Hyperhomocysteinaemia Promotes Doxorubicin-Induced Cardiotoxicity in Mice.

Doxorubicin, a widely used chemotherapeutic drug in clinical oncology, causes a series of cardiac side effects referred to as doxorubicin-induced cardiotoxicity. Hyperhomocysteinaemia is an independent risk factor for multiple cardiovascular diseases. However, whether hyperhomocysteinaemia contributes to doxorubicin-induced cardiotoxicity is currently unknown. In this study, we explored the pathogenic effects of hyperhomocysteinaemia induced by dietary methionine supplementation (2% wt/wt in rodent chow) in a mouse model of doxorubicin-induced cardiotoxicity. Our data showed that methionine supplementation doubled serum homocysteine levels, inducing mild hyperhomocysteinaemia. Doxorubicin at a cumulative dosage of 25 mg/kg body weight led to significant weight loss and severe cardiac dysfunction, which were further exacerbated by methionine-induced mild hyperhomocysteinaemia. Doxorubicin-induced cardiac atrophy, cytoplasmic vacuolisation, myofibrillar disarray and loss, as well as cardiac fibrosis, were also exacerbated by methionine-induced mild hyperhomocysteinaemia. Additional folic acid supplementation (0.006% wt/wt) prevented methionine-induced hyperhomocysteinaemia and inhibited hyperhomocysteinaemia-aggravated cardiac dysfunction and cardiomyopathy. In particular, hyperhomocysteinaemia increased both serum and cardiac oxidative stress, which could all be inhibited by folic acid supplementation. Therefore, we demonstrated for the first time that hyperhomocysteinaemia could exacerbate doxorubicin-induced cardiotoxicity in mice, and the pathogenic effects of hyperhomocysteinaemia might at least partially correlate with increased oxidative stress and could be prevented by folic acid supplementation. Our study provides preliminary experimental evidence for the assessment of hyperhomocysteinaemia as a potential risk factor for chemotherapy-induced cardiotoxicity in cancer patients.

Chinese expert consensus on the construction of the fluoroless cardiac electrophysiology laboratory and related techniques.

Transcatheter radiofrequency ablation has been widely introduced for the treatment of tachyarrhythmias. The demand for catheter ablation continues to grow rapidly as the level of recommendation for catheter ablation. Traditional catheter ablation is performed under the guidance of X-rays. X-rays can help display the heart contour and catheter position, but the radiobiological effects caused by ionizing radiation and the occupational injuries worn caused by medical staff wearing heavy protective equipment cannot be ignored. Three-dimensional mapping system and intracardiac echocardiography can provide detailed anatomical and electrical information during cardiac electrophysiological study and ablation procedure, and can also greatly reduce or avoid the use of X-rays. In recent years, fluoroless catheter ablation technique has been well demonstrated for most arrhythmic diseases. Several centers have reported performing procedures in a purposefully designed fluoroless electrophysiology catheterization laboratory (EP Lab) without fixed digital subtraction angiography equipment. In view of the lack of relevant standardized configurations and operating procedures, this expert task force has written this consensus statement in combination with relevant research and experience from China and abroad, with the aim of providing guidance for hospitals (institutions) and physicians intending to build a fluoroless cardiac EP Lab, implement relevant technologies, promote the standardized construction of the fluoroless cardiac EP Lab.

Effects of temperature control on hyperthermia-related cardiac dysfunction in a porcine model of cardiac arrest.

The outcome of cardiac arrest is worse when there is fever after spontaneous circulation is restored (ROSC). The purpose of this study was to investigate the mechanism of post-ROSC cardiac dysfunction after hyperthermia treatment and the effects of temperature control. Twenty-four male Bama minipigs were randomized into 3 groups (8 per group): CPR + controlled normothermia (CN), CPR + hyperthermia (HT), and CPR + therapeutic mild hypothermia (TMH). Defibrillation was given to pigs with ventricular fibrillation after 8 min of untreated fibrillation. Subsequently, these animals received the post-ROSC treatments of hyperthermia (38 °C), controlled normothermia (37 °C) or hypothermia (33 °C) according to the groups. Hemodynamic parameters, left ventricular ejection fraction, blood samples and myocardial tissues were assessed. At 24 h after the post-ROSC treatments, the pigs treated with hyperthermia showed increments in heart rate and plasma cardiac troponin I, and decreases in mean arterial pressure, cardiac index, and left ventricular ejection fraction, compared to those with the controlled normothermia pigs. However, the deterioration of the above parameters can be attenuated by TMH. The pigs in the TMH group also had a reduced percentage of apoptotic cardiomyocytes, an increased anti-apoptotic Bcl-2/Bax ratio and a decreased caspase-3 activity in myocardium, as compared with both controlled normothermia and hyperthermia pigs. In conclusion, hyperthermia is associated with a worse myocardial dysfunction. TMH improves hyperthermia-induced myocardial dysfunction by attenuating apoptosis in a porcine model of cardiac arrest.

