Harnessing stem cell and lineage reprogramming technology to treat cardiac fibrosis.

Cardiac fibrosis is a pathological response characterized by excessive deposition of fibrous connective tissue within the heart. It typically occurs following cardiac injuries or diseases. However, the lack of suitable models for disease modeling and high-throughput drug discovery has hindered the establishment of an effective treatments for cardiac fibrosis. The emergence and rapid progress of stem-cell and lineage reprogramming technology offer an unprecedented opportunity to develop an improved humanized and patient-specific model for studying cardiac fibrosis, providing a platform for screening potential drugs and synchronously elucidating the underlying molecular mechanisms. Furthermore, reprogramming cardiac fibroblasts into cardiomyocyte-like cells to reduce scar volume and induce myocardial tissue regeneration is a promising approach in treating cardiac fibrosis. In this review, we summarize the current advancements in stem cell technologies applied to study cardiac fibrosis and provide insights for future investigations into its mechanisms, drug discovery as well as therapy method.

Radiofrequency catheter ablation for improving myocardial work in patients with ventricular pre-excitation.

Background: Previous studies have not consistently found significant improvements in left ventricular ejection fraction or global longitudinal strain (GLS) after radiofrequency catheter ablation (RFCA) in patients with ventricular pre-excitation. The aim of this study was thus to explore the effects of RFCA on left ventricular function in patients with ventricular pre-excitation using a new noninvasive echocardiographic method of myocardial work. Methods: A total of 34 patients with ventricular pre-excitation who underwent RFCA and 18 healthy controls were prospectively included in this study. Before and after participants underwent RFCA, electrocardiographic and echocardiographic data of the patients were collected at resting and pacing heart rates (HRs) of 100 beats per minute (bpm) and 120 bpm (controlled by high right atrial pacing during the procedure). Clinical data of the healthy controls at resting HR were also collected. A self-controlled paired sample t test was used to compare the differences before and after participants underwent RFCA. Results: After participants underwent RFCA, the global wasted work (GWW) of the included patients decreased (resting HR: 165.3±68.8 vs. 92.6±42.5 mmHg%, P<0.001; HR of 100 bpm: 276.3±121.2 vs. 187.9±96.0 mmHg%, P<0.001; HR of 120 bpm: 323.9±126.7 vs. 181.0%±74.3 mmHg%. P<0.001), while the global work efficiency (GWE) increased (resting HR: 91.5%±3.8% vs. 94.9%±1.6%; P<0.001; HR of 100 bpm: 87.0%±5.2% vs. 91.0%±3.3%, P<0.001; HR of 120 bpm: 85.0%±5.1% vs. 90.3%±3.7%, P<0.001). Conclusions: In patients with ventricular pre-excitation, impaired GWW and GWE can be improved with RFCA. In clinical practice, noninvasive myocardial work assessment can be used in patients with ventricular pre-excitation.

Cysteine-Based Redox-Responsive Nanoparticles for Fibroblast-Targeted Drug Delivery in the Treatment of Myocardial Infarction.

Upon myocardial infarction (MI), activated cardiac fibroblasts (CFs) begin to remodel the myocardium, leading to cardiac fibrosis and even heart failure. No therapeutic approaches are currently available to prevent the development of MI-induced pathological fibrosis. Most pharmacological trials fail from poor local drug activity and side effects caused by systemic toxicity, largely due to the lack of a heart-targeted drug delivery system that is selective for activated CFs. Here, we developed a reduced glutathione (GSH)-responsive nanoparticle platform capable of targeted delivering of drugs to activated CFs within the infarct area of a post-MI heart. Compared with systemic drug administration, CF-targeted delivery of PF543, a sphingosine kinase 1 inhibitor identified in a high-throughput antifibrotic drug screening, had higher therapeutic efficacy and lower systemic toxicity in a MI mouse model. Our results provide a CF-targeted strategy to deliver therapeutic agents for pharmacological intervention of cardiac fibrosis.

Prospective randomized comparison between upgraded '2C3L' vs. PVI approach for catheter ablation of persistent atrial fibrillation: PROMPT-AF trial design.

