Cardiomyopathy with an LMNA Genetic Variant Affecting Three Consecutive Generations: A Case Series.

We report the case of a family afflicted with cardiac laminopathy who showed atrial fibrillation (AF) and complete atrioventricular block across three generations. Implantable cardioverter defibrillators (ICDs) implantation, or cardiac resynchronization therapy (CRT) were delivered to the three patients (proband; 61 years old, proband's mother: 84 years old, and proband's daughter; 38 years old) to prevent sudden cardiac death or suppress heart failure progression. A novel frameshift mutation (LMNA Exon 9: c.1550dupA;p. N518Efs*34) was found in all three cases through genetic testing, and this mutation may potentially result in the relatively late appearance of a phenotype of left ventricular systolic dysfunction.

Quality of epicardial adipose tissue predicts major adverse cerebral and cardiovascular events following transcatheter aortic valve implantation.

Epicardial adipose tissue (EAT) have been shown to be associated with several heart disease, including coronary artery disease (CAD), atrial fibrillation (AF), and heart failure (HF). It is reported that the quality of EAT, represented by fat attenuation determined using computed tomography (CT) imaging, can detect the histologically-assessed remodeled EAT. We tested the hypothesis that quality of EAT would predict major adverse cerebral and cardiovascular events (MACCE) following transcatheter aortic valve implantation (TAVI) in patients with aortic stenosis (AS). A total of 125 consecutive severe AS patients who underwent TAVI were enrolled (39 male, mean 85.4 ± 4.0 years). Using CT imaging before TAVI, we measured the average CT fat attenuation of EAT (EAT attenuation) and investigated the association with MACCE. During the mean follow up period of 567 ± 371 days, 21 cases of MACCE were observed. Patients with MACCE had greater levels of EAT attenuation compared to those without (- 74 ± 3.7 Hounsfield Units (HU) vs - 77 ± 5.5 HU, p = 0.010). Based on the ROC curves, the high EAT attenuation was defined as > - 74.3 HU. According to this cut-off index, 44 patients were classified into the high EAT attenuation group (28 female, mean age 87 ± 3.6 years), whereas 81 patients were classified into the low EAT attenuation group (13 female, 85 ± 4.1 years). Kaplan-Meier survival curve demonstrated that the patients in the high EAT attenuation group showed greater prevalence of MACCE (log-rank 6.64, p = 0.010). Cox proportional hazards regression analysis revealed that EAT attenuation and Logistic EuroSCORE were independently associated with the incidence of MACCE. Our results suggest that quality of EAT, assessed by EAT attenuation detected by CT imaging, can predict the cerebral and cardiovascular events after TAVI in patients with AS.

R-R' interval in the left bundle branch block predicts long-term outcomes after cardiac resynchronization therapy by estimating greater mechanical dyssynchrony and viable myocardium.

BACKGROUND: Typical left bundle branch block (LBBB) shows 2 peaks of the R wave, which reflect activation reaching the interventricular septum (R) and posterolateral wall (R') sequentially. OBJECTIVE: The purpose of this study was to investigate the relationship among R-R' interval (RR'), mechanical dyssynchrony, extent of viable myocardium, and long-term outcomes in cardiac resynchronization therapy (CRT) candidates. METHODS: The study enrolled 49 patients (34 men; mean age: 69 ± 11 years) with LBBB who received CRT. The LBBB definition used requires the presence of mid-QRS notching in leads V1, V2, V5, V6, I, and aVL. Baseline evaluations were QRS duration (QRSd) and RR' measured from the 12-lead electrocardiogram; eyeball dyssynchrony (apical rocking and septal flash) and opposing-wall delay by speckle tracking from echocardiography, and extent of viable myocardium assessed by thallium-201 single-photon emission computed tomography. Primary outcomes included the combination of all-cause death and heart failure-related hospitalization. RESULTS: RR' predicted volumetric response better than QRSd (area under the curve 0.73 vs 0.67, respectively). The long RR' group (≥48 ms) revealed more frequent eyeball dyssynchrony and significantly greater radial (SL) and circumferential dyssynchrony (AP and SL) and %viable segment than the short RR' group. In multivariate regression analysis, only RR' ≥48 ms was independently associated with higher event-free survival rates following CRT (hazard ratio 0.21; P = .014). CONCLUSION: These findings suggest that RR' in complete LBBB was associated with mechanical dyssynchrony, extent of viable myocardium, and long-term outcomes following CRT.

