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.

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.

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.

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.

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.

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.

Effect of pocket irrigation with antimicrobial on prevention of pacemaker pocket infection: a meta-analysis.

BACKGROUND: The presence of cardiac implantable electronic devices (CIEDs) pocket infection is difficult to treat, causing serious clinical outcomes, but little is known for prevention. Results from some studies suggested that pocket irrigation could reduce infection while others showed conflicting results. We pooled the effects of pocket irrigations on the prevention of pocket infection by meta-analysis methods. METHOD: Relevant studies published before June, 2017 were retrieved mainly by the computer-based search of PubMed, Cochrane, EMBASE, Web of Science, Chinese BioMedical, Global Health and BIOSIS Previews databases. Estimations of relative ratios (RRs) and 95% confidence intervals (95% CIs) were pooled. Subgroup analyses according to potential key factors affecting the effects were conducted, which was confirmed by meta-regression. Sensitivity analysis and test for publication bias were also performed. RESULTS: We identified 10 studies providing data of 5467 patients receiving CIEDs implantations. Pooled infection rates were 1.48 and 3.49% respectively for medication and saline irrigation groups. Meta-analysis showed that medication irrigation conferred protection to pocket infection (RR = 0.44, 95% CI: 0.31-0.63). Subgroup analysis showed that antibiotics, rather than non-antibiotics (antiseptics) exerting the protection. The first and second lines antibiotics against staphylococcus aureus, which is the main pathogen for pocket infection, were both effective (RR = 0.42, 95% CI: 0.24-0.75 and RR = 0.34, 95% CI: 0.20-0.58 respectively for first line and second line therapies). Meta-regression revealed that region and class of irrigation medication completely explained the variance among studies and implied that effects of region were masked by medication types. Sensitivity analysis did not showed any significant change of the result and publication bias were not statistical significance. CONCLUSION: Pocket irrigation with antibiotics were effective for reducing pocket infection and should be encouraged in CIEDs implantation.

A Low-Normal Free Triiodothyronine Level Is Associated with Adverse Prognosis in Euthyroid Patients with Heart Failure Receiving Cardiac Resynchronization Therapy.

Thyroid dysfunction is prevalent in patients with heart failure (HF) and hypothyroidism is related to the adverse prognosis of HF subjects receiving cardiac resynchronization therapy (CRT). We aim to investigate whether low-normal free triiodothyronine (fT3) level is related to CRT response and the prognosis of euthyroid patients with HF after CRT implantation.One hundred and thirteen euthyroid patients who received CRT therapy without previous thyroid disease and any treatment affecting thyroid hormones were enrolled. All of patients were evaluated for cardiac function and thyroid hormones (serum levels of fT3, free thyroxine [fT4] and thyroid-stimulating hormone [TSH]). The end points were overall mortality and hospitalization for HF worsening. During a follow-up period of 39 ± 3 weeks, 36 patients (31.9%) died and 45 patients (39.8%) had hospitalization for HF exacerbation. A higher rate of NYHA III/IV class and a lower fT3 level were both observed in death group and HF event group. Multivariate Cox regression analyses disclosed that a lower-normal fT3 level (HR = 0.648, P = 0.009) and CRT response (HR = 0.441, P = 0.001) were both independent predictors of overall mortality. In addition, they were also both related to HF re-hospitalization event (P < 0.01 for both). Patients with fT3 < 3.00 pmol/L had a significantly higher overall mortality than those with fT3 ≥ 3.00 pmol/L (P = 0.027). Meanwhile, a higher HF hospitalization event rate was also found in patients with fT3 < 3.00 pmol/L (P < 0.001).A lower-normal fT3 level is correlated with a worse cardiac function an adverse prognosis in euthyroid patients with HF after CRT implantation.

Oxidized Low-Density Lipoprotein-Induced Cyclophilin A Secretion Requires ROCK-Dependent Diphosphorylation of Myosin Light Chain.