Leucine Supplementation in Middle-Aged Male Mice Improved Aging-Induced Vascular Remodeling and Dysfunction via Activating the Sirt1-Foxo1 Axis.

Vascular aging is associated with metabolic remodeling, and most studies focused on fatty acid and glucose metabolism. Based on our metabolomic data, leucine was significantly reduced in the aortas of aged mice. Whether leucine supplementation can reverse aging-induced vascular remodeling remains unknown. To investigate the effectiveness of leucine, male mice at 15 or 18 months were supplemented with leucine (1.5%) for 3 months. All the aged mice, with or without leucine, were sacrificed at 21 months. Blood pressure and vascular relaxation were measured. H&E, Masson's trichrome, and Elastica van Gieson staining were used to assess aortic morphology. Vascular inflammation, reactive oxidative stress (ROS), and vascular smooth muscle cell (VSMC) phenotype were also measured in mouse aortas. Compared with the 21-month-old mice without leucine, leucine supplementation from 15 months significantly improved vascular relaxation, maintained the contractile phenotype of VSMCs, and repressed vascular inflammation and ROS levels. These benefits were not observed in the mice supplemented with leucine starting from 18 months, which was likely due to the reduction in leucine transporters Slc3a2 or Slc7a5 at 18 months. Furthermore, we found benefits from leucine via activating the Sirt1-induced Foxo1 deacetylation. Our findings indicated that leucine supplementation in middle-aged mice improved aging-induced vascular remodeling and dysfunction.

Hyperhomocysteinemia Promotes Cardiac Hypertrophy in Hypertension.

Hyperhomocysteinemia (HHcy) is positively linked with several cardiovascular diseases; however, its role and underlying mechanisms in pathological cardiac hypertrophy are still unclear. Here, we focused on the effects and underlying mechanisms of HHcy in hypertensive cardiac hypertrophy, one of the most common and typical types of pathological cardiac hypertrophy. By a retrospective analysis of the association between HHcy and cardiac hypertrophy in a hypertensive cohort, we found that the prevalence of HHcy was higher in patients with hypertrophy and significantly associated with the presence of cardiac hypertrophy after adjusting for other conventional risk factors. In mice, HHcy induced by a methionine (2% wt/wt) diet feeding significantly promoted cardiac hypertrophy as well as cardiac inflammation and fibrosis induced by 3-week angiotensin ІІ (AngІІ) infusion (1000 ng/kg/min), while folic acid (0.006% wt/wt) supplement corrected HHcy and attenuated AngII-stimulated cardiac phenotypes. Mechanistic studies further showed that homocysteine (Hcy) exacerbated AngII-stimulated expression of Calcineurin and nuclear factor of activated T cells (NFAT), which could be attenuated by folic acid both in mice and in neonatal rat cardiomyocytes. Moreover, treatment with cyclosporin A, an inhibitor of Calcineurin, blocked Hcy-stimulated Calcineurin-NFAT signaling and hypertrophy in neonatal rat cardiomyocytes. In conclusion, our study indicates that HHcy promotes cardiac hypertrophy in hypertension, and Calcineurin-NFAT pathway might be involved in the pro-hypertrophic effect of Hcy.

The use of minimal fluoroscopy for cardiac electrophysiology procedures: A meta-analysis and review of the literature.

