Comparison of novel intrinsic versus conventional antitachycardia pacing for ventricular tachycardia among implantable cardioverter-defibrillator recipients.

INTRODUCTION: Intrinsic antitachycardia pacing (iATP) is a novel automated antitachycardia pacing (ATP) that provides individual treatment to terminate ventricular tachycardia (VT). However, the clinical efficacy of iATP in comparison with conventional ATP is unknown. We aim to compare the termination rate of VT between iATP and conventional ATP in patients with implantable cardioverter-defibrillators using a unique setting of different sequential orders of both ATP algorisms. METHODS: Patients with the iATP algorithm were assigned to iATP-first and conventional ATP-first groups sequentially. In the iATP-first group, a maximum of seven iATP sequences were delivered, followed by conventional burst and ramp pacing. In contrast, in the conventional ATP-first group, two bursts and ramp pacing were initially programmed, followed by iATP sequences. We compared the success rates of VT termination in the first and secondary programmed ATP zones between the two groups. RESULTS: Fifty-eight and 56 patients were enrolled in the iATP-first and conventional ATP-first groups, and 67 and 44 VTs were analyzed in each group, respectively. At the first single ATP therapy, success rates were 64% and 70% in the iATP and conventional groups, respectively. At the end of the first iATP treatment zone, the success rate increased from 64% to 85%. Moreover, secondary iATP therapy following the failure of conventional ATPs increased the success rate from 80% to 93%. There was a significant benefit of alternative iATP for VT termination compared to secondary conventional ATP (100% vs. 33%, p = .028). CONCLUSIONS: iATP may be beneficial as a secondary therapy after failure of conventional ATP to terminate VT.

Prognostic impact of polypharmacy and discharge medications in octogenarians and nonagenarian patients with acute heart failure.

With the increasing frequency of heart failure (HF) in elderly patients, polypharmacy has become a major concern owing to its adverse outcomes. However, reports on the clinical impact of polypharmacy and discharge medications in hospitalized super-aged patients with acute HF are rare. Data from 682 patients aged 80 years or older, hospitalized for treating acute HF, were analyzed. We recorded the number of medications at discharge and classified them into three groups: HF, non-HF cardiovascular, and non-cardiovascular medications. We investigated the correlation of polypharmacy, defined as daily administration of 10 or more medications at discharge, and the use of discharge medications with post-discharge prognosis. Polypharmacy was recorded in 24.3% of enrolled patients. Polypharmacy was not an independent predictor of all-cause mortality, the incidence of cardiac-related death, or HF-associated rehospitalization; however, the number of non-cardiovascular medications, multiple usage of potentially inappropriate medications, use of mineralocorticoid receptor antagonists, and doses of loop diuretics were associated with poor prognosis. Polypharmacy was significantly associated with higher mortality in patients with Barthel index ≥ 60 at discharge; hence, physical function at discharge was useful for the stratification of prognostic impacts of polypharmacy. The current study demonstrated that polypharmacy was not essentially associated with poor prognosis in super-aged patients with acute HF. Appropriate medications that consider the patient's physical function, rather than polypharmacy itself, are important for the management of HF.

High-grade Endometrial Carcinoma With a Hepatoid Carcinoma-like Component.

Endometrial carcinoma with hepatoid differentiation is rare and <20 reported cases have been reported as endometrial hepatoid carcinoma (EHC). We present a case of EHC associated with serous carcinoma in a 76-yr-old Japanese woman. The hepatoid component showed trabecular, pseudoglandular, and diffuse proliferation of hepatoid cells. The hepatoid cells were positive for α-fetoprotein, Hep-Per-1, glypican 3, and HNF-1ß, weakly and focally positive for SALL4, and negative for PAX8. Both of the serous and hepatoid components showed overexpression of p53. The serum α-fetoprotein on postoperative day 5 was 3691 ng/mL. The postoperative course has remained uneventful for 4 yr. These findings suggested that EHC developed from serous carcinoma by acquiring hepatocytic features and losing Müllerian features. Both serous and hepatoid components showed p53 overexpression, suggesting they share a TP53 mutation as a common primary driver.

