Xiaoyan Zhao

BACKGROUND: Nonobstructive hypertrophic cardiomyopathy (nHCM) is associated with significant morbidity with no approved treatment. Aficamten is a cardiac myosin inhibitor targeting excess contractility and diastolic impairment, the predominant mechanism responsible for adverse outcomes in nHCM. In the ACACIA-HCM trial (Assessment Comparing Aficamten to Placebo on Cardiac Endpoints in Adults With Non-Obstructive HCM; URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06081894), aficamten significantly improved outcomes in patients with nHCM versus placebo. To contextualize the observed treatment effects, we performed a responder analysis integrating multiple clinically relevant measures. METHODS: Patients with symptomatic nHCM were randomized to daily aficamten (n=258) or placebo (n=259) assessed at week 36, including (1) symptom burden (≥1 improvement in New York Heart Association class or reported improvement in Patient Global Impression of Change); (2) exercise capacity (≥0.5 mL/kg per min in peak oxygen uptake); (3) >10% decrease in left atrial volume index; (4) >10% improvement in septal early diastolic mitral annular velocity (e’); (5) ≥50% reduction in NT-proBNP (N-terminal pro-B-type natriuretic peptide). Overall clinical response was classified by the number of favorable outcomes achieved: nonresponder (none), limited (1 or 2), partial (3 or 4), or complete (all 5). RESULTS: At 36 weeks, a greater proportion of patients treated with aficamten versus placebo experienced improvements in symptom burden (71% versus 53%), peak exercise capacity (45% versus 37%), left atrial volume index (31% versus 23%), septal e’ (51% versus 26%), and NT-proBNP (63% versus 5%) ( P P =0.1). Number needed to treat for aficamten ranged from 1.7 (NT-proBNP reduction) to 14 (peak oxygen uptake improvement) relative to placebo. A partial or complete clinical response (≥3 outcomes) was achieved in 53% of patients on aficamten versus 14% on placebo ( P <0.001). CONCLUSIONS: In patients with nHCM, aficamten was associated with improvements across a broad range of clinically relevant measures including symptom burden and diastolic function. These results underscore a potential benefit of aficamten in the population of patients with nHCM. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06081894.

Iron deficiency is highly prevalent in chronic heart failure (CHF) and is associated with poor clinical outcomes. Although intravenous iron therapy has demonstrated clinical benefits, the therapeutic potential of dietary iron supplementation remains unclear. Here, we investigated whether a high-iron diet protects against chronic doxorubicin (Dox)-induced chronic heart failure in mice. Chronic heart failure was established by repeated intraperitoneal injections of low-dose Dox (2.5 mg/kg/week for 6 weeks). Mice were fed either a standard diet (45 ppm iron) or a high-iron diet (5,000 ppm iron supplemented with ferric citrate). Cardiac function, myocardial injury, fibrosis, mitochondrial ultrastructure, oxidative stress, transcriptomic alterations, and iron metabolism-related proteins were evaluated using echocardiography, histological analysis, biochemical assays, RNA sequencing, and Western blotting. High-iron diet supplementation significantly improved survival and cardiac function while reducing myocardial injury, fibrosis, mitochondrial damage, and oxidative stress. RNA sequencing identified ferroptosis as a significantly enriched pathway in Dox-treated hearts. Mechanistically, Dox disrupted myocardial iron homeostasis, as evidenced by increased serum Fe2+ levels, upregulation of transferrin receptor 1 (TFR1) and nuclear receptor coactivator 4 (NCOA4), and downregulation of ferritin heavy chain 1 (FTH1). These alterations were largely reversed by high-iron diet supplementation, whereas SLC7A11 expression remained unchanged, suggesting that cardioprotection was primarily mediated through restoration of iron homeostasis via inhibition of NCOA4-mediated ferritinophagy rather than the canonical System Xc- pathway. Collectively, dietary iron supplementation attenuates chronic Dox-induced heart failure by restoring myocardial iron homeostasis and suppressing ferroptosis, highlighting NCOA4-mediated ferritinophagy as a potential therapeutic target for heart failure.