OBJECTIVE: Accumulation of cyclophilin A (CyPA) within atherosclerotic lesions is thought to be implicated in the progression of atherosclerosis. However, the source of CyPA within atherosclerotic lesions is still unknown. The aim of this study is to determine the role of oxidized low-density lipoproteins (ox-LDL) in vascular smooth muscle cell (VSMC)-derived CyPA secretion and the underlying mechanism. METHODS AND RESULTS: Abundant CyPA and α-smooth muscle actin (α-SMA) expressed in atherosclerotic lesions was observed in apolipoprotein E-deficient mice. ox-LDL induced CyPA secretion from a primary culture of rat aortic smooth muscle cells in a dose- and time-dependent manner. Sulfosuccinimidyloleate, a CD36 inhibitor, prevented the ox-LDL-induced CyPA secretion. Pre-exposure to either the actin-depolymerizing agent cytochalasin D or the actin-polymerizing agent jasplakinolide inhibited CyPA secretion induced by ox-LDL. Gene silencing of vesicle-associated membrane protein 2 suppressed ox-LDL-induced CyPA secretion. ox-LDL caused the phosphorylation of myosin light chain (MLC). Inhibition of MLC by blebbistatin reversed the secretion of CyPA and the phosphorylation of MLC induced by ox-LDL. MLC kinase inhibitor ML-7 reduced the monophosphorylation of MLC but did not reduce CyPA secretion. Pretreatment with the rho-associated coiled-coil kinase (ROCK) inhibitor Y27632 blocked diphosphorylation of MLC and secretion of CyPA induced by ox-LDL. CONCLUSIONS: ox-LDL-induced CyPA secretion requires vesicle transportation, actin remodeling and ROCK-dependent diphosphorylation of MLC. VSMC-derived CyPA induced by ox-LDL may be associated with increased CyPA expression in atherosclerotic lesions.

Differentiated markers in undifferentiated cells: expression of smooth muscle contractile proteins in multipotent bone marrow mesenchymal stem cells.

In studying the differentiation of stem cells along smooth muscle lineage, smooth muscle cell (SMC) contractile proteins serve as markers for the relative state of maturation. Yet, recent evidence suggests that some SMC markers are probably expressed in multipotent mesenchymal stem cells (MSCs). Such a paradox necessitates investigations to re-examine their role as differentiated markers in MSCs. We tried to detect the expression of four widely used SMC markers including α-smooth muscle actin (α-SMA), h1-calponin, desmin and smooth muscle myosin heavy chain (SM-MHC), as well as the other isoforms of calponin family in resting MSCs. Then we used three different conditions to initiate MSCs differentiation along SMC lineage, and examined the alternation of SMC markers expression at both the transcript level and protein level. Desmin and h1-calponin are expressed in MSCs, in the presence or absence of SMC induction conditions. Moreover, MSCs are shown to express all known isoforms of calponin. Double-staining reveals that h1-calponin +/α-SMA - cells constitute the majority of resting MSCs. Under differentiated conditions, expression of SM-MHC was initiated and expression of α-SMA was promoted. The expression of SM-MHC and upregulation of α-SMA are relatively reliable indications of a mature smooth muscle phenotype in MSCs. Given that the cells are particularly rich in calponins expression, we postulate possible roles of these proteins in regulating cellular function by taking part in actin cytoskeleton and signaling. These findings imply that an extensive study of the cell physiology of MSCs should focus on the functional roles for these proteins, rather than simply regard them as differentiated markers.

[Impact of insulin resistance on prognosis in non-diabetic patients with acute coronary syndromes].

OBJECTIVE: To evaluate the impact of insulin resistance (IR) on prognosis in non-diabetic acute coronary syndrome patients. METHODS: In this prospective study, we enrolled 332 non-diabetic patients suffering from acute coronary syndrome. The patients were divided into three groups by HOMA-IR which calculated by formula: low HOMA-IR group (HOMA-IR < 2), 44 cases; moderate HOMA-IR group (2 ≤ HOMA2-IR < 6), 99 cases; high HOMA-IR group (HOMA ≥ 6) with HOMA index, 179 cases. The in-hospital medical records of patients were compared, and all patients were followed up for one year after discharge. RESULTS: Incidence of hypertension (P = 0.013), dyslipidemia (P < 0.001), faster resting heart rate (P < 0.001) and number of triple vessel coronary artery disease (P = 0.017) in high HOMA-IR group were significantly higher than in low and moderate HOMA-IR group. During follow-up, the major end-point events increased in proportion to IR grade: 64.3% (26/44) in the high HOMA-IR group, 54.7% (52/99) in moderate HOMA-IR group and 41.3% (74/199) in low HOMA-IR group (P = 0.034). Multivariable logistic regression analysis showed that high sensitivity C reactive protein (OR = 1.012, 95%CI:1.002-1.022, P = 0.022), HOMA-IR (OR = 1.250, 95%CI:1.043-1.497, P = 0.015) , triple vessel coronary artery disease (OR = 5.914, 95%CI:2.947-11.868, P < 0.001) , ischemic changes on ECG (OR = 5.495, 95%CI:2.925-10.324, P < 0.001) and low left ventricular ejection fraction (LVEF ≤ 40%) (OR = 13.205, 95%CI:5.000-34.661, P < 0.001) were independent risk factor for major end-point events during follow-up. CONCLUSIONS: Increased insulin resistance is linked with poor prognosis of non-diabetic patients with acute coronary syndrome.

