Search

DCN1, a critical co-E3 ligase during the neddylation process, is overactivated in many diseases, such as cancers, heart failure as well as fibrotic diseases, and has been regarded as a new target for drug development. Herein, we designed and synthesized a new class of 1,2,4-triazole-3-thione-based DCN1 inhibitors based the hit HD1identified from high-throughput screening and optimized through numerous structure–activity-relationship (SAR) explorations. HD2(IC50= 2.96 nM) was finally identified and represented a highly potent and selective DCN1 inhibitor with favorable PK properties and low toxicity. Amazingly, HD2effectively relieved Ang II/TGFβ-induced cardiac fibroblast activation in vitro, and reduced ISO-induced cardiac fibrosis as well as remodeling in vivo, which was linked to the inhibition of cullin 3 neddylation and its substrate Nrf2 accumulation. Our findings unveil a novel 1,2,4-triazole-3-thione-based derivative HD2, which can be recognized as a promising lead compound targeting DCN1 for cardiac fibrosis and remodeling.

Reconnection after mitral isthmus (MI) block with radiofrequency ablation is common.

Long-term benefits of pulmonary artery denervation (PADN) for patients with combined precapillary and postcapillary pulmonary hypertension (CpcPH) secondary to left heart failure are unknown.

Epicardial roof-dependent macro–re-entrant tachycardias (epi-RMAT) after catheter ablation of persistent atrial fibrillation are not rare but the prevalence and characteristics remain unclear.

ObjectiveTo explore the association between three-dimensional (3D) cardiac magnetic resonance (CMR) feature tracking (FT) right ventricular peak global longitudinal strain (RVpGLS) and major adverse cardiovascular events (MACEs) in patients with stage C or D heart failure (HF) with non-ischaemic dilated cardiomyopathy (NIDCM) but without atrial fibrillation (AF).MethodsPatients with dilated cardiomyopathy were enrolled in this prospective cohort study. Comprehensive clinical and biochemical analysis and CMR imaging were performed. All patients were followed up for MACEs.ResultsA total of 192 patients (age 53±14 years) were eligible for this study. A combination of cardiovascular death and cardiac transplantation occurred in 18 subjects during the median follow-up of 567 (311, 920) days. Brain natriuretic peptide, creatinine, left ventricular (LV) end-diastolic volume, LV end-systolic volume, right ventricular (RV) end-diastolic volume and RVpGLS from CMR were associated with the outcomes. The multivariate Cox regression model adjusting for traditional risk factors and CMR variables detected a significant association between RVpGLS and MACEs in patients with stage C or D HF with NIDCM without AF. Kaplan-Meier analysis based on RVpGLS cut-off value revealed that patients with RVpGLS <−8.5% showed more favourable clinical outcomes than those with RVpGLS ≥−8.5% (p=0.0037). Subanalysis found that this association remained unchanged.ConclusionsRVpGLS-derived from 3D CMR FT is associated with a significant prognostic impact in patients with NIDCM with stage C or D HF and without AF.

ObjectiveTo determine AF prevalence and gaps in atrial fibrillation (AF) awareness and management in China.MethodsWe conducted a community-based survey of 47 841 adults (age ≥45 years) in seven geographic regions of China between 2014 and 2016. Participants underwent a structured questionnaire, a standard 12-lead ECG, physical examination and blood sampling. AF prevalence, defined by either ECG detection or self-report, was estimated according to sampling weights, non-response and age and sex distribution of the population. We used multivariable logistic regression to estimate associations among sociodemographic, clinical and geographic factors with the AF prevalence, awareness and treatment.ResultsThe weighted AF prevalence was 1.8% (95% CI 1.7% to 1.9%), but varied from 0.9% to 2.4% across geographical regions and equates to being present in an estimated 7.9 (95% CI 7.4 to 8.4) million people in China. Among men and women, the AF prevalence increased from 0.8% and 0.6% in the age group 45–54 years to 5.4% and 4.9% in the age group ≥75 years, respectively. Proportions of people who were aware of having AF decreased overall from 65.3% in 45–54 year-olds to 53.9% in ≥75 year-olds and varied between sex (men 58.5%, women 68.8%) and residency status (urban 78.3%, rural 35.3%). Only 6.0% of patients with high-risk AF received anticoagulation therapy.ConclusionsAF prevalence is higher than previously reported in China, with low awareness and large treatment gaps. Large-scale efforts are urgently needed to reduce AF adverse consequences.