Therapeutic angiogenesis for patients with no-option critical limb ischemia by adipose-derived regenerative cells: TACT-ADRC multicenter trial.

BACKGROUND: Patients with critical limb ischemia (CLI) still have a high rate of lower limb amputation, which is associated with not only a decrease in quality of life but also poor life prognosis. Implantation of adipose-derived regenerative cells (ADRCs) has an angiogenic potential for patients with limb ischemia. OBJECTIVES: We investigated safety, feasibility, and efficacy of therapeutic angiogenesis by cell transplantation (TACT) of ADRCs for those patients in multicenter clinical trial in Japan. METHODS: The TACT-ADRC multicenter trial is a prospective, interventional, open-labeled study. Patients with CLI (Fontaine class III-IV) who have no other option for standard revascularization therapy were enrolled in this study. Thirty-four target ischemic limbs of 29 patients were received freshly isolated autologous ADRCs implantation. RESULTS: The overall survival rate at a post-operative period and at 6 months follow-up was 100% at any time points. As a primary endpoint for efficacy evaluation, 32 limbs out of 34 (94.1%) were free from major amputation for 6 months. Numerical rating scale (from 6 to 1) as QOL score, ulcer size (from 317 mm2 at to 109 mm2), and 6-min walking distance (from 255 to 369 m) improved in 90.6%, 83.3%, and 72.2% patients, respectively. CONCLUSIONS: Implantation of autologous ADRCs could be safe and effective for the achievement of therapeutic angiogenesis in the multicenter settings, as a result in no major adverse event, optimal survival rate, and limb salvage for patients with no-conventional option against critical limb ischemia. TRN: jRCTb040190118; Date: Nov. 24th, 2015.

Characteristics of successful reactive atrial-based antitachycardia pacing in patients with cardiac implantable electronic devices: History of catheter ablation of atrial fibrillation as a predictor of high treatment efficacy.

INTRODUCTION: Reactive atrial-based antitachycardia pacing (rATP) in patients with cardiac implantable electronic devices (CIEDs) suppresses the progression of atrial fibrillation (AF) to the persistent form. However, the clinical factors associated with successful reactive atrial-based antitachycardia pacing (rATP) treatment are unknown. This study aimed to examine the predictors of high rATP efficacy in patients with CIEDs. METHODS: The data of 101,325 rATP-treated atrial tachyarrhythmia (AT/AF) episodes in 51 patients, obtained through remote monitoring and device interrogation, were analyzed. The study population was divided into the high and low efficacy groups based on the overall median success rate of rATP. Clinical characteristics were compared between the two groups. RESULTS: During a follow-up period of 28.6 ± 8.6 months, the median success rate was 43.7% (31.5%-64.9%). The prevalence of a history of catheter ablation of AF was significantly higher in the high efficacy group than in the low efficacy group (73.0% vs. 44.0%, p = .048) and was the only independent predictor of high rATP efficacy (odds ratio, 3.45; p = .038). The rATP success rate in patients with (n = 30) and without (n = 21) a history of catheter ablation was 53.9% (40.0%-67.5%) and 36.4% (22.2%-47.7%), respectively (p = .012). The effect of rATP after ablation was more pronounced in patients with long cycle length episodes (≥75% of AT/AF sequences having a cycle length of 200-449 ms) (67.3% [46.0%-73.6%] vs. 30.6% [18.1%-60.3%], p = .027). The high efficacy group had a significantly lower incidence of AT/AF lasting ≥1, ≥7, and ≥30 days than the low efficacy group. CONCLUSION: rATP combined with catheter ablation therapy is effective in suppressing AT/AF.

Efficacy and feasibility of cryoballoon ablation for atrial fibrillation in patients with heart failure: A large-scale multicenter study.

