Vericiguat suppresses ventricular tachyarrhythmias inducibility in a rabbit myocardial infarction model.

BACKGROUND: The VICTORIA trial demonstrated a significant decrease in cardiovascular events through vericiguat therapy. This study aimed to assess the potential mechanisms responsible for the reduction of cardiovascular events with vericiguat therapy in a rabbit model of myocardial infarction (MI). METHODS: A chronic MI rabbit model was created through coronary artery ligation. Following 4 weeks, the hearts were harvested and Langendorff perfused. Subsequently, electrophysiological examinations and dual voltage-calcium optical mapping studies were conducted at baseline and after administration of vericiguat at a dose of 5 µmol/L. RESULTS: Acute vericiguat therapy demonstrated a significant reduction in premature ventricular beat burden and effectively suppressed ventricular arrhythmic inducibility. The electrophysiological influences of vericiguat therapy included an increased ventricular effective refractory period, prolonged action potential duration, and accelerated intracellular calcium (Cai) homeostasis, leading to the suppression of action potential and Cai alternans. The pacing-induced ventricular arrhythmias exhibited a reentrant pattern, attributed to fixed or functional conduction block in the peri-infarct zone. Vericiguat therapy effectively mitigated the formation of cardiac alternans as well as the development of reentrant impulses, providing additional anti-arrhythmic benefits. CONCLUSIONS: In the MI rabbit model, vericiguat therapy demonstrates anti-ventricular arrhythmia effects. The vericiguat therapy reduces ventricular ectopic beats, inhibiting the initiation of ventricular arrhythmias. Furthermore, the therapy successfully suppresses cardiac alternans, preventing conduction block and, consequently, the formation of reentry circuits.

Comparing Artificial Intelligence-Enabled Electrocardiogram Models in Identifying Left Atrium Enlargement and Long-term Cardiovascular Risk.

BACKGROUND: The role of P-wave in identifying left atrial enlargement (LAE) with the use of artificial intelligence (AI)-enabled electrocardiography (ECG) models is unclear. It is also unknown if AI-enabled single-lead ECG could be used as a diagnostic tool for LAE surveillance. We aimed to build AI-enabled P-wave and single-lead ECG models to identify LAE using sinus rhythm (SR) and non-SR ECGs, and compare the prognostic ability of severe LAE, defined as left atrial diameter ≥ 50 mm, assessed by AI-enabled ECG models vs echocardiography. METHODS: This retrospective study used data from 382,594 consecutive adults with paired 12-lead ECG and echocardiography performed within 2 weeks of each other at Chang Gung Memorial Hospital. UNet++ was used for P-wave segmentation. ResNet-18 was used to develop deep convolutional neural network-enabled ECG models for discriminating LAE. External validation was performed with the use of data from 11,753 patients from another hospital. RESULTS: The AI-enabled 12-lead ECG model outperformed other ECG models for classifying LAE, but the single-lead ECG models also showed excellent performance at a left atrial diameter cutoff of 50 mm. AI-enabled ECG models had excellent and fair discrimination on LAE using the SR and the non-SR data set, respectively. Severe LAE identified by AI-enabled ECG models was more predictive of future cardiovascular disease than echocardiography; however, the cumulative incidence of new-onset atrial fibrillation and heart failure was higher in patients with echocardiography-severe LAE than with AI-enabled ECG-severe LAE. CONCLUSIONS: P-Wave plays a crucial role in discriminating LAE in AI-enabled ECG models. AI-enabled ECG models outperform echocardiography in predicting new-onset cardiovascular diseases associated with severe LAE.

Machine learning-based prediction of acute mortality in emergency department patients using twelve-lead electrocardiogram.