BACKGROUND: In randomized studies, the strategy of pulmonary vein antral isolation (PVI) plus linear ablation has failed to increase success rates for persistent atrial fibrillation (PeAF) ablation when compared with PVI alone. Peri-mitral reentry related atrial tachycardia due to incomplete linear block is an important cause of clinical failures of a first ablation procedure. Ethanol infusion (EI) into the vein of Marshall (EI-VOM) has been demonstrated to facilitate a durable mitral isthmus linear lesion. OBJECTIVE: This trial is designed to compare arrhythmia-free survival between PVI and an ablation strategy termed upgraded '2C3L' for the ablation of PeAF. STUDY DESIGN: The PROMPT-AF study (clinicaltrials.gov 04497376) is a prospective, multicenter, open-label, randomized trial using a 1:1 parallel-control approach. Patients (n = 498) undergoing their first catheter ablation of PeAF will be randomized to either the upgraded '2C3L' arm or PVI arm in a 1:1 fashion. The upgraded '2C3L' technique is a fixed ablation approach consisting of EI-VOM, bilateral circumferential PVI, and 3 linear ablation lesion sets across the mitral isthmus, left atrial roof, and cavotricuspid isthmus. The follow-up duration is 12 months. The primary end point is freedom from atrial arrhythmias of >30 seconds, without antiarrhythmic drugs, in 12 months after the index ablation procedure (excluding a blanking period of 3 months). CONCLUSIONS: The PROMPT-AF study will evaluate the efficacy of the fixed '2C3L' approach in conjunction with EI-VOM, compared with PVI alone, in patients with PeAF undergoing de novo ablation.

The Value of Myocardial Fibrosis Parameters Derived from Cardiac Magnetic Resonance Imaging in Risk Stratification for Patients with Hypertrophic Cardiomyopathy.

RATIONALE AND OBJECTIVES: The aim of the study was to determine whether myocardial fibrosis parameters of cardiac magnetic resonance imaging (MRI) has added value in the risk stratification of hypertrophic cardiomyopathy (HCM) patients. MATERIALS AND METHODS: In this retrospective study, 108 patients with HCM (mean age ± standard deviation, 55.5 ± 13.4 years) were included from January 2019 to April 2022, and were followed up for 2 years to record sudden cardiac death (SCD) adverse events. All HCM patients underwent cardiac MRI and were divided into a training cohort (n = 81; mean age, 56.1 ± 13.0 years) and a validation cohort (n = 27; mean age, 57.8 ± 13.9 years). According to the presence of SCD risk factors defined by the 2020 AHA/ACC guidelines, HCM patients were classified into low-risk and high-risk groups. Cardiac MRI features, including late gadolinium enhancement (LGE), T1 mapping, and extracellular volume fraction (ECV), were assessed and compared between the two groups. Logistic regression analysis was used to select the optimal predictors of SCD from cardiac MRI features and HCM Risk-SCD score to construct prediction models. Receiver operating curve (ROC) analysis was used to assess the predictive performance of the constructed prediction model. Cox regression analysis was also used to determine the optimal predictors of SCD adverse events. RESULTS: Multivariate logistic analysis showed that the global ECV was the single myocardial fibrosis parameter predictive of the risk of SCD (p < 0.001). The areas under the ROC curves (AUC) of global ECV were higher than those of LGE, global native T1, global postcontrast T1, and HCM Risk-SCD (AUC = 0.85 vs. 0.74, 0.77, 0.63, 0.78). An integrative risk stratification model combining global ECV (odds ratio, 1.36 [95% CI: 1.16-1.60]; p < 0.001) and HCM Risk-SCD score (odds ratio, 1.63 [95% CI: 1.08-2.47]; p < 0.001) achieved an AUC of 0.89 (95% CI: 0.81-0.96) in the training cohort, which was significantly higher than that of HCM Risk-SCD score alone (p = 0.03). The AUC of the integrative model was 0.93 (95% CI: 0.84-1.00) in the validation cohort. Multivariate Cox regression analysis also showed that the global ECV was an independent predictor of SCD adverse events (hazard ratio, 1.27 [95% CI: 1.10-1.47]). CONCLUSION: The ECV derived from cardiac MRI is comparable to the HCM Risk-SCD scale in predicting the SCD risk stratification in patients with HCM.

Twelve-week high-fat diet for improving adverse ventricular remodeling post-myocardial infarction by alleviating local inflammation.