INTRODUCTION: Data are limited regarding outcomes of cryoballoon ablation for atrial fibrillation (AF) in patients with heart failure (HF). This large-scale multicenter study aimed to evaluate the prognosis of patients with HF after cryoballoon ablation for AF. METHODS: Among 3655 patients undergoing cryoballoon ablation at 17 institutions, 549 patients (15%) (391 with paroxysmal AF and 158 with persistent AF) diagnosed with HF preoperatively were analyzed. Clinical endpoints were recurrence, mortality, and HF hospitalization after ablation. RESULTS: Most patients had a preserved left ventricular ejection fraction (LVEF) ≥ 50%. During a mean follow-up period of 25.7 months, recurrence, all-cause death, and HF hospitalization occurred in 29%, 4.0%, and 4.8%, respectively. Cardiac function on echocardiography and B-type natriuretic peptide (BNP) levels significantly improved postoperatively, and the effect was more pronounced in the nonrecurrence group. Major complications occurred in 33 patients (6.0%), but most complications were phrenic nerve palsy (3.6%). Although death and HF hospitalization occurred more frequently in patients with LVEF ≤ 40% (n = 73) and New York Heart Association (NYHA) class III-IV (n = 19) than other subgroups, the BNP levels, and LVEF significantly improved after ablation in all LVEF and NYHA class subgroups. High BNP levels, NHYA class, CHADS2 score, and structural heart disease, but not postablation recurrence, independently predicted death, and HF hospitalization on multivariate analysis. The patients with tachycardia-induced cardiomyopathy had better recovery of BNP levels and LVEF after ablation than those with structural heart disease. CONCLUSIONS: Cryoballoon ablation for AF in HF patients is feasible and leads to significantly improved cardiac function.

Important Role of Concomitant Lymphangiogenesis for Reparative Angiogenesis in Hindlimb Ischemia.

[Figure: see text].

Identification of high priority focal activations in persistent atrial fibrillation using a novel mapping strategy.

Focal activation is believed to be an atrial fibrillation (AF) driver; however, little is known about whether all focal activations are necessary for AF persistence. The purpose of this study was to assess the electrical nature of focal activation and identify high-priority focal activations using a novel mapping system (CARTOFINDER). Thirty-five patients with persistent AF who underwent catheter ablation were assessed. Cycle length (CL) and CL standard deviation (CLSD) on unipolar recordings and voltage amplitude and electrogram morphologies on bipolar recordings were evaluated at all points of interest. The most frequent CL at each mapping site was defined as the dominant CL. We identified dominant focal activations (DFAs) that had a shorter dominant CL on the integrated CARTOFINDER map. The effect of elimination of DFAs on AF maintenance was assessed by the composite endpoint (termination to sinus rhythm, organization of the rhythm to atrial tachycardia, and AF CL slowing). In all, 450 focal activations were identified among 10,868 points, and 50.4% of focal activations were DFAs. Focal activations showed relatively long CL and regularity with short CLSD. Most focal activations showed an isoelectric baseline and were located outside of the fractionated electrogram area. Both DFAs and non-DFAs were typically observed in the normal voltage range. Elimination of DFAs was achieved in 19 (54.3%) patients, with a remarkable impact on AF maintenance (68.4% vs. 25.0%, p = 0.018). In conclusion, DFAs may play an important role in AF maintenance and could be an attractive therapeutic target for AF.

Depolarization and repolarization dynamics after His-bundle pacing: Comparison with right ventricular pacing and native ventricular conduction.

BACKGROUND: The current study aimed to evaluate changes in electrical depolarization and repolarization parameters after His-bundle pacing (HBP) compared with right ventricular pacing (RVP) and its association with ventricular arrhythmia (VA). METHODS: Forty-one patients (13 with HBP, 14 with RVP, and 14 controls [AAI mode]) were evaluated. After continuous pacing algorithm, QRS duration, QT interval, QTc, JT interval, T-peak to T-end (Tpe), and Tpe/QT ratio were measured on electrocardiography at baseline and 1 week, 1 month, and 6 months postoperatively. We investigated VA occurrence and adverse events after implantation. RESULTS: At 6 months, QRS duration was significantly shorter in the HBP (121.6 ± 15.6 ms) than in the RVP (150.1 ± 14.9 ms) group. The QT intervals were lower in the HBP (424.0 ± 40.9 ms) and control (405.9 ± 23.0 ms) groups than in the RVP (453.0 ± 40.2 ms) group. The Tpe and Tpe/QT ratios at 6 months differed significantly between the HBP and RVP groups (Tpe, 69.8 ± 19.7 ms vs 87.4 ± 11.9 ms and Tpe/QT, 0.16 ± 0.03 vs 0.19 ± 0.02, respectively). The Tpe and Tpe/QT ratios were similarly shortened in the HBP and control groups. VA occurred less frequently in the HBP (15%) and control (7.1%) groups than in the RVP (50%) group (p = 0.020). The non-RVP group showed significantly lower rates of VA and major adverse events than the RVP group. Patients with VA demonstrated significantly longer QRS duration, QT interval, Tpe, and Tpe/QT at 6 months than those without VA. CONCLUSION: HBP showed better depolarization and repolarization stability than RVP.