Empagliflozin Suppresses the Differentiation/Maturation of Human Epicardial Preadipocytes and Improves Paracrine Secretome Profile.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce epicardial adipose tissue (EAT) in humans, enhancing cardioprotective effects on heart failure and atrial fibrillation. We investigated the direct effect of the SGLT2 inhibitor empagliflozin on human primary epicardial adipocytes and preadipocytes. SGLT2 is primarily expressed in human preadipocytes in the EAT. The expression levels of SGLT2 significantly diminished when the preadipocytes were terminally differentiated. Adipogenesis of preadipocytes was attenuated by empagliflozin treatment without affecting cell proliferation. The messenger RNA levels and secreted protein levels of interleukin 6 and monocyte chemoattractant protein 1 were significantly decreased in empagliflozin-treated adipocytes. Coculture of human induced pluripotent stem cell-derived atrial cardiomyocytes and adipocytes pretreated with or without empagliflozin revealed that empagliflozin significantly suppressed reactive oxygen species. IL6 messenger RNA expression in human EAT showed significant clinically relevant associations. Empagliflozin suppresses human epicardial preadipocyte differentiation/maturation, likely inhibiting epicardial adipogenesis and improving the paracrine secretome profile of EAT, particularly by regulating IL6 expression.

Association between interatrial septum adiposity and atrial fibrillation: transesophageal echocardiography imaging and autopsy study.

Recent clinical evidence has suggested that interatrial septal (IAS) adiposity contributes to atrial fibrillation (AF). The present study aimed to confirm the usefulness of transesophageal echocardiography (TEE) to estimate IAS adiposity in patients with AF. The histological IAS analysis based on autopsy samples sought to clarify characteristics that underlie the contribution of IAS adiposity to AF. The imaging study analyzed the TEE results in patients with AF (n = 184) in comparison with transthoracic echocardiography (TTE) and computed tomography (CT) results. The autopsy study histologically analyzed IAS in subjects with (n = 5) and without (n = 5) history of AF. In the imaging study, the ratio of interatrial septum adipose tissue (IAS-AT) volume per epicardial adipose tissue (EpAT) volume was greater in patients with persistent AF compared (PerAF) to those with paroxysmal AF (PAF). Multivariable analysis revealed that both TEE-assessed IAS thickness and TTE-assessed left atrial dimension were predicted by CT-assessed IAS-AT volume. In the autopsy study, the histologically-assessed IAS section thickness was greater in the AF group than that in the non-AF group and was positively correlated with the IAS-AT area percentage. In addition, the size of adipocytes in IAS-AT was smaller, compared to EpAT and subcutaneous adipose tissue (SAT). IAS-AT infiltrated into the IAS myocardium, as if adipose tissue split the myocardium (designated as myocardial splitting by IAS-AT). The number of island-like myocardium pieces as a result of myocardial splitting by IAS-AT was greater in the AF group than in the non-AF group and was positively correlated with the IAS-AT area percentage. The present imaging study confirmed the usefulness of TEE to estimate IAS adiposity in patients with AF without radiation exposure. The autopsy study suggested that the myocardial splitting by IAS-AT may contribute to atrial cardiomyopathy leading to AF.

Role of epicardial adipose tissue in human atrial fibrillation.

A recent meta-analysis among which four reports were conducted in Japan demonstrated that epicardial adipose tissue (EAT) is closely associated with an increased risk of atrial fibrillation (AF) recurrence after catheter ablation. We previously investigated the role of EAT in AF in humans. Left atrial (LA) appendage samples were obtained from AF patients during cardiovascular surgery. Histologically, the severity of fibrotic EAT remodeling was associated with LA myocardial fibrosis. Total collagen in the LA myocardium (i.e., LA myocardial fibrosis) was positively correlated with proinflammatory and profibrotic cytokines/chemokines, including interleukin-6, monocyte chemoattractant protein-1, and tumor necrosis factor-α, in EAT. Human peri-LA EAT and abdominal subcutaneous adipose tissue (SAT) were obtained by autopsy. EAT- or SAT-derived conditioned medium was applied to the rat LA epicardial surface using an organo-culture system. EAT-conditioned medium induced atrial fibrosis in organo-cultured rat atrium. The profibrotic effect of EAT was greater than that of SAT. The fibrotic area of the organo-cultured rat atrium treated with EAT from patients with AF was greater than in patients without AF. Treatment with human recombinant angiopoietin-like protein 2 (Angptl2) induced fibrosis in organo-cultured rat atrium, which was suppressed by concomitant treatment with anti-Angptl2 antibody. Finally, we attempted to detect fibrotic EAT remodeling on computed tomography (CT) images, which demonstrated that the percent change in EAT fat attenuation was positively correlated with EAT fibrosis. Based on these findings, we conclude that the percent change in EAT fat attenuation determined using CT non-invasively detects EAT remodeling.

Risk stratification of ventricular fibrillation in patients with symptomatic Brugada syndrome using pharmacological tests.