BACKGROUND: Conventional catheter ablation involves prolonged exposure to ionizing radiation, potentially leading to detrimental health effects. Minimal fluoroscopy (MF) represents a safer alternative, which should be explored. Data on the safety and efficacy of this technique are limited. HYPOTHESIS: Our hypothesis is that MF is of equal efficacy and safety to conventional catheter ablation with the use of fluoroscopy by performing a meta-analysis of both randomized controlled trials (RCTs) and real-world registry studies. METHODS: Pubmed and Embase were searched from their inception to July 2020 for RCTs, cohort and observational studies that assessed the outcomes of catheter ablation using a MF technique versus the conventional approach. RESULTS: Fifteen studies involving 3795 patients were included in this meta-analysis. There was a significant reduction in fluoroscopy and procedural time with no difference in acute success (odds ratio [OR]:0.74, 95% CI: 0.50-1.10, p = .14), long-term success (OR:0.92, 95% CI: 0.65-1.31, p = .38), arrhythmia recurrence (OR:1.24, 95% CI: 0.75-2.06, p = .97) or rate of complications. (OR:0.83, 95% CI: 0.46-1.48, p = .65). Additionally sub-group analysis for those undergoing catheter ablation for atrial fibrillation (AF) did not demonstrate a difference in success or complication rates (OR:0.86, 95% CI: 0.30-2.42, p = .77). Multivariate meta-regression did not identify the presence of moderator variables. CONCLUSION: This updated meta-analysis demonstrated an overall reduction in procedural and fluoroscopy time for those undergoing a minimal fluoroscopic approach. There was no significant difference in either acute or chronic success rates or complications between a MF approach and conventional approach for the management of all arrhythmias including those undergoing catheter ablation for AF.

Appropriate intraprocedural initial heparin dosing in patients undergoing catheter ablation for atrial fibrillation receiving uninterrupted non-vitamin-K antagonist oral anticoagulant treatment.

BACKGROUND: To clarify the appropriate initial dosage of heparin during radiofrequency catheter ablation (RFCA) in patients with atrial fibrillation (AF) receiving uninterrupted nonvitamin K antagonist oral anticoagulant (NOAC) treatment. METHODS: A total of 187 consecutive AF patients who underwent their first RFCA in our center were included. In the warfarin group (WG), an initial heparin dose of 100 U/kg was administered (control group: n = 38). The patients who were on NOACs were randomly divided into 3 NOAC groups (NG: n = 149), NG110, NG120, and NG130, and were administered initial heparin doses of 110 U/kg, 120 U/kg, and 130 U/kg, respectively. During RFCA, the activated clotting time (ACT) was measured every 15 min, and the target ACT was maintained at 250-350 s by intermittent heparin infusion. The baseline ACT and ACTs at each 15-min interval, the average percentage of measurements at the target ACT, and the incidence of periprocedural bleeding and thromboembolic complications were recorded and analyzed. RESULTS: There was no significant difference in sex, age, weight, or baseline ACT among the four groups. The 15 min-ACT, 30 min-ACT, and 45 min-ACT were significantly longer in the WG than in NG110 and NG120. However, no significant difference in 60 min-ACT or 75 min-ACT was detected. The average percentages of measurements at the target ACT in NG120 (82.2 ± 23.6%) and NG130 (84.8 ± 23.7%) were remarkably higher than those in the WG (63.4 ± 36.2%, p = 0.007, 0.003, respectively). These differences were independent of the type of NOAC. The proportion of ACTs in 300-350 s in NG130 was higher than in WG (32.4 ± 31.8 vs. 34.7 ± 30.6, p = 0.735). Severe periprocedural thromboembolic and bleeding complications were not observed. CONCLUSIONS: For patients with AF receiving uninterrupted NOAC treatment who underwent RFCA, an initial heparin dosage of 120 U/kg or 130 U/kg can provide an adequate intraprocedural anticoagulant effect, and 130 U/kg allowed ACT to reach the target earlier. TRIAL REGISTRATION: Registration number: ChiCTR1800016491, First Registration Date: 04/06/2018 (Chinese Clinical Trial Registry http://www.chictr.org.cn/index.aspx ).

Mobile health technology-supported atrial fibrillation screening and integrated care: A report from the mAFA-II trial Long-term Extension Cohort.