Objective:The aim of this study was to validate the accuracy of a new automatic method for scar segmentation and compare its performance with that of two other frequently used segmentation algorithms.Methods:Twenty-six late gadolinium enhancement cardiovascular magnetic resonance images of diseased hearts were segmented by the full width at half maximum (FWHM) method, the nstandard deviations (nSD) method, and our new automatic method. The results of the three methods were compared with the consensus ground truth obtained by manual segmentation of the ventricular boundaries.Results:Our automatic method yielded the highest Dice score and the lowest volume difference compared with the consensus ground truth segmentation. The nSD method produced large variations in the Dice score and the volume difference. The FWHM method yielded the lowest Dice score and the greatest volume difference compared with the automatic, 6SD, and 8SD methods, but resulted in less variation when different observers segmented the images.Conclusion:The automatic method introduced in this study is highly reproducible and objective. Because it requires no manual intervention, it may be useful for processing large datasets produced in clinical applications.

Background:Significant left ventricular dysfunction may arise in right-sided accessory pathways with ventricular preexcitation in the absence of recurrent or incessant tachycardia. This has just been realized and not enough attention has been paid to it.Methods: In the last 7 years, we identified 12 consecutive children with a diagnosis of ventricular preexcitation‐induced dilated cardiomyopathy. This report describes the clinical and echocardiographic characteristics of the patients before and after ablation.Results:Dyssynchronous ventricular contraction was observed by M-mode echocardiography and two-dimensional strain analysis in all patients. The basal and middle segments of the interventricular septum became thin and moved similarly to an aneurysm, with typical bulging during the end of systole. The locations of the accessory pathways were the right-sided septum (n=5) and the free wall (n=7). Left ventricular synchrony was obtained shortly after ablation. The left ventricular function recovered to normal and the left ventricular end-diastolic diameter decreased gradually during follow-up.Conclusions:A causal relationship between ventricular preexcitation and the development of dilated cardiomyopathy is supported by the complete recovery of left ventricular function and reversed left ventricular remodeling after the loss of ventricular preexcitation. Preexcitation-related dyssynchrony was thought to be the crucial mechanism. Ventricular preexcitation‐induced dilated cardiomyopathy is an indication for ablation with a good prognosis.

Objective:The purpose of this work was to obtain the phenotypes and detect potential mutations in three Chinese patients with Marfan syndrome (MFS) or incomplete MFS phenotypes.Methods:Three unrelated patients with a definite or suspected clinical diagnosis of MFS and their family members were recruited for research. Genomic DNA was extracted from peripheral blood of these patients and their family members. All the exons were sequenced by next-generation sequencing and the variants were further validated by Sanger sequencing. The functional consequences of the mutations were analyzed with various genomic resources and bioinformatics tools.Results:Three FBN1mutations were identified in the three patients, including one novel mutation (2125G > A) and two previously reported mutations (4786C > T and 6325C > T). It was interesting to note that the parents of these patients were normal as assessed by clinical features or genetic testing, but all these mutations were detected in their offspring, except for the variant 6325C > T. We also found that a few young members of the family of probands (proband 1 and proband 2) have exhibited no manifestations of MFS so far, although they carry the same disease-causing mutation.Conclusions:We found three FBN1mutations in three unrelated Chinese families with MFS by genome sequencing, and the relationship between genotypes and phenotypes in MFS patients needs further exploration.

Familial dilated cardiomyopathy (DCM) is associated with numerous genes, especially those of the sarcomere family. The titin gene (TTN) consists of 365 exons and encodes the largest sarcomere protein (titin) in our bodies. Titin is associated with many diseases, such as hypertrophic cardiomyopathy and DCM. Here we screened three Chinese families affected by DCM, and found that each harbors a stop-gain or splice site mutation in TTN(c.G20137T,c. G52522T,c.44610-2A>C). Assessment of the probands by electrocardiogram, B-mode echocardiography, and cardiac magnetic resonance imaging revealed impaired cardiac function, arrhythmia, or abnormal cardiac structure. In conclusion, using whole exome sequencing, we found three unreported TTNmutations associated with DCM. This has expanded the TTNmutation spectrum of Chinese DCM patients, especially in Henan, the most populous province. These data provide new genetic targets for the diagnosis and treatment of DCM, and will increase our understanding of the relationship between TTNmutation and DCM clinical symptoms.

Long QT syndrome (LQTS), which is caused by an ion channel‐related gene mutation, is a malignant heart disease with a clinical course of a high incidence of ventricular fibrillation and sudden cardiac death in the young. Mutations in KCNH2 (which encodes potassium voltage-gated channel subfamily H member 2) are responsible for LQTS in many patients. Here we report the novel mutation c.1898A>C in KCNH2 in a Chinese family with LQTS through whole-exome sequencing. The c.916dupA mutation in JUP (which encodes junction plakoglobin) is also discovered. Mutations in JUP were found to be associated with arrhythmogenic right ventricular cardiomyopathy. The double mutation in the proband may help explain his severe clinical manifestations, such as sudden cardiac death at an early age. Sequencing for the proband’s family members revealed that the KCNH2 mutation descends from his paternal line, while the mutation in JUP came from his maternal line. The data provided in this study may help expand the spectrum of LQTS-related KCNH2 mutations and add support to the genetic diagnosis and counseling of families affected by malignant arrhythmias.