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.

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.

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.

Altered serum levels of IL-33 in patients with advanced systolic chronic heart failure: correlation with oxidative stress.

BACKGROUND: Interleukin-33 (IL-33) has been linked to chronic heart failure (CHF) in animal studies, but data on serum IL-33 levels in human CHF are not available. We analyzed levels of IL-33 in serum, and investigated the possible role of IL-33 in oxidative stress. METHODS: A total of 191 subjects with advanced systolic CHF (CHF group), 175 patients with pre-existing cardiac diseases but no CHF (non-CHF group), and 177 healthy controls (HC group) were enrolled. Serum levels of IL-33, soluble ST2 (sST2) and N-terminal-pro-brain natriuretic peptide (NT-proBNP), malondialdehyde (MDA) content, erythrocyte superoxide dismutase (eSOD) activity, as well as left ventricular ejection fraction (LVEF), were determined. The exact form of IL-33 in serum was identified. Effects of IL-33 and sST2 on MDA content and SOD activity in angiotensin (Ang II)-stimulated AC16 cells were assessed. RESULTS: Serum levels of IL-33 and sST2 were elevated in CHF patients, whereas IL-33/sST2 ratios were decreased. In CHF patients, pre-existing cardiac diseases and medications used upon hospital admission did not affect IL-33 concentrations or the IL-33/sST2 ratio. Full-length IL-33, which could not be detected in serum from HC and barely detected in non-CHF patients, was significantly up-regulated in CHF patients. IL-33 levels were positively correlated with markers of CHF severity. IL-33/sST2 ratios were slightly and negatively related to MDA concentrations. IL-33 directly reduced MDA and enhanced SOD activity in Ang II-stimulated AC16 cells, which were greatly attenuated by sST2. CONCLUSIONS: Serum levels of IL-33, especially the full-length form, were elevated in CHF patients whereas IL-33 bioactivity was reduced. In advanced CHF, IL-33 may exert anti-oxidation effects, which may be overwhelmed by concurrently elevated levels of sST2.

Inhibition of protein kinase C ß(2) prevents tumor necrosis factor-α-induced apoptosis and oxidative stress in endothelial cells: the role of NADPH oxidase subunits.

We investigate the cell signal transduction pathway protein kinase C (PKC) and the role of NADPH subunits in the process of TNF-α-induced endothelial apoptosis. Human umbilical vein endothelial cells (HUVEC) were treated with one of these: 1 mM PKC ß(2) inhibitor CGP53353, 10 mM PKC δ inhibitor rottlerin, combination CGP53353 with rottlerin, 3 ×10(-4)M NADPH oxidase inhibitor apocynin, 5 × 10(-6)M NADPH oxidase peptide inhibitor gp91ds-tat. The apoptosis process was assessed by Hoechst 33342 stain, flow cytometry and Western blot analysis, while intracellular reactive oxygen species (ROS) production was detected by 2,7'-dichlorodihydrofluorescein diacetate (DCFH-DA). The NADPH oxidase subunit gene and protein expression were assessed by quantitative real-time PCR and Western blot analysis, respectively. TNF-α significantly induced HUVEC apoptosis and ROS production, accompanying with dramatic upregulation of NADPH oxidase subunits: NOX2/gp91(phox), NOX4, p47(phox) and p67(phox), whereas these enhancements were abolished by the treatment with PKC inhibitors. High TNF-α level exposure induces HUVEC apoptosis, as well as a ROS generation increase via the PKC ß(2)-dependent activation of NADPH oxidase. Although the PKC δ pathway may enhance TNF-α-induced HUVEC apoptosis, it does not involve the ROS pathway. Upregulation of expression of NADPH subunits is important in this process, which leads to a new target in antioxidative therapy for vascular disease prevention.

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.

Enrichment of cardiac differentiation of mouse embryonic stem cells by optimizing the hanging drop method.

Hanging drop (HD) culture is used to induce differentiation of embryonic stem cells (ESCs) into other cell types including cardiomyocytes. However, the factors affecting cardiac differentiation of ESCs with this method remain incompletely understood. We have investigated the effects of the starting number of ESCs in embryoid bodies (EBs) and the time of EB adherence to gelatin-coated plates on cardiac differentiation: cardiac differentiation was increased in the EBs by a larger number of ESCs and was decreased by plating EBs at day 4 or earlier. These two factors can thus be optimized to enrich the cardiac differentiation in ESCs using the HD method.