A Comparative Study of Three Nutritional Risk/Screening Indices for Predicting Cardiac Events and Physical Functioning Among Patients with Acute Heart Failure.

Undernutrition is very common among patients with heart failure (HF). This study evaluated the prognostic values of three nutritional risk/screening indices among patients with acute HF. We retrospectively calculated scores for 465 patients with acute HF using the Controlling Nutritional Status (CONUT) tool, the Geriatric Nutritional Risk Index (GNRI), and the Mini-Nutritional Assessment Short Form (MNA-SF). The outcomes of interest were the 1-year rate of cardiac events (cardiac-related death or HF-related readmission) and the Barthel index as an index of physical function during hospitalization. The CONUT, GNRI, and MNA-SF scores were significantly correlated, although the proportions of a normal nutritional state varied (CONUT: 18.3%, GNRI: 32.9%, and MNA-SF: 43.9%). Kaplan-Meier estimates revealed that cardiac events were more common among patients with undernutrition based on the CONUT score, and multivariable regression analysis revealed that only the CONUT score independently predicted poor outcomes. Furthermore, changes in the Barthel index during hospitalization were significantly correlated with the CONUT score but not with the GNRI and MNA-SF scores. In receiver operating characteristic analyses, the CONUT score had the most powerful predictive values on both the postdischarge incidence of cardiac events and the decline of physical function during hospitalization compared with the GNRI and the MNA-SF. These results indicate that the CONUT score might provide useful information for predicting poor outcomes in patients with acute HF.

Evaluation of the Novel Automated Anti-Tachycardia Pacing Algorithm Successfully Terminating Sustained Monomorphic Ventricular Tachycardia in an Electrophysiology Study.

We report the usefulness of novel automated anti-tachycardia pacing (ATP) for ventricular tachycardia (VT) termination evaluated in an electrophysiology study. This intrinsic, automated ATP with an implanted cardiac resynchronization therapy-defibrillator successfully terminated the sustained VT, which had not been suppressed by repetitive burst pacing from the electrode catheter. The reproduction of programed pacing of the automated ATP by a right ventricular electrode catheter was effective in terminating VT, and this termination was absolute and reproducible. Further detailed assessment in an electrophysiology study could highlight the algorithm of the automated ATP and its possible benefit in terminating the reentrant VT.

No influence on tumor growth by intramuscular injection of adipose-derived regenerative cells: safety evaluation of therapeutic angiogenesis with cell therapy.

Therapeutic angiogenesis with autologous stem/progenitor cells is a promising novel strategy for treatment of severe ischemic diseases. Human clinical trials utilizing autologous adipose-derived regenerative cells (ADRCs) have not reported treatment-related critical adverse effects thus far. However, there is still a large knowledge gap regarding whether treatment of ischemic diseases with angiogenic therapy using ADRCs would promote unfavorable angiogenesis associated with tumors in vivo. Herein, we addressed this clinical question using a mouse hindlimb ischemia (HLI) and simultaneous remote tumor implantation model. C57BL/6J background wild-type mice were injected with murine B16F10 melanoma cells on their back, 1 day before ischemic surgery. These mice were subjected to surgical unilateral hindlimb ischemia, followed by ADRC implantation or PBS injection into the hindlimb ischemic muscles on the next day. Intramuscular implantation of ADRCs enhanced tissue capillary density and blood flow examined by a laser Doppler blood perfusion analysis in hind limb. However, this therapeutic regimen for ischemic limb using ADRCs did not affect remote melanoma growth nor the density of its feeder artery, angiogenesis, and lymphatic vessels compared with the PBS group. In addition, no distant metastases were detected in any of the mice regardless of the group. In conclusion, local implantation of ADRCs promotes angiogenesis in response to tissue ischemia in the hindlimb without promoting remote tumor growth and related angio/lymphangiogenesis. Therapeutic angiogenesis to the ischemic hindlimb using ADRCs seems to be safe regarding remote tumor growth.NEW & NOTEWORTHY In this study, we demonstrated that local injection of ADRCs can promote angiogenesis in response to tissue ischemia without promoting remote tumor growth in a mouse model. Our findings indicate that therapeutic angiogenesis to the ischemic hindlimb using ADRCs seems to be safe regarding remote tumor growth.