Background: The risk of mortality is relatively high among patients who visit the emergency department (ED), and stratifying patients at high risk can help improve medical care. This study aimed to create a machine-learning model that utilizes the standard 12-lead ECG to forecast acute mortality risk in ED patients. Methods: The database included patients who visited the EDs and underwent standard 12-lead ECG between October 2007 and December 2017. A convolutional neural network (CNN) ECG model was developed to classify survival and mortality using 12-lead ECG tracings acquired from 345,593 ED patients. For machine learning model development, the patients were randomly divided into training, validation and testing datasets. The performance of the mortality risk prediction in this model was evaluated for various causes of death. Results: Patients who visited the ED and underwent one or more ECG examinations experienced a high incidence of 30-day mortality [18,734 (5.42%)]. The developed CNN model demonstrated high accuracy in predicting acute mortality (hazard ratio 8.50, 95% confidence interval 8.20-8.80) with areas under the receiver operating characteristic (ROC) curve of 0.84 for the 30-day mortality risk prediction models. This CNN model also demonstrated good performance in predicting one-year mortality (hazard ratio 3.34, 95% confidence interval 3.30-3.39). This model exhibited good predictive performance for 30-day mortality not only for cardiovascular diseases but also across various diseases. Conclusions: The machine learning-based ECG model utilizing CNN screens the risks for 30-day mortality. This model can complement traditional early warning scoring indexes as a useful screening tool for mortality prediction.

Long-term efficacy of sodium-glucose cotransporter 2 inhibitor therapy in preventing atrial fibrillation recurrence after catheter ablation in type 2 diabetes mellitus patients.

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce new-onset atrial fibrillation (AF) in patients with type 2 diabetes mellitus (T2DM). We aimed to determine the long-term effects of SGLT2i on atrial tachyarrhythmia recurrence after catheter ablation (CA) in T2DM patients. Methods: This retrospective study enrolled consecutive patients with T2DM undergoing CA for AF between January 2016 and December 2021. Patient baseline demographic characteristics and use of anti-diabetic and anti-arrhythmic medications were analyzed. Echocardiographic parameters were obtained one day and 6 months after CA. Results: Our study population comprised 122 patients (70% paroxysmal AF). The baseline patient characteristics were similar between the SGLT2i-treated group (n = 45) and the non-SGLT2i-treated group (n = 77) except for stroke. At 6-month follow-up, body-mass index (BMI) was significantly decreased and left ventricular ejection fraction (LVEF) was significantly increased only in the SGLT2i group. E/e' was decreased 6 months after CA in both groups. During a mean follow-up of 33.7 ± 21.6 months, 22 of 122 patients had atrial tachyarrhythmia recurrence. The long-term atrial tachyarrhythmia-free survival rate was significantly higher in the SGLT2i-treated patients, and multivariate analysis revealed that AF type and SGLT2i use were independently associated with atrial tachyarrhythmia recurrence after CA. Conclusion: The use of SGLT2i and AF type were independent risk factors associated with atrial tachyarrhythmia recurrence after CA in T2DM patients with AF. This result was at least partly due to the pleiotropic effects of SGLT2i on BMI reduction and left ventricular function improvement.

Artificial intelligence-enabled electrocardiographic screening for left ventricular systolic dysfunction and mortality risk prediction.

Background: Left ventricular systolic dysfunction (LVSD) characterized by a reduced left ventricular ejection fraction (LVEF) is associated with adverse patient outcomes. We aimed to build a deep neural network (DNN)-based model using standard 12-lead electrocardiogram (ECG) to screen for LVSD and stratify patient prognosis. Methods: This retrospective chart review study was conducted using data from consecutive adults who underwent ECG examinations at Chang Gung Memorial Hospital in Taiwan between October 2007 and December 2019. DNN models were developed to recognize LVSD, defined as LVEF <40%, using original ECG signals or transformed images from 190,359 patients with paired ECG and echocardiogram within 14 days. The 190,359 patients were divided into a training set of 133,225 and a validation set of 57,134. The accuracy of recognizing LVSD and subsequent mortality predictions were tested using ECGs from 190,316 patients with paired data. Of these 190,316 patients, we further selected 49,564 patients with multiple echocardiographic data to predict LVSD incidence. We additionally used data from 1,194,982 patients who underwent ECG only to assess mortality prognostication. External validation was performed using data of 91,425 patients from Tri-Service General Hospital, Taiwan. Results: The mean age of patients in the testing dataset was 63.7 ± 16.3 years (46.3% women), and 8,216 patients (4.3%) had LVSD. The median follow-up period was 3.9 years (interquartile range 1.5-7.9 years). The area under the receiver-operating characteristic curve (AUROC), sensitivity, and specificity of the signal-based DNN (DNN-signal) to identify LVSD were 0.95, 0.91, and 0.86, respectively. DNN signal-predicted LVSD was associated with age- and sex-adjusted hazard ratios (HRs) of 2.57 (95% confidence interval [CI], 2.53-2.62) for all-cause mortality and 6.09 (5.83-6.37) for cardiovascular mortality. In patients with multiple echocardiograms, a positive DNN prediction in patients with preserved LVEF was associated with an adjusted HR (95% CI) of 8.33 (7.71 to 9.00) for incident LVSD. Signal- and image-based DNNs performed equally well in the primary and additional datasets. Conclusion: Using DNNs, ECG becomes a low-cost, clinically feasible tool to screen LVSD and facilitate accurate prognostication.