BACKGROUND: In the mobile Atrial Fibrillation App (mAFA)-II trial, the use of mobile health (mHealth) technology, incorporating AF screening and integrated management strategy, was associated with improved short-term clinical outcomes. The aim of this study was to report adherence/persistence and long term (≥1 year) clinical outcomes of the mAFA-II trial, with mHealth-supported optimised stroke prevention, symptom control and comorbidity management. METHODS: We studied an adult population screened for AF, where identified patients could enter a structured program of holistic and integrated care based on the ABC (Atrial fibrillation Better Care) pathway using mHealth with a mAFA intervention. In this cluster randomised trial, comparing mHeath intervention to usual care, the primary composite outcome was 'stroke/thromboembolism, all-cause death and rehospitalization'. RESULTS: The 1261 subjects (mean age 67.0 years, 38.0% female) who were followed up over one year (mean follow-up 687 (standard deviation, SD 191) days) in the intervention arm, had a lower risk of the composite outcome of 'ischaemic stroke/systemic thromboembolism, death, and rehospitalization' (hazard ratio, HR 0.18, 95% confidence interval, CI: 0.13-0.25, P < 0.001), compared to usual care (1212 subjects, mean age 70.1 years, 42.1% female). Of 842 patients using their smart devices for 'Better symptom management', 70.8% had good management adherence (monitoring time/follow-up since initial monitoring ≥ 70%), with the persistence of use of 91.7%. CONCLUSION: Amongst AF patients with long term use (≥1 year) of mHealth technology for optimising stroke prevention, symptom control and comorbidity management, adherence/persistence was good and associated with a reduction in adverse clinical outcomes.

Mobile Health Technology to Improve Care for Patients With Atrial Fibrillation.

BACKGROUND: Current management of patients with atrial fibrillation (AF) is limited by low detection of AF, non-adherence to guidelines, and lack of consideration of patients' preferences, thus highlighting the need for a more holistic and integrated approach to AF management. OBJECTIVE: The objective of this study was to determine whether a mobile health (mHealth) technology-supported AF integrated management strategy would reduce AF-related adverse events, compared with usual care. METHODS: This is a cluster randomized trial of patients with AF older than 18 years of age who were enrolled in 40 cities in China. Recruitment began on June 1, 2018 and follow-up ended on August 16, 2019. Patients with AF were randomized to receive usual care, or integrated care based on a mobile AF Application (mAFA) incorporating the ABC (Atrial Fibrillation Better Care) Pathway: A, Avoid stroke; B, Better symptom management; and C, Cardiovascular and other comorbidity risk reduction. The primary composite outcome was a composite of stroke/thromboembolism, all-cause death, and rehospitalization. Rehospitalization alone was a secondary outcome. Cardiovascular events were assessed using Cox proportional hazard modeling after adjusting for baseline risk. RESULTS: There were 1,646 patients allocated to mAFA intervention (mean age, 67.0 years; 38.0% female) with mean follow-up of 262 days, whereas 1,678 patients were allocated to usual care (mean age, 70.0 years; 38.0% female) with mean follow-up of 291 days. Rates of the composite outcome of 'ischemic stroke/systemic thromboembolism, death, and rehospitalization' were lower with the mAFA intervention compared with usual care (1.9% vs. 6.0%; hazard ratio [HR]: 0.39; 95% confidence interval [CI]: 0.22 to 0.67; p < 0.001). Rates of rehospitalization were lower with the mAFA intervention (1.2% vs. 4.5%; HR: 0.32; 95% CI: 0.17 to 0.60; p < 0.001). Subgroup analyses by sex, age, AF type, risk score, and comorbidities demonstrated consistently lower HRs for the composite outcome for patients receiving the mAFA intervention compared with usual care (all p < 0.05). CONCLUSIONS: An integrated care approach to holistic AF care, supported by mHealth technology, reduces the risks of rehospitalization and clinical adverse events. (Mobile Health [mHealth] technology integrating atrial fibrillation screening and ABC management approach trial; ChiCTR-OOC-17014138).

l-arginine alleviates doxorubicin-induced endothelium-dependent dysfunction by promoting nitric oxide generation and inhibiting apoptosis.

BACKGROUND/AIMS: Patients with doxorubicin (Dox) treatment have a high risk of developing vascular toxicity with an unknown mechanism. l-arginine is a substrate for nitric oxide (NO). The decreased level of arginine-NO metabolite in Dox-treated cancer patients was associated with increased level of vascular damage, which promoted us to investigate the mechanism of Dox-induced vascular dysfunction and verify whether l-arginine supplement could alleviate this vasculotoxic effect. METHOD: Within a mouse model of Dox injection (5 mg/kg i.p., 2 or 4 weeks), we measured vascular relaxation, blood pressure, vascular NO generation, apoptosis, and oxidative stress. We tested the efficacy of l-arginine (1.5 mg/g/day, 4 weeks) on Dox-induced vascular relaxation, blood pressure, vascular NO generation, apoptosis, as well as oxidative stress. RESULTS: Dox induced endothelium-dependent vascular dysfunction, which was associated with increased reactive oxidative stress (ROS) production and reduced NO generation in the vessel. ROS was required for Dox-induced apoptosis of both smooth muscle cells and endothelial cells. Dox treatment in mice increased blood pressure, but had no effect on vascular inflammation and fibrosis. L-aringine restored Dox-induced vascular dysfunction via enhancing vascular NO production and alleviating ROS-mediated apoptosis. CONCLUSION: We for the first time demonstrated l-arginine was effectively in suppressing Dox-induced vascular dysfunction, by attenuating vascular NO release and apoptosis. Our results provide a therapeutic target or a circulating marker for assessing vascular dysfunction which response to Dox treatment, and advance our understanding of the mechanisms of Dox-induced vascular dysfunction.