Background: Many studies have examined how to achieve better outcomes in myocardial infarction (MI) patients with mild obesity or who are overweight. However, the influence of a high-fat diet (HFD) and the underlying mechanisms by which it can affect ventricular remodeling following MI are poorly understood. This study investigated the impact of a 12-week HFD on the left ventricular (LV) remodeling of permanent MI models and immune cell involvement. Methods: Male C57BL/6J mice were fed HFD or normal diet (ND). After 8 weeks of feeding, mice underwent cardiac left anterior descending coronary artery ligation, and the same diet was continued for a further 4 weeks. Cardiac structure and function were detected using echocardiography. Cardiac fibrosis was evaluated using histological staining at 7 and 28 days post-MI. Infiltration of various immune cells was examined using flow cytometry and immunofluorescence at 7 days post-MI. Results: Compared with a ND, the 12-week HFD feeding significantly alleviated ventricular remodeling following MI. HFD mice showed reduced infiltration of neutrophils, a higher proportion of M2/M1 macrophages, decreased conventional and monocyte-derived dendritic cells (moDCs) in the injured myocardium, and elevated levels of regulatory T cells (Tregs). Further investigation of dendritic cells (DCs) phenotypes indicated downregulated expression of major histocompatibility complex class II (MHCII). It also showed costimulatory molecules CD40 and CD86 on conventional and moDCs in mediastinal lymph nodes (mLNs). Conclusions: This study demonstrated the protective effect of a 12-week HFD on ventricular remodeling following MI via the alleviation of local inflammation.

Oxidized low-density lipoprotein inhibits the degradation of cyclophilin A via the lysosome in vascular smooth muscle cells.

BACKGROUND: Cyclophilin A (CyPA) plays an important role in the progression of atherosclerosis. Additionally, it has been reported that lysosomal function is markedly impaired in atherosclerosis induced by oxidized low-density lipoprotein (ox-LDL). As the CyPA degradation pathway remains to be elucidated, we aimed to uncover the role of lysosomes and ox-LDL in the degradation of CyPA. METHODS: We exploited RNA interference (RNAi) in combination with either the lysosomal inhibitor chloroquine (CQ) or the proteasomal inhibitor MG-132 to examine CyPA turnover. We also investigated the role of ox-LDL in lysosomal function and the CyPA degradation pathway and determined whether CyPA interacts with the selective autophagy adaptor p62. RESULTS: CQ markedly reversed the CyPA downregulation induced by RNAi and increased intracellular levels of LC3 and p62. MG-132 significantly suppressed polyubiquitinated protein degradation but did not inhibit RNAi-induced CyPA downregulation. Additionally, neither CQ nor MG-132 influenced the gene-silencing efficiency of CyPA siRNA. Moreover, ox-LDL induced cytosolic accumulation of p62 was inconsistent with increased expression of LC3-II. Meanwhile, ox-LDL inhibited RNAi-induced downregulation of CyPA. Immunofluorescence indicated colocalization of endogenous CyPA with ubiquitin and with p62 in response to CQ treatment, and co-immunoprecipitation analysis confirmed interaction between CyPA and p62. CONCLUSION: CyPA is degraded by a lysosome-dependent pathway that may involve p62-mediated selective autophagy. Furthermore, ox-LDL modulates the degradation of CyPA via its inhibitory role in lysosomes, contributing to increased expression of CyPA in atherosclerotic plaques.

Association of scar distribution with epicardial electrograms and surface ventricular tachycardia QRS duration in nonischemic cardiomyopathy.

INTRODUCTION: The association of late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) with epicardial and surface ventricular tachycardia (VT) electrogram features, in nonischemic cardiomyopathy (NICM), is unknown. We sought to define the association of LGE and viable wall thickness with epicardial electrogram features and exit site paced QRS duration in patients with NICM. METHODS: A total of 19 patients (age 53.5 ± 11.5 years) with NICM (ejection fraction 40.2 ± 13.2%) underwent CMR before VT ablation. LGE transmurality was quantified on CMR and coregistered with 2294 endocardial and 2724 epicardial map points. RESULTS: Both bipolar and unipolar voltage were associated with transmural signal intensity on CMR. Longer electrogram duration and fractionated potentials were associated with increased LGE transmurality, but late potentials or local abnormal ventricular activity were more prevalent in nontransmural versus transmural LGE regions (p < .05). Of all critical VT sites, 19% were located adjacent to regions with LGE but normal bipolar and unipolar voltage. Exit site QRS duration was affected by LGE transmurality and intramural scar location, but not by wall thickness, at the impulse origin. CONCLUSIONS: In patients with NICM and VT, LGE is associated with epicardial electrogram features and may predict critical VT sites. Additionally, exit site QRS duration is affected by LGE transmurality and intramural location at the impulse origin or exit.