Acute inflammation often contributes to the increased arrhythmogenesis in the cardiomyocytes. We investigated the protective effects of pravastatin on calcium disorders induced by acute administration of pro-inflammatory cytokines in isolated ventricular myocytes and its underlying mechanisms. Wild-type mice were intraperitoneally injected for five days with either pravastatin 20 mg/kg per day or an equal volume of normal saline. Cytosol Ca2+handling was studied in freshly isolated ventricular myocytes after acute exposure of interleukin-6 (IL-6) (1 ng/ml) for 120 min by Ionoptix and confocal microscopy. Acute administration of clinically relevant concentrations of IL-6 disturbed calcium handling in ventricular myocytes, which presented as decreased amplitudes, prolonged decay times of Ca2+transients, and reduced sarcoplasmic reticulum (SR) calcium stores. The frequency of spontaneous Ca2+release, including calcium sparks and spontaneous calcium waves, was dramatically enhanced in the setting of IL-6. Notably, the pretreatment of pravastatin alleviated disturbed Ca2+cycling, reduced spontaneous Ca2+leakage induced by IL-6. Mitochondrial ROS pathway may constitute the underlying mechanism of the protective effects of pravastatin. Pravastatin protected the cardiomyocytes against calcium disorders induced by IL-6 via the mitochondrial ROS pathway, which suggests that pravastatin may represent a promising auxiliary therapeutic strategy for cardiac injury under acute inflammation.

Supplemental Digital Content is available in the text.

Background:Left bundle branch block (LBBB)-induced cardiomyopathy has been proposed, but the association between LBBB and cardiac resynchronization therapy (CRT) response remains unclear and practical criteria for selecting CRT candidates are needed.Methods:One hundred and seventeen consecutive heart failure patients were reviewed, 24 of whom received CRT. Only two patients had a clear temporal relation between cardiomyopathy and LBBB.Results:Compared with the patient with “cardiomyopathy-induced LBBB,” the patient with “LBBB-induced cardiomyopathy” had higher left ventricular (LV) wall thickness, higher LV wall thickening rate, higher peak circumferential strain, and longer peak circumferential strain delay. The LV deformation patterns in the two patients were obviously distinct on cardiovascular magnetic resonance tissue tracking. During follow-up, the patient with LBBB-induced cardiomyopathy had a good response to CRT (LV ejection fraction 23 before CRT vs. 30% at 6 months vs. 29 at 12 months vs. 32% at 18 months; LV end-diastolic diameter 77 mm before CRT vs. 66 mm at 6 months vs. 62 mm at 12 months vs. 63 mm at 18 months), and the other patient had no response to CRT (LV ejection fraction 29 before CRT vs. 29% at 6 months vs. 26 at 12 months vs. 22% at 24 months; LV end-diastolic diameter 85 mm before CRT vs. 88 mm at 6 months vs. 85 mm at 12 months vs. 84 mm at 24 months).Conclusion:The temporal relation between cardiomyopathy and LBBB could be a determinant for CRT response. Cardiovascular magnetic resonance tissue tracking may be a useful tool to identify the chronological order and a principal consideration for selecting candidates for CRT. Larger prospective clinical trials are needed to study the prevalence of, time course of, and risk factors for LBBB-induced cardiomyopathy.

Background:Elderly adults with atrial fibrillation (AF) are at increased risk of frailty and thromboembolic complications. However, studies on the prevalence of frailty in AF patients and data on the relationship between frailty and the use of anticoagulants are limited.Methods:We conducted a cross-sectional study involving 500 participants. Patients aged 65 years or older were consecutively selected from the Chinese Atrial Fibrillation Registry study. The patient’s frailty status was assessed with use of the Canadian Study of Health and Aging Clinical Frailty Scale. We assessed the prevalence of and factors associated with frailty, and how frailty affects anticoagulant therapy.Results:In 500 elderly adults with AF (age 75.2±6.7 years; 51.6% female), 201 patients (40.2%) were frail. The prevalence of frailty was higher in females (P=0.002) and increased with age and CHA2DS2-VASc score (P for trend less than 0.001 for both). The factors associated with frailty were a history of heart failure (odds ratio [OR] 2.40, 95% confidence interval [CI] 1.39‐4.14), female sex (OR 2.09, 95% CI 1.27‐3.43), and advanced age (OR 1.13, 95% CI 1.09‐1.17). Frail patients were significantly less likely to have ever been prescribed anticoagulants compared with nonfrail patients (81.7 vs. 54.9%, P<0.001).Conclusions:Frailty is prevalent in elderly adults with AF, especially in females, those of advanced age, and those with heart failure. Frailty status has a significant impact on prescription of anticoagulants for high-risk AF patients.