Electrocardiographic conduction and repolarization markers associated with sudden cardiac death: moving along the electrocardiography waveform.

The QT interval along with its heart rate corrected form (QTc) are well-established ECG markers that have been found to be associated with malignant ventricular arrhythmogenesis. However, extensive preclinical and clinical investigations over the years have allowed for novel clinical ECG markers to be generated as predictors of arrhythmogenesis and sudden cardiac death. Repolarization markers include the older QTc, QT dispersion and newer Tpeak - Tend intervals, (Tpeak - Tend) / QT ratios, T-wave alternans (TWA), microvolt TWA and T-wave area dispersion. Meanwhile, conduction markers dissecting the QRS complex, such as QRS dispersion (QRSD) and fragmented QRS, were also found to correlate conduction velocity and unidirectional block with re-entrant substrates in various cardiac conditions. Both repolarization and conduction parameters can be combined into the excitation wavelength (λ). A surrogate marker for λ is the index of Cardiac Electrophysiological Balance (iCEB: QT / QRSd). Other markers based on conduction-repolarization are [QRSD x (Tpeak-Tend) / QRSd] and [QRSD x (Tpeak-Tend) / (QRSd x QT)]. Advancement in technology permitted sophisticated electrophysiological analyses such as principal component analysis and periodic repolarization dynamics to further improve risk stratification. This was closely followed by other novel indices including ventricular ectopic QRS interval, the f99 index and EntropyXQT, which integrates mathematical and physical calculations for determining the risk markers. Though proven to be effective in limited patient cohorts, more clinical studies across different cardiac pathologies are required to confirm their validity. As such, this review seeks to encapsulate the development of old and new ECG markers along with their associated utility and shortcomings in clinical practice.

A New Formula for Estimating the True QT Interval in Left Bundle Branch Block.

INTRODUCTION: QT prolongation is an independent risk factor for cardiac mortality. Left bundle branch block (LBBB) is more common in patients as they age. Widening of the QRS in LBBB causes false QT prolongation and thus makes true QT assessment difficult. We aimed to develop a simple formula to achieve a good estimate of the QT interval in the presence of LBBB. METHODS AND RESULTS: To determine the effect of QRS duration on the QT interval, QRS and QT were measured in sinus rhythm and during right ventricular apical pacing in 62 patients (age 55 ± 11 years, 60% male) undergoing electrophysiology studies. A QT formula for LBBB (QT-LBBB) was derived based on the effect of increased QRSLBBB on QTLBBB . The predictive accuracy of the QT-LBBB formula was then tested in 22 patients (age 66 ± 13 years, 64% male) with intermittent LBBB with comparisons to prior QT formulae and JT index. On average, the net increase in QRSLBBB constituted 92% of the net increase in QTLBBB . A new formula, QT-LBBB = QTLBBB - (0.86 * QRSLBBB - 71), which takes the net increase in QRSLBBB into account, best predicted the QT interval with heart rate corrected QTc in the test set of LBBB ECGs when compared to the baseline value and prior formulae. CONCLUSION: The QT-LBBB formula developed in this study best estimates the true QT interval in the presence of LBBB. It is simple and therefore can be easily utilized in clinical practice.

Frequency Gradient Within Coronary Sinus Predicts the Long-Term Outcome of Persistent Atrial Fibrillation Catheter Ablation.