The Release of Cyclophilin A from Rapamycin-Stimulated Vascular Smooth Muscle Cells Mediated by Myosin II Activation: Involvement of Apoptosis but Not Autophagy.

INTRODUCTION: The exocytosis of cyclophilin A (CyPA) by a vesicular pathway in response to reactive oxygen species has been determined. However, other sources of extracellular CyPA remain obscure. OBJECTIVE: The aim of this study was to determine the role of autophagy in the secretion of CyPA. METHODS AND RESULTS: Rapamycin induced the activation of autophagy and release of CyPA from primary cultured rat aortic smooth muscle cells (RASMCs). However, inhibition of autophagy by knockdown of Atg7 or chloroquine did not affect the rapamycin-induced release of CyPA. With the exception of myosin II activity, rho-associated coiled-coil kinase (ROCK), actin remodelling, and synaptic vesicles were not implicated in the release of rapamycin-induced CyPA. Finally, we confirmed that rapamycin-induced extracellular CyPA originated from apoptotic RASMCs. Furthermore, the decreased activation of myosin II by blebbistatin blocked the release of CyPA from apoptotic RASMCs induced by rapamycin. CONCLUSIONS: Rapamycin induced the release of CyPA from apoptotic RASMCs but did not affect exocytosis through autophagosomes. ROCK, actin remodelling, and synaptic vesicles were not involved in the apoptosis-related release of CyPA. Myosin II activation modulated the apoptosis of vascular smooth muscle cells and the release of CyPA from rapamycin-induced apoptotic cell death.

Analysis of local ventricular repolarization using unipolar recordings in patients with arrhythmogenic right ventricular cardiomyopathy.

PURPOSE: In arrhythmogenic right ventricular cardiomyopathy (ARVC), abnormal electroanatomic mapping (EAM) areas are proportional to extent of T-wave inversion on 12-lead ECG. We aimed to evaluate local repolarization changes and their relationship to EAM substrate in ARVC. METHODS: Using unipolar recordings, we analyzed the proportion of negative T waves ≥ 1 mV in depth (NegT), NegT area, Q-Tpeak (QTP), Tpeak-Tend (TPE) intervals and their relationship to bipolar (< 1.5 mV ENDO, < 1.0 mV EPI) and unipolar (< 5.5 mV) endocardial (ENDO) and epicardial (EPI) low-voltage area (LVA) in 21 pts. (15 men, mean age 39 ± 14) with ARVC. Control group included 5 pts. with normal hearts and idiopathic PVCs. RESULTS: On ENDO, the % of NegT (7 ± 5% vs 30 ± 20%, p = 0.004) and the NegT area (12.9 ± 9.7 c m2 vs 61.4 ± 30.0 cm2, p = 0.001) were smaller in ARVC compared to controls. On EPI, the % of NegT was similar (5 ± 7% vs 3 ± 4%, p = 0.323) and the NegT area, larger (11.0 ± 8.4 cm2 vs 2.7 ± 0.9 cm2, p = 0.027) in ARVC group. In ARVC group, the % of NegT area inside LVA was larger on EPI compared to ENDO for both bipolar (81 ± 27% vs 31 ± 33%, p < 0.001) and unipolar (90 ± 19% vs 73 ± 28%, p = 0.036) recordings. Compared to normal voltage regions, QTP inside ENDO abnormal LVA was on average 58 ± 26 ms shorter and TPE, 25 ± 56 ms longer (97 ± 26 ms and 56 ± 86 ms on EPI, respectively). CONCLUSIONS: In ARVC, NegT areas are more closely associated with abnormal depolarization LVA on the EPI and QTP is shorter and TPE longer inside ENDO and EPI abnormal LVA compared to normal voltage regions. The results add to our understanding of ARVC arrhythmia substrate.