Both warfarin and nonvitamin K antagonist oral anticoagulants (NOACs) are increasingly used for thromboembolic prevention in patients with nonvalvular atrial fibrillation (NVAF). However, there are limited data concerning anticoagulation for left atrial (LA) thrombus or sludge. We aimed to determine the efficacy of warfarin and NOACs in LA thrombus or sludge in patients with NVAF or atrial flutter (AFL).

Patients diagnosed with atrial fibrillation suffer more from anxiety and depression than the general population. This study sought to evaluate the association between mental health status and recurrence of atrial tachyarrhythmia (AT) after catheter ablation.

Objective We aimed to determine the prevalence of and the factors associated with intraventricular conduction disturbance in the Chinese population.Methods Electrocardiographic data from 42,031 people were retrospectively analysed. The weighted prevalences of left bundle branch block (LBBB), right bundle branch block (RBBB), bifascicular block and nonspecific intraventricular conduction delay (NS-IVCD) were calculated. The independently associated factors were determined using logistic regression analysis.Results The weighted prevalence for Chinese people older than 45 years was 0.17% for LBBB, 2.16% for RBBB and 0.44% for NS-IVCD. The weighted prevalence for RBBB combined with left anterior fascicular block was 0.17%, and 0.05% for RBBB combined with left posterior fascicular block. There were significant differences in the weighted prevalences of RBBB and NS-IVCD between men and women. The weighted prevalence of LBBB and RBBB increased markedly with increasing age. Age and diabetes were independent factors associated with LBBB, compared with age and sex for RBBB and sex and coronary artery disease for NS-IVCD.Conclusions This study provided reliable data for the weighted prevalence of and factors associated with LBBB, RBBB and NS-IVCD in Chinese adults.

Previous studies have suggested that systematic ablation of ganglionated plexi (GP) could increase the short-term success rate of radiofrequency ablation for atrial fibrillation, but the long-term efficacy of this approach is not fully established.

Objective —Previous studies have shown that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) could reverse structural and electrical atria remodeling and decrease atrial fibrillation (AF) onset or recurrence.The aim of this retrospective study was to investigate whether ACEIs/ARBs had beneficial effects on ablation outcome of chronic persistent AF.Methods and results —This study included 139patients with chronic persistent AF who underwent radiofrequency ablation in our centre. Patients were divided into an ACEIs/ARBs group or a non-ACEIs/ARBs group. During follow-up (14.6±8.9months) after AF ablation, AF-free survival in the ACEIs/ARBs group was not significantly different from the non-ACEIs/ARBs group (P=0.339). Univariate analysis showed that predictors for AF-free survival were AF history (HR, 1.064; 95% CI, 1.021-1.108; P=0.003) and duration of chronic persistent AF (HR, 1.012; 95% CI, 1.005-1.019; P=0.001). Multivariate analysis showed that predictors for AF-free survival were AF history (HR, 1.051; 95% CI, 1.004-1.101; P=0.035) and duration of chronic persistent AF (HR, 1.012; 95%CI, 1.004-1.020; P=0.004).ACEIs/ARBs therapy was not a predictor for AF-free survival neither in univariate nor multivariate analysis.Conclusion —In this observational study, no effect of ACEIs or ARBs was seen on the AF recurrence after ablation of chronic persistent AF.ACEIs/ARBs did not help to predict a better ablation outcome. Predictors for ablation outcome are AF history and duration of chronic persistent AF.

Consequences of reduced acute coronary syndrome (ACS) admissions during COVID-19 pandemic periods were reported by different countries. However, admissions, treatments, and prognosis of ACS during and after COVID-19 pandemic in Beijing, China was unknown.

AbstractA 58-year-old male with recurrent atrial tachycardia (AT) after atrial fi brillation ablation was admitted for a second procedure. During the second procedure, the activation map showed a focal tachycardia with centrifugal activation. However, it was fi nally identifi ed as a macroreentrant AT. This case highlights the signifi cance of entrainment mapping in diff erentiating the mechanism of recurrent AT even when the activation map suggests focal AT. Focal AT can be excluded when a perfect post-pacing interval (PPI) is observed in the atrial segment opposite to the “earliest” activation site.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.