Dynamic Changes in Electrocardiogram Parameters After Epicardial Substrate Catheter Ablation of Brugada Syndrome.

BACKGROUND: Catheter ablation (CA) is effective for recurrent episodes of ventricular fibrillation (VF) in Brugada syndrome (BrS). VF development in BrS is associated with several electrocardiogram (ECG) abnormalities. This study investigated changes in ECG parameters in high-risk BrS patients who underwent epicardial CA.Methods and Results:In all, 27 BrS patients were implanted with an implantable cardioverter-defibrillator (ICD). Patients were divided into 2 groups: (1) an ablation group (n=11) that underwent epicardial CA because of VF recurrence; and (2) a primary prevention (PP) group (n=16) with ICD implantation only. ECG parameters were evaluated before and 12 months after CA and compared with ECG parameters in the PP group. The T wave peak-to-end interval was significantly longer and the number of abnormal spikes in leads V1-V3 at the second, third, and fourth intercostal spaces was greater in the ablation than PP group. After ablation, ST levels and the sum of abnormal spikes in leads V1-V3 were significantly decreased. The mean (±SD) number of ICD shocks decreased markedly during a mean follow-up period of 42.0 months (from 3.8±3.7 to 0.2±0.4/year). Four patients had an ICD shock following the ablation procedure. Greater reductions in ST-segment elevation and abnormal spikes were observed in the group without than with VF recurrence. CONCLUSIONS: Improvements in surface ECG parameters appear to be associated with successful ablation in high-risk BrS patients.

The mechanism and prognosis of acute and late improvement in mitral regurgitation after cardiac resynchronization therapy.

Cardiac resynchronization therapy (CRT) improves functional mitral regurgitation (MR); however, the mechanism and differences in acute and late improvement in MR are unclear. We aimed to evaluate the factors associated with the acute and late MR improvements and the prognosis of MR improvement after CRT. This retrospective study included 121 patients who underwent CRT implantation with full echocardiography assessment at baseline, 1 week, and 6 months after implantation. MR severity was classified into five grades (0: none to 4: severe). Two-dimensional speckle-tracking echocardiography with radial strain was used to assess dyssynchrony, and the time difference between the lateral and inferior segments at papillary muscle levels (TDlate-inf) was calculated. The MR improved 1 week and 6 months after CRT in 40 (33%) and 45 (37%) patients, respectively. On multivariate analyses, TDlate-inf (baseline-1 week) and SPWMD were independently associated with acute MR improvement. The %reduction in left ventricular end-systolic volume (LVESV) (baseline-6 months) and TDlate-inf (baseline-1 week) were independently correlated with late MR improvement. The patients with pre-MR grades 2-4 and improved MR after CRT showed significantly better prognosis in heart failure hospitalization. Cutoff values of ≥ 19.5 ms of the reduction of TDlate-inf and ≥ 30.8% of the %reduction of LVESV were significantly associated with the decrease in heart failure hospitalization. The improved interpapillary muscle activation time delay and volume reduction after CRT were associated with acute and late MR improvements. There may be different time course of recovery and distinct causes for late MR improvement.

Early improvement of daily physical activity after catheter ablation for atrial fibrillation in an accelerometer assessment: A prospective pilot study.