BACKGROUND: The coronary sinus (CS), as a junction of the atria, contributes to atrial fibrillation (AF) by developing unstable reentry, and isolating the atria by ablation at the CS could terminate AF. The present study evaluated whether AF activities at the CS in a subset of patients contributed to AF maintenance and predicted clinical outcome of ablation. METHODS AND RESULTS: We studied 122 consecutive patients who had a first-time radiofrequency ablation for persistent AF. Bipolar electrograms were obtained from multiple regions of the left atrium by a Lasso mapping catheter before ablation. Pulmonary vein isolation terminated AF in 12 patients (9.8%). Sequential stepwise ablation was conducted in pulmonary vein isolation nontermination patients and succeeded in 22 patients (18%). In the stepwise termination group, AF frequency in the proximal CS (CSp) was significantly higher (10.2±2.1 Hz versus 8.3±1.8 Hz, P<0.001), and the ratio of distal CS (CSd) to proximal CS (CSd/CSp ratio, 56.6%±10.11% versus 70.7%±9.8%, P<0.001) was significantly lower than that in the nontermination group. The stepwise logistic regression analysis indicated that the CSd/CSp ratio was an independent predictor with an odds ratio of 1.131 (95%CI 1.053-1.214; P=0.001). With a cutoff of 67%, the patients with lower CSd/CSp ratios had significantly better index and long-term outcomes than those with higher ratios during a follow-up of 46±18 months. CONCLUSIONS: Rapid repetitive activities in the musculature of the proximal CS may contribute to maintenance of AF after pulmonary vein isolation alone in persistent AF. A cutoff at 67%, of the CSd/CSp frequency ratio might be an indicator to stratify the subset of patients who might benefit from CS ablation.

Atrial average conduction velocity in patients with and without paroxysmal atrial fibrillation.

OBJECTIVES: To evaluate intra-atrial conduction delay in patients with atrial fibrillation (AF) via calculation of conduction velocities (CVs) of the right and left atria. METHODS: Electroanatomic mapping was performed during sinus rhythm, in the right atrium (RA) in eight patients with paroxysmal AF, in 12 controls with atrioventricular nodal re-entrant tachycardia (AVNRT) and in the left atrium (LA) in additional 16 AF patients. Three-dimensional maps of activation sequences of the RA and LA were obtained. Local CVs were specifically calculated in the direction of wave-front propagation on the activation maps by using 3-dimensional coordinates and local activation times of triads of sites. Average CVs of each atrium and each of 8 predefined RA and LA regions were calculated. RESULTS: During sinus rhythm, the average CVs of the RA were significantly slower (P<0·05) in the AF group (0·60 ± 0·12 m s-1 ) than in the controls (0·83 ± 0·13 m s-1 ). The average CVs of the RA basal, septal and annulus regions were significantly slower than the corresponding regions in controls (P<0·05). In patients with AF, the average CV of the LA was 0·51 ± 0·11 m s-1 , which is significantly slower than that of the RA and than that of LA as previously reported (P<0·05). CONCLUSION: Compared to patients with AVNRT, patients with AF are associated with conduction delay in both atria with the delay being more marked in the LA than in the RA, which suggests the involvement of conduction disturbances in the genesis and/or perpetuation of AF.

Branched Chain Amino Acids Cause Liver Injury in Obese/Diabetic Mice by Promoting Adipocyte Lipolysis and Inhibiting Hepatic Autophagy.

The Western meat-rich diet is both high in protein and fat. Although the hazardous effect of a high fat diet (HFD) upon liver structure and function is well recognized, whether the co-presence of high protein intake contributes to, or protects against, HF-induced hepatic injury remains unclear. Increased intake of branched chain amino acids (BCAA, essential amino acids compromising 20% of total protein intake) reduces body weight. However, elevated circulating BCAA is associated with non-alcoholic fatty liver disease and injury. The mechanisms responsible for this quandary remain unknown; the role of BCAA in HF-induced liver injury is unclear. Utilizing HFD or HFD+BCAA models, we demonstrated BCAA supplementation attenuated HFD-induced weight gain, decreased fat mass, activated mammalian target of rapamycin (mTOR), inhibited hepatic lipogenic enzymes, and reduced hepatic triglyceride content. However, BCAA caused significant hepatic damage in HFD mice, evidenced by exacerbated hepatic oxidative stress, increased hepatic apoptosis, and elevated circulation hepatic enzymes. Compared to solely HFD-fed animals, plasma levels of free fatty acids (FFA) in the HFD+BCAA group are significantly further increased, due largely to AMPKα2-mediated adipocyte lipolysis. Lipolysis inhibition normalized plasma FFA levels, and improved insulin sensitivity. Surprisingly, blocking lipolysis failed to abolish BCAA-induced liver injury. Mechanistically, hepatic mTOR activation by BCAA inhibited lipid-induced hepatic autophagy, increased hepatic apoptosis, blocked hepatic FFA/triglyceride conversion, and increased hepatocyte susceptibility to FFA-mediated lipotoxicity. These data demonstrated that BCAA reduces HFD-induced body weight, at the expense of abnormal lipolysis and hyperlipidemia, causing hepatic lipotoxicity. Furthermore, BCAA directly exacerbate hepatic lipotoxicity by reducing lipogenesis and inhibiting autophagy in the hepatocyte.