Obstetric and fetal/neonatal outcomes in pregnant women with frequent premature ventricular complexes and structurally normal heart.

BACKGROUND: High premature ventricular complex (PVC) burden may increase the risk of left ventricular dysfunction and all-cause mortality. We aimed to evaluate maternal and neonatal outcomes of pregnant women with structurally normal heart having PVC burden ≥1%. METHODS: This retrospective cohort study used data from Chang Gung Research Database. Pregnancies from January 1, 2005, through June 30, 2020, with documented maternal PVC burden ≥1% by 24-h Holter monitor were identified. Pregnant women with a diagnosis of structural heart disease or arrhythmias other than PVC were excluded. We used propensity score matching (PSM) to balance the covariates between the PVC group and normal control group. The PVC group was classified into low-PVC (<10%) and high-PVC burden subgroups. The maternal and neonatal outcomes were assessed through 6 months after delivery or termination. RESULTS: After PSM, there were 214, 61, and 46 pregnant women enrolled in the normal control group, low-PVC burden, and high-PVC burden subgroups, respectively. The high-PVC and low-PVC burden subgroups had composite adverse maternal and neonatal events similar to the control group without use of antiarrhythmic drugs (AADs), but a higher proportion of placental abruption was observed in the high-PVC burden subgroup. Maternal age, diabetes, and overweight were significant predictors of composite adverse maternal events, whereas only maternal age was a significant predictor of composite adverse neonatal events. CONCLUSIONS: High PVC burden was not associated with poor composite adverse maternal and neonatal outcomes with no need of AADs therapy in pregnant women with structurally normal heart.

Cannabinoid receptor 1 antagonist genistein attenuates marijuana-induced vascular inflammation.

Epidemiological studies reveal that marijuana increases the risk of cardiovascular disease (CVD); however, little is known about the mechanism. Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of marijuana, binds to cannabinoid receptor 1 (CB1/CNR1) in the vasculature and is implicated in CVD. A UK Biobank analysis found that cannabis was an risk factor for CVD. We found that marijuana smoking activated inflammatory cytokines implicated in CVD. In silico virtual screening identified genistein, a soybean isoflavone, as a putative CB1 antagonist. Human-induced pluripotent stem cell-derived endothelial cells were used to model Δ9-THC-induced inflammation and oxidative stress via NF-κB signaling. Knockdown of the CB1 receptor with siRNA, CRISPR interference, and genistein attenuated the effects of Δ9-THC. In mice, genistein blocked Δ9-THC-induced endothelial dysfunction in wire myograph, reduced atherosclerotic plaque, and had minimal penetration of the central nervous system. Genistein is a CB1 antagonist that attenuates Δ9-THC-induced atherosclerosis.

Clinical Outcomes of low-voltage area-guided left atrial linear ablation for non-paroxysmal atrial fibrillation patients.

BACKGROUND: The therapeutic effect of low-voltage area (LVA)-guided left atrial (LA) linear ablation for non-paroxysmal atrial fibrillation (non-PAF) is uncertain. We aimed to investigate the efficacy of LA linear ablation based on the preexisting LVA and its effects on LA reverse remodeling in non-PAF patients. METHODS: We retrospectively evaluated 145 consecutive patients who underwent radiofrequency catheter ablation for drug-refractory non-PAF. CARTO-guided bipolar voltage mapping was performed in atrial fibrillation (AF). LVA was defined as sites with voltage ≤ 0.5 mV. If circumferential pulmonary vein isolation couldn't convert AF into sinus rhythm, additional LA linear ablation was performed preferentially at sites within LVA. RESULTS: After a mean follow-up duration of 48 ± 33 months, 29 of 145 patients had drugs-refractory AF/LA tachycardia recurrence. Low LA emptying fraction, large LA size and high extent of LVA were associated with AF recurrence. There were 136 patients undergoing LA linear ablation. The rate of linear block at the mitral isthmus was significantly higher via LVA-guided than non-LVA-guided linear ablation. Patients undergoing LVA-guided linear ablation had larger LA size and higher extent of LVA, but the long-term AF/LA tachycardia-free survival rate was higher than the non-LVA-guided group. The LA reverse remodeling effects by resuming sinus rhythm were noted even in patients with a diseased left atrium undergoing extensive LA linear ablation. CONCLUSIONS: LVA-guided linear ablation through targeting the arrhythmogenic LVA and reducing LA mass provides a better clinical outcome than non-LVA guided linear ablation, and outweighs the harmful effects of iatrogenic scaring in non-PAF patients.