P-wave morphology and multipolar intracardiac atrial activation to facilitate nonpulmonary vein trigger localization.

INTRODUCTION: Nonpulmonary vein (non-PV) triggers of atrial fibrillation (AF) are targets for ablation but their localization remains challenging. The aim of this study was to describe P-wave (PW) morphologic characteristics and intra-atrial activation patterns and timing from multipolar coronary sinus (CS) and crista terminalis (CT) catheters that localize non-PV triggers. METHODS AND RESULTS: Selective pacing from six right and nine left atrial common non-PV trigger sites was performed in 30 consecutive patients. We analyzed 12 lead ECG features based on PW duration, amplitude and morphology, and patterns and timing of multipolar activation for all 15 sites. Regionalization and then precise localization required criteria present in at least 70% of assessments at each pacing site. The algorithm was then prospectively evaluated by four blinded observers in a validation cohort of 18 consecutive patients undergoing the same pacing protocol and 60 consecutive patients who underwent successful non-PV trigger ablation. The algorithm for site regionalization included 1) negative PW in V1, ≥30 µV change in PW amplitude across the leads V1-V3, and PW duration ≤100 milliseconds in lead 2 and 2) unique intra-atrial activation patterns and timing noted in the multipolar catheters. Specific ECG and intra-atrial activation timing characteristics included in the algorithm allowed for more precise site localization after regionalization. In the prospective evaluation, the algorithm identified the site of origin for 72% of paced and 70% of spontaneous non-PV trigger sites. CONCLUSION: An algorithm based on PW morphology and intra-atrial multipolar activation pattern and timing can help identify non-PV trigger sites of origin.

Hydrogen sulfide improves vascular repair by promoting endothelial nitric oxide synthase-dependent mobilization of endothelial progenitor cells.

BACKGROUND: Endothelial progenitor cells (EPCs) play a crucial role in endothelial repair after arterial injury. Hydrogen sulfide (H2S) is a novel gasotransmitter that regulates vascular homeostasis. METHOD: We investigated whether exogenous H2S could facilitate EPCs in repairing arterial injury. RESULTS: Sodium hydrosulfide (NaHS), a precursor of H2S, promoted re-endothelialization and inhibited neointima formation in a rodent carotid artery injury model. Flow cytometric analysis revealed that NaHS treatment significantly increased the yield of EPCs after vascular injury. Furthermore, NaHS enhanced the capacity of EPCs to the luminal surface of injured arteries in wild-type mice, which had received a bone marrow transplantation from tie2-GFP donor mice. However, this enhancing effect was greatly attenuated in endothelial nitric oxide synthase knockout mice (eNOS). In-vitro incubation of human EPCs with NaHS not only increased the yield of EPCs, but also enhanced their adhesion and colony formation capacities. Treatment with an eNOS inhibitor (L-NAME) blocked the effects of NaHS on EPCs functions. CONCLUSION: H2S enhances eNOS-dependent mobilization of bone marrow-derived EPCs and facilitates re-endothelialization following vascular injury.