The early stage of the atrial electroanatomic remodeling as substrates for atrial fibrillation in hypertensive patients.

BACKGROUND: Hypertension is one of the most important risk factors for atrial fibrillation (AF). Recent studies suggest right atrial remodeling in hypertensive patients may be associated with increased inducibility of AF. This study sought to characterize the electroanatomic features of left and right atria and pulmonary veins (PVs) in hypertensive patients. METHODS AND RESULTS: A prospective observational study was conducted on patients who underwent ablation for paroxysmal supraventricular tachycardia or paroxysmal AF. Electrophysiological features of the PVs and atria, including event-related potentials, conduction time, and inducibility and vulnerability of AF, were characterized during cardiac catheterization. Anatomic and hemodynamic features were assessed by using echocardiographic and computer tomography imaging. When 15 hypertensive patients with paroxysmal supraventricular tachycardia were compared with 17 normotensive patients with paroxysmal supraventricular tachycardia, the hypertensive patients had significantly shortened PV event-related potentials with increased dispersions (P<0.001) but slightly prolonged atrial event-related potentials (P=NS) and had prolonged interatrial and intra-atrial conduction times (P<0.001). Additionally, the hypertensive patients had increased vulnerability and inducibility of AF and prolonged duration of induced AF (P<0.01). All of these changes were more pronounced in hypertensive patients with paroxysmal AF. Anatomically, compared with the normotensive patients, the diameters of 4 PVs in the hypertensive patients with paroxysmal supraventricular tachycardia were significantly enlarged (P<0.01) and became more remarkable in hypertensive patients with paroxysmal AF (P<0.0001), although the diameter and volume index of the left atrium among 3 groups were similar. CONCLUSIONS: The hypertensive patients showed electroanatomic changes associated with increased vulnerability to AF, including shortened event-related potentials with increased dispersion, prolonged conduction time, and increased PV diameter, but these changes were not appreciated in the atria. Additionally, these changes became more dramatic in hypertensive patients with paroxysmal AF.

Substrate of complex fractionated atrial electrograms: evidence by pathologic analysis.

BACKGROUND: Ablation of complex fractionated atrial electrograms (CFAE) is an important adjunctive therapy in atrial fibrillation (AF). The present study was to elucidate the substrate underlying CFAE. METHODS: Nine adult mongrel dogs were involved in the present study. AF was induced through rapid atrial pacing with vagosympathetic nerve stimulation. CFAE was recorded during AF. Ablation was performed at CFAE sites. Based on the location of the ablation scar, the atrial specimens were divided into CFAE and non-CFAE sites. Serial sections of the atrium were stained respectively with hematoxylin-eosin (HE) and the general neural marker protein gene product 9.5 (PGP9.5). We compared the characteristics of the myocardium and the ganglionated plexus (GPs) distribution between the CFAE and non-CFAE sites. RESULTS: The myocardium of non-CFAE sites was well-organized with little intercellular substance. However, the myocardium in the CFAE site was disorganized with more interstitial tissue ((61.7 ± 24.3)% vs. (34.1 ± 9.2)%, P < 0.01). GPs in the CFAE site were more abundant than in non-CFAE sites ((34.45 ± 37.46) bundles/cm(2) vs. (6.73 ± 8.22) bundles/cm(2), P < 0.01). CONCLUSION: The heterogeneity of the myocardium and GPs distribution may account for the substrate of CFAE and serve as a potential target of ablation.

Effect of ablation of complex fractionated atrial electrogram on vagal modulation in dogs.