P wave duration ≥150 ms predicts poor left atrial function and ablation outcomes in non-paroxysmal atrial fibrillation.

BACKGROUND: It remains unknown whether P wave duration (PWD) ≥ 150 ms measured after extensive radiofrequency catheter ablation (RFCA) can identify non-paroxysmal atrial fibrillation (non-PAF) patients at increased risk of atrial tachyarrhythmia recurrence. We investigated the predicting power of PWD and its association with left atrial (LA) reverse remodeling in patients with non-PAF undergoing pulmonary vein isolation with LA linear ablation. METHODS: We retrospectively evaluated 136 patients who underwent RFCA for drug-refractory non-PAF. Electroanatomic mapping was acquired during AF. Low-voltage area (LVA) was defined as an area with bipolar voltage ≤0.5 mV. Electrocardiography and echocardiography were performed during sinus rhythm 1 day and 3 months after RFCA. PWD was measured using amplified 12­lead electrocardiography. Prolonged PWD was defined as maximum PWD ≥ 150 ms. RESULTS: Over a mean follow-up duration of 48 ± 35 months, 28 patients experienced atrial tachyarrhythmia recurrence. PWD was positively correlated with LVA (r = 0.527, p < 0.001) and inversely correlated with LA emptying fraction (r = -0.399, p < 0.001). PWD was shortened and LA emptying fraction (LAEF) was increased in patients without atrial tachyarrhythmia recurrence during follow-up. Atrial tachyarrhythmia-free survival was significantly more likely in patients without a prolonged PWD (83.5% vs 60.7%, p = 0.002). Multivariate analysis showed that LAEF and PWD were independent predictors of atrial tachyarrhythmia recurrence. CONCLUSIONS: PWD ≥ 150 ms measured after RFCA can identify patients with non-PAF at increased risk of atrial tachyarrhythmia recurrence. PWD is correlated with LVA and LAEF and reflects LA reverse remodeling.

Beneficial Electrophysiological Effects of Rotigaptide Are Unable to Suppress Therapeutic Hypothermia-Provoked Ventricular Fibrillation in Failing Rabbit Hearts With Acute Ischemia-Reperfusion Injury.

Aims: Whether therapeutic hypothermia (TH) is proarrhythmic in preexisting failing hearts with acute ischemia-reperfusion (IR) injury is unknown. Additionally, the effectiveness of rotigaptide on improving conduction slowing in hearts with IR injury is ambiguous. We investigated the electrophysiological effects of TH and rotigaptide in failing rabbit hearts with acute IR injury and determined the underlying molecular mechanisms. Methods and Results: Heart failure was induced by right ventricular pacing (320 beats/min, 4 weeks). Rabbits with pacing-induced heart failure were randomly divided into TH (n = 14) and non-TH (n = 7) groups. The IR rabbit model was created by ligating the coronary artery for 60 min, followed by reperfusion for 15 min in vivo. Then, the hearts were excised quickly and Langendorff-perfused for simultaneous voltage and intracellular Ca2+ (Cai) optical mapping. Electrophysiological studies were conducted, and vulnerability to ventricular fibrillation (VF) was evaluated using pacing protocols. TH (33°C) was instituted after baseline studies, and electrophysiological studies were repeated. Rotigaptide (300 nM) was infused for 20 min, and electrophysiological studies were repeated under TH. Cardiac tissues were sampled for Western blotting. TH increased the dispersion and beat-to-beat variability of action potential duration (APD), aggravated conduction slowing, and prolonged Cai decay to facilitate spatially discordant alternans (SDA) and VF induction. Rotigaptide reduced the dispersion and beat-to-beat variability of APD and improved slowed conduction to defer the onset of arrhythmogenic SDA by dynamic pacing and elevate the pacing threshold of VF during TH. However, the effect of rotigaptide on TH-enhanced VF inducibility was statistically insignificant. TH attenuated IR-induced dysregulation of protein expression, but its functional role remained uncertain. Conclusion: Therapeutic hypothermia is proarrhythmic in failing hearts with acute IR injury. Rotigaptide improves TH-induced APD dispersion and beat-to-beat variability and conduction disturbance to defer the onset of arrhythmogenic SDA and elevate the VF threshold by dynamic pacing, but these beneficial electrophysiological effects are unable to suppress TH-enhanced VF inducibility significantly.