Objective: To explore the clinical efficacy and follow-up results of the valve-in-valve transcatheter mitral valve replacement (TMVR) technique in patients with mitral bioprosthetic valve dysfunction. Methods: The medical data of patients with biological valve dysfunction after mitral valve replacement who underwent TMVR in our hospital from January 2019 to January 2024 were retrospectively collected. The echocardiography data, New York Heart Association (NYHA) grade, EuroQol visual analogue scale (EQ-VAS) score, and 6-minute walking distance before and after the operation were compared. Results: A total of 33 patients, 8 males and 25 females, with an average age of 70.70 ± 9.04 years, were included in this study. All 33 patients underwent TMVR surgery successfully. Seven patients underwent surgery via the atrial septal approach, and 26 patients underwent surgery via the apical approach. The success rate of the TMVR was 100.0%. One patient had a complication of cerebral infarction and eventually died 7 days after the operation. Compared with those prior to the operation, the NYHA grade, EQ-VAS score and the 6-minute walking distance were improved significantly at follow-up (all P < 0.05). Conclusion: Valve-in-valve TMVR is a feasible option for patients with degenerated bioprosthetic mitral valves. However, follow-up studies are still needed to determine the long-term effects.

Original Article Relationships between QRS duration and left ventricular deformation in hypertrophic cardiomyopathy Shi Chen, Mingxuan Duan, Xi Zhao, Dakui Zhang, Hongyun Qin, Shuoyan An, Beiyao Gao, Xiaoyan Zhao

The combination of percutaneous coronary intervention (PCI) and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) has become a widely used approach for resuscitating patients with acute myocardial infarction (AMI) complicated by cardiac arrest (CA). Nonetheless, limited research has focused on predicting in-hospital mortality in affected patients. This study aims to identify factors associated with in-hospital mortality and develop a clinical prediction model for these patients. Clinical presentations of AMI patients with CA undergoing PCI supported by VA-ECMO at two hospitals in Zhengzhou were evaluated. Patients were stratified based on their survival status at discharge. A comprehensive analysis, which included univariate logistic regression, LASSO regression, and multivariate logistic regression, was conducted to identify predictors and develop a nomogram for in-hospital mortality. The nomogram's predictive performance was subsequently compared to that of existing models. The study included 139 patients, of whom 84 died during hospitalization. Using factors such as age, current smoking, left main culprit vessel, lactic acid levels, and serum creatinine, a nomogram model was developed. The model demonstrated good predictive performance, with an area under the curve of 0.826 (95% CI 0.757–0.894) in the training dataset and 0.783 (95% CI 0.706–0.859) in the internal validation dataset, indicating high accuracy and stability. Clinical decision curve analysis confirmed the model’s utility, particularly for risk thresholds above 20%, outperforming existing models. This study identified independent predictors of in-hospital mortality in AMI patients with CA undergoing PCI supported by VA-ECMO and developed a clinically applicable prediction model.

BACKGROUND: Genetic variants in desmosomal cadherins, desmoglein 2 ( DSG2 ) and desmocollin 2 ( DSC2 ), cause a distinct form of arrhythmogenic right ventricular cardiomyopathy (ARVC), which remains poorly reported. In this study, we aimed to provide a comprehensive description of the phenotypic expression, natural history, and clinical outcomes of patients with this ARVC subset. METHODS: Genetic and clinical data of DSG2 and DSC2 variant carriers were collected from 5 countries in Europe and Asia. We assessed the phenotypic profile of these patients and their clinical outcomes, focusing on heart failure and ventricular arrhythmia events. RESULTS: Overall, 271 subjects, 254 with DSG2 variants, were included in this study (median age, 38 years [interquartile range, 25–52]; 62.7% male). Of these, 165 were probands, and 200 were diagnosed with definite ARVC. A total of 181 (66.8%) individuals carried missense variants, mainly distributed in the extracellular domains. Notably, we included 78 (28.8%) individuals with multiple variants. Of the 200 cases with diagnosed ARVC, 41 (20.5%) experienced premature cardiac death before the age of 65. Among the 81 individuals for whom both left ventricular ejection fraction and right ventricular fractional area change data were available at presentation, 29 (35.8%) had isolated right ventricular dysfunction, and 16 (19.8%) had biventricular dysfunction. Single-variant carriers who engaged in intense physical exercise were younger at disease onset compared with those who did not ( P =0.001). Compared with single-variant carriers, those with multiple variants were more likely to be diagnosed with ARVC (96.2% versus 64.8%; P P =0.001) and right ventricular dilation (88.9% versus 55.8%, P P P P =0.004) were significantly more frequent in multiple-variant compared with single-variant carriers. Compared with PKP2 patients, DSG2/DSC2 patients exhibited a significantly higher risk of end-stage heart failure ( P <0.001). CONCLUSIONS: ARVC attributable to variants in desmosomal cadherins mostly present with right ventricular or biventricular disease. Multiple variants are common in these patients and are associated with more frequent clinical penetrance, earlier onset of disease, and adverse clinical outcomes.