BACKGROUND: Clinical observations have shown that the complex fractionated atrial electrogram (CFAE) associates with ganglionated plexus activity in the cardiac autonomic nervous system. This study aimed to investigate the impact of CFAE ablation on vagal modulation to atria and vulnerability to develop atrial fibrillation (AF). METHODS: Ten adult mongrel dogs were involved. Cervical sympathovagal trunks were decentralized and sympathetic effects were blocked. CFAE was color tagged on the atrial 3-dimensional image and ablated during AF induced by S1S2 programmed stimulation plus sympathovagal trunk stimulation. Atrial effective refractory period (ERP) and vulnerability window (VW) of AF were measured on baseline and at vagal stimulation at 4 atrium sites. Serial tissue sections from ablative and control specimens received hematoxylin and eosin staining for microscopic examination. RESULTS: Most CFAE areas were localized at the right superior pulmonary quadrant, distal coronary sinus (CS(d)) quadrant, and proximal coronary sinus (CS(p)) quadrant (21.74%, separately). Sinus rhythm cycle length (SCL) shortening did not decrease significantly after ablation at the sites, including right atrial appendage, left atrial appendage, CS(d), and CS(p) (P > 0.05). ERP shortening during vagal stimulation significantly decreased after ablation (P < 0.01); the VW to vagal stimulation significantly decreased after ablation (P < 0.05). The architecture of individual ganglia altered after ablation. CONCLUSIONS: CFAE has an autonomic basis in dogs. The decreased SCL and ERP shortening to vagal stimulation after CFAE ablation demonstrate that CFAE ablation attenuates vagal modulation to the atria, thereby suppressing AF mediated by enhanced vagal activity. CFAE ablation could suppress AF mediated by enhanced vagal activity.

Interatrial conduction can be accurately determined using standard 12-lead electrocardiography: validation of P-wave morphology using electroanatomic mapping in man.

BACKGROUND: Different P-wave morphologies during sinus rhythm as displayed on standard ECGs have been postulated to correspond to differences in interatrial conduction. OBJECTIVE: The purpose of this study was to evaluate the hypothesis by comparing P-wave morphologies using left atrial activation maps. METHODS: Twenty-eight patients (mean age 49 +/- 9 years) admitted for ablation of paroxysmal atrial fibrillation were studied. Electroanatomic mapping of left atrial activation was performed at baseline during sinus rhythm with simultaneous recording of standard 12-lead ECG. Unfiltered signal-averaged P waves were analyzed to determine orthogonal P-wave morphology. The morphology was subsequently classified into one of three predefined types. All analyses were blinded. RESULTS: The primary left atrial breakthrough site was the fossa ovalis in 8 patients, Bachmann bundle in 18, and coronary sinus in 2. Type 1 P-wave morphology was observed in 9 patients, type 2 in 17, and type 3 in 2. Seven of eight patients with fossa ovalis breakthrough had type 1 P-wave morphology, 16 of 18 patients with Bachmann bundle breakthrough had type 2 morphology, and both patients with coronary sinus breakthrough had type 3 P-wave morphology. Overall, P-wave morphology criteria correctly identified the site of left atrial breakthrough in 25 (89%) of 28 patients. CONCLUSION: In the vast majority of patients, P-wave morphology derived from standard 12-lead ECG can be used to correctly identify the left atrial breakthrough site and the corresponding route of interatrial conduction.

Focal atrial tachycardia originating from the non-coronary aortic sinus: electrophysiological characteristics and catheter ablation.

OBJECTIVES: We sought to investigate electrophysiological characteristics and catheter ablation in patients with focal atrial tachycardia (AT) originating from the non-coronary aortic sinus (AS). BACKGROUND: In patients with failed ablation of focal AT near the His bundle (HB) region, an origin from the non-coronary AS should be considered because of the close anatomical relationship. METHODS: This study included 9 patients with focal AT, in 6 of whom attempted radiofrequency (RF) ablation had previously failed. Activation mapping was performed during tachycardia to identify an earliest activation in the atria and the AS. The aortic root angiography was performed to identify the origin in the AS before RF ablation. RESULTS: Focal AT was reproducibly induced by atrial pacing. Mapping in atria demonstrated that the earliest atrial activation was located at the HB region, whereas mapping in the non-coronary AS demonstrated that an earliest atrial activation preceded the atrial activation at the HB by 12.2 +/- 6.9 ms and was anatomically located superoposterior to the HB in all 9 patients. Also, His potentials were not found at the successful site in the non-coronary AS in all 9 patients. The focal AT was terminated in <8 s in all 9 patients. Junctional beats and PR prolongation did not occur during RF application in all 9 patients. No complications occurred in any of the nine patients. All 9 patients were free of arrhythmias without antiarrhythmic drugs during a follow-up of 9 +/- 3 months. CONCLUSIONS: In patients with focal AT near the HB region, mapping in the non-coronary AS can improve clinical outcome.