Differential Responses of Transplanted Stem Cells to Diseased Environment Unveiled by a Molecular NIR-II Cell Tracker.

Stem cell therapy holds high promises in regenerative medicine. The major challenge of clinical translation is to precisely and quantitatively evaluate the in vivo cell distribution, migration, and engraftment, which cannot be easily achieved by current techniques. To address this issue, for the first time, we have developed a molecular cell tracker with a strong fluorescence signal in the second near-infrared (NIR-II) window (1,000-1,700 nm) for real-time monitoring of in vivo cell behaviors in both healthy and diseased animal models. The NIR-II tracker (CelTrac1000) has shown complete cell labeling with low cytotoxicity and profound long-term tracking ability for 30 days in high spatiotemporal resolution for semiquantification of the biodistribution of transplanted stem cells. Taking advantage of the unique merits of CelTrac1000, the responses of transplanted stem cells to different diseased environments have been discriminated and unveiled. Furthermore, we also demonstrate CelTrac1000 as a universal and effective technique for ultrafast real-time tracking of the cellular migration and distribution in a 100 µm single-cell cluster spatial resolution, along with the lung contraction and heart beating. As such, this NIR-II tracker will shift the optical cell tracking into a single-cell cluster and millisecond temporal resolution for better evaluating and understanding stem cell therapy, affording optimal doses and efficacy.

Mechanisms of ranolazine pretreatment in preventing ventricular tachyarrhythmias in diabetic db/db mice with acute regional ischemia-reperfusion injury.

Studies have demonstrated that diabetic (db/db) mice have increased susceptibility to myocardial ischemia-reperfusion (IR) injury and ventricular tachyarrhythmias (VA). We aimed to investigate the antiarrhythmic and molecular mechanisms of ranolazine in db/db mouse hearts with acute IR injury. Ranolazine was administered for 1 week before coronary artery ligation. Diabetic db/db and control db/+ mice were divided into ranolazine-given and -nongiven groups. IR model was created by 15-min left coronary artery ligation and 10-min reperfusion. In vivo electrophysiological studies showed that the severity of VA inducibility was higher in db/db mice than control (db/ +) mice. Ranolazine suppressed the VA inducibility and severity. Optical mapping studies in Langendorff-perfused hearts showed that ranolazine significantly shortened action potential duration, Cai transient duration, Cai decay time, ameliorated conduction inhomogeneity, and suppressed arrhythmogenic alternans induction. Western blotting studies showed that the expression of pThr17-phospholamban, calsequestrin 2 and voltage-gated sodium channel in the IR zone was significantly downregulated in db/db mice, which was ameliorated with ranolazine pretreatment and might play a role in the anti-arrhythmic actions of ranolazine in db/db mouse hearts with IR injury.

Sacubitril/Valsartan Therapy Ameliorates Ventricular Tachyarrhythmia Inducibility in a Rabbit Myocardial Infarction Model.

BACKGROUND: Coronary artery disease is the most common cause of heart failure (HF) in developed countries. The aim of this study was to elucidate the mechanisms of reduction of arrhythmias after sacubitril/valsartan (LCZ696) therapy in a myocardial infarction (MI)-HF rabbit model. METHODS AND RESULTS: Chronic MI in rabbits with HF were divided into 3 groups: placebo control, valsartan 30 mg/day and LCZ696 60 mg/day. After 4 weeks of therapy, an electrophysiologic study and a dual voltage-calcium optical mapping study were performed. The LCZ696 group had significantly better left ventricular ejection fraction and lower ventricular tachyarrhythmia inducibility than the valsartan and placebo groups. The most common ventricular tachyarrhythmia pattern was 1 or 2 ectopic beats originating from the peri-infarct areas, followed by re-entrant beats surrounding phase singularity points. Compared to the valsartan and placebo groups, the LCZ696 group had significantly shorter action-potential duration, shorter intracellular calcium tau constant, faster conduction velocity, and shorter pacing cycle length to induce arrhythmogenic alternans. LCZ696 therapy reduced the phosphorylated calmodulin-dependent protein kinase II (CaMKII-p) expression. CONCLUSIONS: In a rabbit model with chronic MI and HF, LCZ696 therapy ameliorated postinfarct heart function impairment and electrophysiologic remodeling and altered CaMKII-p expression, leading to reduced ventricular tachyarrhythmia inducibility.