Background: Epicardial adipose tissue (EAT) remodeling is associated with atrial fibrillation (AF). However, there is limited research on the contribution of EAT to the risk of AF recurrence (AFR). The purpose of this research was to assess the relationship between the risk of AFR after radiofrequency catheter ablation and the volume and attenuation of the EAT.Methods: We included a total of 123 consecutive individuals who received AF ablation, 31 of whom suffered AFR. The volume and mean density of the whole-heart and periatrial EAT were measured on computed tomography images using four attenuation ranges. The clinical, atrial, and EAT characteristics of patients with and without AFR were compared. Logistic regression was used to identify independent risk factors and to build a model to predict recurrence. The relationship between EAT characteristics and recurrence was analyzed for the subtypes of AF.Results: The AFR group had a larger left atrial anteroposterior diameter (47.4 ± 7.4 vs. 43.7 ± 8.0 mm), left–right diameter (78.6 ± 7.9 vs. 74.7 ± 9.1 mm), and volume (145.9 vs. 127.0 mL) than the non-recurrence group (P = 0.021, 0.037, 0.015, respectively). The total EAT volume in the AFR group was significantly larger than that in the non-recurrence group, for both the overall and persistent AF groups (all P < 0.1). The periatrial EAT volume of the AFR group was significantly larger than that of the non-recurrence group for those with persistent AF (P = 0.047, 0.048, 0.048, 0.031 for four attenuation ranges). The total EAT volume and left atrial anteroposterior diameter were independent risk factors for AFR (P = 0.035, 0.045, respectively).Conclusion: The EAT volume and left atrial anteroposterior diameter were of great significance in predicting AFR.

Background: TGF-β-activated kinase 1 binding protein 2 (TAB2) is an intermediary protein that links Tumor necrosis factor receptor 1 (TNFR1) and other receptor signals to the TGF-β-activated kinase 1 (TAK1) signaling complex. TAB2 frameshift mutations have been linked to dilated cardiomyopathy (DCM), while the exact mechanism needs further investigation. Methods: In this study, we generated a TAB2 compound heterozygous knockout cell line in induced pluripotent stem cells (iPSCs) derived from a healthy individual using CRISPR/Cas9 technology. IPSCs are not species-dependent, are readily accessible, and raise fewer ethical concerns. Results: TAB2 disruption had no impact on the cardiac differentiation of iPSCs and led to confirmed TAB2 deficiency in human iPSC-derived cardiomyocytes (hiPSC-CMs). TAB2-deficient hiPSC-CMs were found to develop phenotypic features of DCM, such as distorted sarcomeric ultrastructure, decreased contractility and energy production, and mitochondrial damage at day 30 post differentiation. Paradoxically, TAB2 knockout cell lines showed abnormal calcium handling after 40 days, later than reduced contractility, suggesting that the main cause of impaired contractility was abnormal energy production due to mitochondrial damage. As early as day 25, TAB2 knockout cardiomyocytes showed significant mitochondrial calcium overload, which can lead to mitochondrial damage. Furthermore, TAB2 knockout activated receptor-interacting protein kinase 1 (RIPK1), leading to an increase in mitochondrial calcium uniporter (MCU) expression, thereby augmenting the uptake of mitochondrial calcium ions. Finally, the application of the RIPK1 inhibitor Nec-1s prevents the progression of these phenotypes. Conclusions: In summary, TAB2 abatement cardiomyocytes mimic dilated cardiomyopathy in vitro. This finding emphasizes the importance of using a human model to study the underlying mechanisms of this specific disease. More importantly, the discovery of a unique pathogenic pathway introduces a new notion for the future management of dilated cardiomyopathy.