Utility of ripple mapping for identification of slow conduction channels during ventricular tachycardia ablation in the setting of arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Ripple mapping displays every deflection of a bipolar electrogram and enables the visualization of conduction channels (RMCC) within postinfarction ventricular scar to guide ventricular tachycardia (VT) ablation. The utility of RMCC identification for facilitation of VT ablation in the setting of arrhythmogenic right ventricular cardiomyopathy (ARVC) has not been described. OBJECTIVE: We sought to (a) identify the slow conduction channels in the endocardial/epicardial scar by ripple mapping and (b) retrospectively analyze whether the elimination of RMCC is associated with improved VT-free survival, in ARVC patients. METHODS: High-density right ventricular endocardial and epicardial electrograms were collected using the CARTO 3 system in sinus rhythm or ventricular pacing and reviewed for RMCC. Low-voltage zones and abnormal myocardium in the epicardium were identified by using standardized late-gadolinium-enhanced (LGE) magnetic resonance imaging (MRI) signal intensity (SI) z-scores. RESULTS: A cohort of 20 ARVC patients that had undergone simultaneous high-density right ventricular endocardial and epicardial electrogram mapping was identified (age 44 ± 13 years). Epicardial scar, defined as bipolar voltage less than 1.0 mV, occupied 47.6% (interquartile range [IQR], 30.9-63.7) of the total epicardial surface area and was larger than endocardial scar, defined as bipolar voltage less than 1.5 mV, which occupied 11.2% (IQR, 4.2 ± 17.8) of the endocardium (P < 0.01). A median 1.5 RMCC, defined as continuous corridors of sequential late activation within scar, were identified per patient (IQR, 1-3), most of which were epicardial. The median ratio of RMCC ablated was 1 (IQR, 0.6-1). During a median follow-up of 44 months (IQR, 11-49), the ratio of RMCC ablated was associated with freedom from recurrent VT (hazard ratio, 0.01; P = 0.049). Among nine patients with adequate MRI, 73% of RMCC were localized in LGE regions, 24% were adjacent to an area with LGE, and 3% were in regions without LGE. CONCLUSION: Slow conduction channels within endocardial or epicardial ARVC scar were delineated clearly by ripple mapping and corresponded to critical isthmus sites during entrainment. Complete elimination of RMCC was associated with freedom from VT.

Lead I R-wave amplitude to differentiate idiopathic ventricular arrhythmias with left bundle branch block right inferior axis originating from the left versus right ventricular outflow tract.

INTRODUCTION: Differentiation of right versus left ventricular outflow tract (RVOT vs. LVOT) arrhythmia origin with left bundle branch block right inferior axis (LBRI) morphology is relevant to ablation planning and risk discussion. Our aim was to determine if lead I R-wave amplitude is useful for differentiation of RVOT from LVOT arrhythmias with LBRI morphology. METHODS: The R-wave amplitude in lead I was measured in a retrospective cohort of 75 consecutive patients with LBRI pattern ventricular arrhythmias (VAs) successfully ablated from the RVOT (n = 54), LVOT (n = 16), or the anterior interventricular vein (AIV; n = 5). The optimal R-wave threshold was identified and diagnostic indices were compared with the previously reported transitional zone (TZ) index and V2S/V3R index. RESULTS: An R-wave amplitude greater than or equal to 0.1 mV predicted LVOT origin with 75% sensitivity and 98.2% specificity. In comparison, the TZ and V2S/V3R indices had 50% and 68.8% sensitivity, and 75.9% and 88.9% specificity, respectively, for predicting LVOT origin. The area under the curve (AUC) was 0.85 for lead I R-wave amplitude, 0.87 for V2S/V3R, and 0.72 for the TZ index. Of 36 cases with QS in lead I, 30 (83.3%) were from the anterior RVOT, three (8.3%) from the LVOT, and three (8.3%) from the AIV. CONCLUSION: The presence of R-wave amplitude in lead I (≥0.1 mV) is a simple and useful criterion to identify LVOT cusp or endocardium focus in LBRI arrhythmias. A QS pattern in lead I suggests an origin in the anterior RVOT, or less commonly the adjacent LV summit.

Prognostic Impact of Fasting Plasma Glucose on Mortality and Re-Hospitalization in Patients with Acute Heart Failure.