A Novel Approach for Predicting Atrial Fibrillation Recurrence After Ablation Using Deep Convolutional Neural Networks by Assessing Left Atrial Curved M-Mode Speckle-Tracking Images.

Aims: Curved M-mode images of global strain (GS) and strain rate (GSR) provide sufficiently detailed spatiotemporal information of deformation mechanics. This study investigated whether a deep convolutional neural network (CNN) could accurately classify these images in patients with atrial fibrillation (AF) who underwent radiofrequency catheter ablation (RFCA) with different outcomes. Methods and Results: We retrospectively evaluated 606 consecutive patients who underwent RFCA for drug-refractory AF. Patients were divided into AF-free (n = 443) and AF-recurrent (n = 163) groups. Transthoracic echocardiography was performed within 24 h after RFCA. Left atrial curved M-mode speckle-tracking images were acquired from randomly selected 163 patients in AF-free group and 163 patients in AF-recurrent group as the dataset for deep CNN modeling. We used the ReLu activation function and repeatedly performed CNN model for 32 times to evaluate the stability of hyperparameters. Logistic regression models with the left atrial dimension, emptying fraction, and peak systolic GS as predictor variables were used for comparisons. Images from the apical 2-chamber (2-C) and 4-chamber (4-C) views had distinct features, leading to different CNN performance between settings; of them, the "4-C GS+4-C GSR" setting provided the highest performance index values. All four predictor variables used for logistic regression modeling were significant; however, none of them, individually or in any combined form, could outperform the optimal CNN model. Conclusion: The novel approach using deep CNNs for learning features of left atrial curved M-mode speckle-tracking images seems to be optimal for classifying outcome status after AF ablation.

Single Bolus Rosuvastatin Accelerates Calcium Uptake and Attenuates Conduction Inhomogeneity in Failing Rabbit Hearts With Regional Ischemia-Reperfusion Injury.

Acute statin therapy reduces myocardial ischemia/reperfusion (IR) injury-induced ventricular fibrillation (VF), but the underlying electrophysiological mechanisms remain unclear. This study sought to investigate the antiarrhythmic effects of a single bolus rosuvastatin injection in failing rabbit hearts with IR injury and to unveil the underlying molecular mechanisms. Rabbits were divided into rosuvastatin, rosuvastatin + L-NAME, control, and L-NAME groups. Intravenous bolus rosuvastatin (0.5 mg/kg) and/or L-NAME (10 mg/kg) injections were administered 1 hour and 15 minutes before surgery, respectively. Heart failure was induced using rapid ventricular pacing. Under general anesthesia with isoflurane, an IR model was created by coronary artery ligation for 30 minutes, followed by reperfusion for 15 minutes. Plasma NO end product levels were measured during IR. Then, hearts were excised and Langendorff-perfused for optical mapping studies. Cardiac tissues were sampled for Western blot analysis. Rosuvastatin increased plasma NO levels during IR, which was abrogated by L-NAME. Spontaneous VF during IR was suppressed by rosuvastatin (P < 0.001). Intracellular calcium (Cai) decay and conduction velocity were significantly slower in the IR zone. Rosuvastatin accelerated Cai decay, ameliorated conduction inhomogeneity, and reduced the inducibility of spatially discordant alternans and VF significantly. Western blots revealed significantly higher expression of enhancing endothelial NO-synthase and phosphorylated enhancing endothelial NO-synthase proteins in the Rosuvastatin group. Furthermore, SERCA2a, phosphorylated connexin43, and phosphorylated phospholamban were downregulated in the IR zone, which was attenuated or reversed by rosuvastatin. Acute rosuvastatin therapy before ischemia reduced IR-induced VF by improving SERCA2a function and ameliorating conduction disturbance in the IR zone.

LCZ696 Therapy Reduces Ventricular Tachyarrhythmia Inducibility in a Myocardial Infarction-Induced Heart Failure Rat Model.