BACKGROUND: Catheter ablation improves physical activity in patients with atrial fibrillation (AF). However, continuous daily evaluation and time course of improvement in physical activity after ablation have not been fully assessed. This prospective study was conducted to evaluate the daily physical activities and changes in the physical performance in patients undergoing catheter ablation for AF by continuous monitoring of a portable accelerometer. METHODS: Ten patients scheduled for catheter ablation for AF were fitted with a uniaxial accelerometer prior to and 6 months after the procedure. This study evaluated changes in daily steps, activity intensity, and activity duration. We also evaluated changes in activity intensity using a short version of the International Physical Activity Questionnaire (IPAQ). RESULTS: The maximum daily steps significantly increased from baseline to postablation (baseline, 9,232 [6,716-11,485]; after 1-3 months, 11,605 [8,285-14,802]; and after 4-6 months, 11,412 [8,939-13,808], p = .020). Similarly, Δ maximum-mean daily steps increased significantly (baseline, 2,431 [1,199-6,181]; after 1-3 months, 4,674 [4,164-6,474]; and after 4-6 months, 4,871 [3,657-6,117], p = .014). These improvements were more pronounced in patients with paroxysmal and symptomatic AF. The total IPAQ score significantly improved from baseline to after 6 months ablation (from 1,170 [693-3,930] to 4,312 [1,865-6,569], p = .037). All patients were recurrence-free from AF after ablation. CONCLUSIONS: The physical activity improved significantly even in the early phase following catheter ablation. The effect of suppressing AF on activity levels was apparent soon after the procedure.

A Case of Metastatic Fumarate Hydratase-Deficient-like Renal Cell Carcinoma Successfully Managed by Ipilimumab plus Nivolumab.

We report a 62-year-old male with metastatic fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) without fumarate hydratase (FH) mutation (FH-deficient-like RCC). The International Metastatic RCC Database Consortium risk score was intermediate, and immunotherapy with nivolumab and ipilimumab (Ipi/ Nivo) was initiated. Four cycles of Ipi/Nivo and 5 cycles of nivolumab resulted in a complete response of the metastases. Hypophysitis occurred as an immune-related adverse event after four cycles of Ipi/Nivo. The prognosis of patients with FH-deficient RCC is generally poor. Few reports of FH-deficient RCC successfully treated with Ipi/Nivo have been published. Ipi/Nivo can be effective for treating FH-deficient RCC.

Upregulated Expression of Activation-Induced Cytidine Deaminase in Ocular Adnexal Marginal Zone Lymphoma with IgG4-Positive Cells.

Immunoglobulin G4-related disease (IgG4-RD) is a systemic disorder characterized by tissue fibrosis and intense lymphoplasmacytic infiltration, causing progressive organ dysfunction. Activation-induced cytidine deaminase (AID), a deaminase normally expressed in activated B-cells in germinal centers, edits ribonucleotides to induce somatic hypermutation and class switching of immunoglobulin. While AID expression is strictly controlled under physiological conditions, chronic inflammation has been noted to induce its upregulation to propel oncogenesis. We examined AID expression in IgG4-related ophthalmic disease (IgG4-ROD; n = 16), marginal zone lymphoma with IgG4-positive cells (IgG4+ MZL; n = 11), and marginal zone lymphoma without IgG4-positive cells (IgG4- MZL; n = 12) of ocular adnexa using immunohistochemical staining. Immunohistochemistry revealed significantly higher AID-intensity index in IgG4-ROD and IgG4+ MZL than IgG4- MZL (p < 0.001 and = 0.001, respectively). The present results suggest that IgG4-RD has several specific causes of AID up-regulation in addition to inflammation, and AID may be a driver of oncogenesis in IgG4-ROD to IgG4+ MZL.

Utility of the Nutritional Screening in Predicting Adverse Outcome of Patients With Overweight/Obesity and Acute Heart Failure.