BACKGROUND: The impact of fasting plasma glucose (FPG) on survival outcomes in patients with acute heart failure (HF) is unclear, and the relationship between intensity of glycemic control of FPG in diabetes mellitus (DM) patients and HF prognosis remains uncertain. This retrospective study aimed to evaluate the prognostic impact of FPG in patients with acute HF. METHODS: A total of 624 patients hospitalized with acute HF from October 2000 to April 2014 were enrolled in this study. All patients were stratified by three groups according to their admission FPG levels (i.e., DM, impaired fasting glucose [IFG], and non-DM). All-cause and cardiovascular mortality was the primary end point, and HF re-hospitalization was the secondary end point during follow-up period. RESULTS: A total of 587 patients were included in final analysis. The all-cause mortality rates of patients with DM, IFG, and non-DM were 55.5%, 40.3%, and 39.2%, with significant difference (P = 0.001). Moreover, compared with those with IFG (34.3%) and non-DM (32.6%), patients with DM had significantly higher rate of cardiovascular mortality (45.1%). Multiple Cox regression analysis showed that DM as well as IFG was related to all-cause mortality (DM: hazard ratio [HR] = 1.936, P < 0.001; IFG: HR = 1.672, P = 0.019) and cardiovascular mortality (DM: HR = 1.739, P < 0.001; IFG: HR = 1.817, P = 0.013). However, they were both unrelated to HF re-hospitalization. DM patients with strictly controlled blood glucose (FPG <3.9 mmol/L) had higher all-cause mortality than patients with non-DM, IFG, and DM patients with moderately controlled glucose (3.9 mmol/L≤ FPG <7.0 mmol/L). Likewise, both the primary end point and secondary end point were found to be worse in DM patients with poorly controlled blood glucose (FPG ≥7.0 mmol/L). CONCLUSIONS: IFG and DM were associated with higher all-cause mortality and cardiovascular mortality in patients with acute HF. The association between mortality and admission FPG in DM patients with acute HF appeared U-shaped.

Effect of Endoplasmic Reticulum Stress and Autophagy in the Regulation of Post-infarct Cardiac Repair.

BACKGROUND: Acute myocardial infarction (AMI) is reported to be accompanied by endoplasmic reticulum (ER) stress and autophagy induction. Nevertheless, the roles of ER stress and autophagy in post-infarct reparative fibrosis remain to be elucidated. AIM: To investigate the effects of ER stress and autophagy on the regulation of post-infarct reparative fibrosis. METHODS: The expression of GRP78 and LC3 in cardiac fibroblasts in human heart tissues obtained from patients with or without AMI was assessed by immunofluorescence. In vitro, human cardiac fibroblasts (HCFs) were stimulated by various agents, the expression of GRP78, LC3 and fibronectin in these was evaluated by immunoblot and/or immunofluorescence. RESULTS: After AMI, HCFs expressed significantly higher levels of GRP78 and LC3. ER stress inducer, tunicamycin (200 ng/mL) significantly increased the level of autophagy and reduced expression of fibronectin in HCFs, both of which were reversed by 4 Phenylbutyric acid. Under the condition of ER stress, the expression of fibronectin in HCFs was regulated by different levels of autophagy. LC3 co-localized with fibronectin when stimulated HCFs with tunicamycin. CONCLUSION: AMI induces ER stress in cardiac fibroblasts, down-regulating fibronectin via enhanced autophagy. These findings suggest that ER stress and autophagy may be a therapeutic target to improve prognosis of patients with AMI.

Electrocardiographic Repolarization Abnormalities and Electroanatomic Substrate in Arrhythmogenic Right Ventricular Cardiomyopathy.

BACKGROUND: Repolarization abnormalities in arrhythmogenic right ventricular (RV) cardiomyopathy and their relationship to ventricular tachycardia substrate are incompletely understood. METHODS AND RESULTS: In 40 patients (29 men, mean age 38 years) with arrhythmogenic RV cardiomyopathy, we compared the extent and location of abnormal T (NegT) waves ≥1 mm in depth (n=32) and downsloping elevated ST segment (n=13), in ≥2 adjacent leads, to area and location of endocardial bipolar (<1.5 mV) and unipolar (<5.5 mV) and epicardial bipolar (<1.0 mV) voltage abnormalities. Abnormal unipolar RV endocardial area of 33.4±19.3% was present in 8 patients without NegT waves. Patients with NegT waves extending beyond lead V3 (n=20) had larger low bipolar (31.4±18.9% versus 16.5±14.6%; P=0.008) and unipolar endocardial areas (66.0±19.6% versus 47.4±25.1%; P=0.013) and larger epicardial low bipolar area (56.0±19.3% versus 40.1±24.9%; P=0.030) compared with those with NegT waves limited to leads V1 through V3 (n=20). ECG location of NegT waves regionalized to location of substrate. Patients with downsloping elevated ST segment, all localized to leads V1 and V2, had more unipolar endocardial abnormalities (71.8±18.1% versus 49.4±23.5%; P=0.005) involving outflow and mid-RV, compared with patients without downsloping elevated ST segment. CONCLUSIONS: In arrhythmogenic RV cardiomyopathy, abnormal electroanatomic mapping areas are proportional to extent of T-wave inversion on 12-lead ECG. Marked voltage abnormalities can exist without repolarization change. Downsloping elevated ST-segment pattern in V1 and V2 occurs with more unipolar endocardial voltage abnormality, consistent with more advanced transmural disease.