BACKGROUND: LCZ696 (valsartan/sacubitril) therapy significantly reduced mortality in patients with heart failure (HF). Although a clinical trial (PARADISE-MI Trial) has been ongoing to examine the effects of LCZ696 in myocardial infarction (MI) patients, the effects of LCZ696 on remodeling of cardiac electrophysiology in animal models remain largely unclear. METHODS: We performed coronary artery ligation to create MI in Sprague-Dawley rats. Echocardiography was performed one week after MI to confirm the development of HF with left ventricular ejection fraction ≤ 40%. MI rats were randomly assigned to receive medical therapy for 4 weeks: LCZ696, enalapril, or vehicle. The sham-operation rats received sham operation without MI creation. In vivo electrophysiological exams were performed under general anesthesia. Western blot analyses were conducted to quantify ion channel proteins. RESULTS: The HF-vehicle group did not show significant changes in LVEF. Both enalapril and LCZ696 therapy significantly improved LVEF. The HF-vehicle group had higher ventricular arrhythmia (VA) inducibility than the sham group. As compared with the HF-vehicle group, LCZ696 therapy significantly reduced VA inducibility, but enalapril therapy did not. Western blot analyses showed significant downregulation of NaV1.5, ERG, KCNE1, and KCNE2 channel proteins in the HF vehicle group compared with the sham group. LCZ696 therapy upregulated protein expression of ERG, KCNE1, and KCNE2. CONCLUSION: As compared with enalapril therapy, LCZ696 therapy led to improvement of LVEF, reduced VA inducibility, and upregulated expression of K+ channel proteins.

An in Vivo miRNA Delivery System for Restoring Infarcted Myocardium.

A major challenge in myocardial infarction (MI)-related heart failure treatment using microRNA is the efficient and sustainable delivery of miRNAs into myocardium to achieve functional improvement through stimulation of intrinsic myocardial restoration. In this study, we established an in vivo delivery system using polymeric nanoparticles to carry miRNA (miNPs) for localized delivery within a shear-thinning injectable hydrogel. The miNPs triggered proliferation of human embryonic stem cell-derived cardiomyocytes and endothelial cells (hESC-CMs and hESC-ECs) and promoted angiogenesis in hypoxic conditions, showing significantly lower cytotoxicity than Lipofectamine. Furthermore, one injected dose of hydrogel/miNP in MI rats demonstrated significantly improved cardiac functions: increased ejection fraction from 45% to 64%, reduced scar size from 20% to 10%, and doubled capillary density in the border zone compared to the control group at 4 weeks. As such, our results indicate that this injectable hydrogel/miNP composite can deliver miRNA to restore injured myocardium efficiently and safely.

Left atrial emptying fraction predicts recurrence of atrial fibrillation after radiofrequency catheter ablation.

BACKGROUND: Compared with left atrial (LA) dimension, LA emptying fraction (LAEF) has received less emphasis as a predictor of atrial fibrillation (AF) recurrence after radiofrequency catheter ablation (RFCA). In addition, patients experiencing post-RFCA AF recurrence may respond to previously ineffective antiarrhythmic drugs (AADs). Classifying these patients into a third RFCA outcome category is recommended. OBJECTIVE: To identify predictors of RFCA outcome classified into three categories, and to build proportional odds logistic regression models for clinical applicability to predict AF recurrence. METHODS: Data were retrospectively collected from 483 consecutive patients with drug-refractory AF undergoing RFCA (328 men; age 58.4 ± 11.5 years; 383 paroxysmal). Patients were classified into 3 groups based on the last RFCA outcome: group 1, free from AF without AADs; group 2, free from AF with AADs; and group 3, recurrence of AADs-refractory atrial tachyarrhythmia. RESULTS: After a mean follow-up duration of 64.5 ± 43.2 months and mean ablation procedure number of 1.37 ± 0.68, the RFCA outcome showed 76.0%, 9.5% and 14.5% of patients in groups 1, 2, and 3, respectively. In multivariate analysis, LAEF was the most stable and important predictor of AF recurrence, followed by body mass index, stroke, AF duration, mitral regurgitation, and LA linear ablation. For patients undergoing repeat RFCA, LAEF was the only independent predictor (cutoffs: 43% and 35% for groups 1 and 3, respectively). CONCLUSION: LAEF provides optimal prognostic information regarding the risk stratification of AF patients undergoing RFCA.