BACKGROUND: Undernutrition is a negative predictor of adverse outcomes in patients with heart failure (HF). Despite the survival advantage of elevated body mass index (BMI) in patients with HF, BMI does not necessarily reflect a favorable nutritional status. In the present study, we investigated the clinical impact of nutritional screening in patients with HF and overweight/obesity. METHODS: We examined the data from 170 patients with overweight or obesity status (defined as BMI ≥ 25 kg/m2) who admitted for acute HF. Their controlling nutritional status (CONUT) score was calculated on admission. The CONUT score is regarded as an index of the nutritional status. RESULTS: The median duration of follow-up was 1096 days (interquartile range, 805-1096 days). Undernutrition was identified in 66.5% of the patients. Kaplan-Meier survival analysis demonstrated that patients with undernutrition had a higher incidence of all-cause death and readmission due to HF than those without undernutrition. Multivariate Cox regression analysis revealed that the CONUT score, but not BMI and the geriatric nutritional risk index, was independently correlated with poor prognosis. CONCLUSIONS: Undernutrition is highly prevalent and independently predicts poor outcomes in patients with overweight/obesity and acute HF.

Myonectin Is an Exercise-Induced Myokine That Protects the Heart From Ischemia-Reperfusion Injury.

RATIONALE: Physical exercise provides benefits for various organ systems, and some of systemic effects of exercise are mediated through modulation of muscle-derived secreted factors, also known as myokines. Myonectin/C1q (complement component 1q)/TNF (tumor necrosis factor)-related protein 15/erythroferrone is a myokine that is upregulated in skeletal muscle and blood by exercise. OBJECTIVE: We investigated the role of myonectin in myocardial ischemic injury. METHODS AND RESULTS: Ischemia-reperfusion in myonectin-knockout mice led to enhancement of myocardial infarct size, cardiac dysfunction, apoptosis, and proinflammatory gene expression compared with wild-type mice. Conversely, transgenic overexpression of myonectin in skeletal muscle reduced myocardial damage after ischemia-reperfusion. Treadmill exercise increased circulating myonectin levels in wild-type mice, and it reduced infarct size after ischemia-reperfusion in wild-type mice, but not in myonectin-knockout mice. Treatment of cultured cardiomyocytes with myonectin protein attenuated hypoxia/reoxygenation-induced apoptosis via S1P (sphingosine-1-phosphate)-dependent activation of cAMP/Akt cascades. Similarly, myonectin suppressed inflammatory response to lipopolysaccharide in cultured macrophages through the S1P/cAMP/Akt-dependent signaling pathway. Moreover, blockade of S1P-dependent pathway reversed myonectin-mediated reduction of myocardial infarct size in mice after ischemia-reperfusion. CONCLUSIONS: These data indicate that myonectin functions as an endurance exercise-induced myokine which ameliorates acute myocardial ischemic injury by suppressing apoptosis and inflammation in the heart, suggesting that myonectin mediates some of the beneficial actions of exercise on cardiovascular health.

The impact of the dominant frequency of body surface electrocardiography in patients with persistent atrial fibrillation.

The dominant frequency (DF) of atrial fibrillation (AF) reflects atrial electrical activity. However, the relationship between DF measured using surface electrocardiography (ECG) and AF ablation success remains unclear. This study aimed to clarify whether the DF of surface ECG in patients with persistent AF could predict arrhythmia recurrence after catheter ablation. We investigated 125 patients with persistent AF who underwent catheter ablation between January 2009 and December 2016. Thirty-four patients (27%) had arrhythmia recurrence after catheter ablation. These patients showed a significantly high DF value in leads aVL (7.2 ± 0.7 Hz vs 6.6 ± 0.9 Hz, p < 0.001) and V1 (7.4 ± 0.8 Hz vs 6.7 ± 0.7 Hz, p < 0.001). We set the cutoff value of DF as 6.9 Hz in lead aVL (sensitivity, 80%; specificity, 63%) and as 7.1 Hz in lead V1 (sensitivity, 72%; specificity, 67%). Patients with DF < 6.9 Hz in lead aVL showed a significantly higher recurrence-free rate than those with DF ≥ 6.9 Hz (88% vs 45%; p < 0.001). Patients with DF of < 7.1 Hz in lead V1 showed a significantly higher recurrence-free rate than those with DF of ≥ 7.1 (87% vs 47%; p < 0.001). Patients with a high DF in leads aVL and V1 showed a lower success rate of persistent AF ablation. The DF measured from surface ECG can be a useful marker to predict ablation success.