Association of regional epicardial right ventricular electrogram voltage amplitude and late gadolinium enhancement distribution on cardiac magnetic resonance in patients with arrhythmogenic right ventricular cardiomyopathy: Implications for ventricular tachycardia ablation.

BACKGROUND: Criteria for identification of anatomic ventricular tachycardia substrates in arrhythmogenic right ventricular cardiomyopathy (ARVC) on late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) are unclear. OBJECTIVE: The purpose of this study was to define (1) the association of regional right ventricular (RV) epicardial voltage amplitude with the distribution of LGE; and (2) appropriate image signal intensity (SI) thresholds for ventricular tachycardia substrate identification in ARVC. METHODS: Preprocedural LGE-CMR and epicardial electrogram mapping were performed in 10 ARVC patients. The locations of epicardial electrogram map points, obtained during sinus rhythm with intrinsic conduction or RV pacing, were retrospectively registered to the corresponding LGE image regions. Standardized SI z-scores (standard deviation distance from the mean) were calculated for each 10-mm region surrounding map points. RESULTS: In patient-clustered, generalized estimating equations models that included 3205 epicardial electroanatomic points and corresponding SI measures, bipolar (-1.43 mV/z-score; P <.001) and unipolar voltage amplitude (-1.22 mV/z-score; P <.001) were associated with regional SI z-scores. In contrast to the QRS-late potential (LP) interval (P = .362), the LP activation index, defined as electrogram duration divided by QRS-LP, was associated with regional SI z-scores (P <.001). SI z-score thresholds >0.05 (95% confidence interval -0.05 to 0.15) and <-0.16 (95% confidence interval -0.26 to 0.06) corresponded to bipolar voltage measures <0.5 and >1.0 mV, respectively. CONCLUSION: Increased RV gadolinium uptake is associated with lower epicardial bipolar and unipolar electrogram voltage amplitude. Standardized LGE-CMR SI z-scores may augment preprocedural planning for identification of low-voltage zones and abnormal myocardium in ARVC.

Electrocardiographic and electrophysiologic differentiation between atriofascicular, long atrioventricular, and short atrioventricular decrementally conducting accessory pathways.

Aims: We aimed to examine the electrocardiographic and electrophysiologic characteristics of anterograde-conducting decremental accessory pathways (DAP) and to identify surrogate criteria to distinguish short atrioventricular (SAV) DAP from atriofascicular (AF) AP and long atrioventricular (LAV) DAP. Methods and results: We identified all patients with DAPs and analysed electrocardiographic and electrophysiologic characteristics. Distal insertion sites were examined using existing criteria, including V-H interval, ventricular activation at the right ventricular apex, and around tricuspid annulus during antidromic atrioventricular re-entrant tachycardia (A-AVRT) or complete pre-excitation and evaluated the AV node-like properties according to the response to adenosine and radiofrequency ablation. Out of 45 patients with DAPs, 28 (62.2%) had SAV-DAP (13 with definite AF-AP, 2 with definite LAV-DAP, 2 indeterminate). In all, 50% of SAV-DAPs and 53.3% of AF-AP/LAV-DAPs had 'rS' pattern in lead III. Longer QRS duration (159.9 ± 17.4 ms vs. 139.2 ± 14.3 ms, P < 0.0001) during full pre-excitation or A-AVRT differentiated SAV-DAP from AF-AP. The QRS-V(His) interval was longer for those with SAV-DAP compared vs. AF-AP/LAV-DAP (45.3 ± 2.4 ms vs. 22.9 ± 2.5 ms, P < 0.0001) and a cut-off value of 33.0 ms differentiated the two (sensitivity 81.3%, specificity 87.5%). Conclusion: The majority of the SAV-DAPs are located at the TA free wall. An 'rS' pattern in lead III is frequently seen in SAV-DAP as well as AF-AP/LAV-DAPs. Measuring the QRS-V(His) interval would be helpful to distinguish SAV-DAP from AF-AP/LAV-DAP.