV short-axis shortening rate as significant predictors of AF recurrence. However, multivariate analyses showed only LAV (OR = 1.043 [1.011–1.077]; p = 0.009), hs-CRP (OR = 1.176 [1.025–1.349], p = 0.021), and Gal-3 (OR = 2.019 [1.332–3.06], p = 0.001) as independent predictors of recurrence.

Conclusion: Elevated Gal-3 and hs-CRP levels along with increased LAV are predictive of AF recurrence, irrespective of AF type. This finding holds a significant potential for guiding therapeutic strategies in clinical practice.

Background: Calcific aortic valve disease (CAVD) is a prevalent heart valve disease. The ratio of two apolipoproteins with distinct functions, Apolipoprotein B/Apolipoprotein A1 (APOB/APOA1), has been proposed as a novel assessment index for the evaluation of cardiovascular diseases. The aim of this article is to discuss the role of lipid parameters such as APOB/APOA1 in CAVD and the risk factors for CAVD, to develop a predictive model for CAVD, and to evaluate the sensitivity and specificity of this model.

Method: Patients who initially presented to the Department of Cardiology of the Second Affiliated Hospital of Dalian Medical University between 1 January 2023 and 31 December 2023 were retrospectively identified and included in the study. Patients were divided into an aortic valve calcification group (111 cases) and a control group (201 cases) based on computed tomography (CT) findings. The clinical data, laboratory examination results, and chest CT images of the patients were collected and analyzed. A variety of statistical methods were used to analyze risk factors for CAVD, to construct a CAVD prediction model, and to assess its sensitivity and specificity.

Results: Lipid parameters APOA1, APOB/APOA1, cumulative low-density lipoprotein (LDL) exposure, and non–high-density lipoprotein/high-density lipoprotein (non-HDL/HDL) were significantly associated with aortic valve calcification. Age, history of diabetes, diastolic blood pressure (DBP), APOB/APOA1, Cystatin C (Cys-c), and neutrophil-to-lymphocyte ratio (NLR) are identified as independent risk factors for CAVD, and the combined model achieved an AUC of 0.796 for CAVD prediction, corresponding to a sensitivity of 0.769 and a specificity of 0.755.

Conclusion: The lipid parameters APOA1, APOB/APOA1, cumulative LDL exposure, and non-HDL/HDL have been demonstrated to be associated with aortic valve calcification. Furthermore, APOB/APOA1 can be used for the prediction of CAVD, and the combination of APOB/APOA1 with age, history of diabetes, DBP, Cys-c, and NLR has better prediction performance for CAVD.

X. Shi, B. Zhang, Z. Chu, et al., “Wogonin Inhibits Cardiac Hypertrophy by Activating Nrf-2-Mediated Antioxidant Responses”, Cardiovascular Therapeutics 2021 (2021): 9995342, https://doi.org/10.1155/2021/9995342

In the article, there is an error in Figure 4e due to the incorrect selection of images during manuscript preparation. The correct Figure 4 is shown below:

The authors apologize for this error.