BACKGROUND: Brugada syndrome (BrS), which is characterized by J-point elevation in right precordial leads of a 12-lead electrocardiogram, is associated with the occurrence of ventricular fibrillation (VF). However, risk stratification of VF in patients with BrS remains challenging. OBJECTIVE: The aim of this study was to identify a risk predictor of VF in patients with BrS using pharmacological tests. METHODS: Twenty-one consecutive patients with BrS and a history of documented spontaneous VF (n = 16) or syncope presumed to be caused by lethal ventricular arrhythmia (n = 5) were enrolled. J-wave changes in response to intravenous verapamil, propranolol, and pilsicainide were separately assessed. RESULTS: During the median follow-up period of 86.0 months, 8 patients had VF recurrence (recurrence group) and 13 patients did not have VF recurrence (non-recurrence group). Intravenous propranolol injection induced significant J-wave augmentation (i.e., increase in amplitude >0.1 mV) in the inferior and/or lateral leads in the recurrence group compared to the non-recurrence group (p = .048 and p = .015, respectively). Kaplan-Meier analysis revealed that VF recurrence is significantly higher in patients with BrS and J-wave augmentation due to intravenous propranolol than in patients without J-wave augmentation (p = .014). CONCLUSION: The study results show that propranolol-induced J-wave augmentation is involved in the risk of VF in patients with BrS. The results suggest that early repolarization patterns in response to pharmacological tests may be useful for risk stratification of VF in patients with symptomatic BrS.

Role of computed tomography-based evaluation of skeletal muscle area in predicting cardiovascular outcomes in patients with chronic heart failure after cardiac resynchronization therapy.

AIM: This study aimed to determine possible associations between sarcopenia and poor cardiovascular outcomes in patients with chronic heart failure after cardiac resynchronization therapy. METHODS: This retrospective study evaluated 120 patients who underwent cardiac resynchronization therapy between March 2004 and June 2018. In total, 58 patients who underwent computed tomography within 30 days of cardiac resynchronization therapy implantation were eligible for inclusion, and their data were analyzed (25 women; 33 men; mean age 71.6 ± 8.7 years). Skeletal muscle area was measured at the third lumbar vertebra, and skeletal muscle index was calculated. Major adverse cardiovascular events included cardiovascular death, hospitalization due to heart failure, cerebral infarction, acute myocardial infarction and cardiac arrest. RESULTS: During the follow-up period (mean 868 ± 617 days), major adverse cardiovascular events occurred in 22 of 58 patients (38%). The patients were allocated to two groups according to sex-based tertiles of skeletal muscle index. The lowest tertile was defined as the low skeletal muscle index group. Kaplan-Meier survival analysis showed that the low skeletal muscle index group had a higher incidence of major adverse cardiovascular events (log-rank 4.38; P = 0.036). Cox proportional hazards regression analysis also showed that low skeletal muscle index values were significantly associated with major adverse cardiovascular events (hazard ratio 3.08; 95% confidence interval 1.26-7.66, P = 0.014). CONCLUSIONS: Decreases in skeletal mass index on computed tomography might predict the occurrence of major adverse cardiovascular events in patients with chronic heart failure who underwent cardiac resynchronization therapy. Geriatr Gerontol Int 2022; 22: 1013-1018.

Prehospital 12-Lead Electrocardiography System in Oita Assisted Transport of "True" Acute Coronary Syndrome Patients to Optimal Institutes.

BACKGROUND: Mobile cloud electrocardiography (C-ECG) can reduce the door-to-balloon time of acute coronary syndrome (ACS) patients, so we hypothesized it would also assist in transporting ACS-suspected patients to the optimal institutes.Methods and Results: Initially, 10 fire departments in Oita had 10 ambulances equipped with C-ECG. Ambulance crews recorded a 12-lead ECG from the patient at the first point of contact and transmitted them to 18 hospitals (13 institutions (PCII) with 24-h availability for percutaneous coronary intervention (PCI) and 5 regional core hospitals (RCH) without 24-h PCI) for analysis by a cardiologist. During 41 months, 476 ECGs suspected to be ACS were transmitted and analyzed. Of these, 24 ECGs transmitted to PCII were judged as not requiring PCI, and the patients were directly transported to a RCH (PCII-RCH); 35 ECGs sent to a RCH were judged as requiring PCI, and the patients were directly transported to a PCII (RCH-PCII). The prevalence of cardiovascular disease was significantly higher in the RCH-PCII group than in the PCII-RCH group (P<0.01). There was no significant difference in the door-to-balloon time between the RCH-PCII and the group in which the C-ECG was sent to a PCII and the patients were transported directly to PCII (PCII-PCII) (49±14 vs. 59±20 min, P=0.14). CONCLUSIONS: Prehospital 12-lead ECG can assist in transporting ACS-suspect patients to the optimal treatment facility.

Atrial Structural Remodeling in Patients With Atrial Fibrillation Is a Diffuse Fibrotic Process: Evidence From High-Density Voltage Mapping and Atrial Biopsy.

Background Low-voltage areas (LVAs) in the atria of patients with atrial fibrillation are considered local fibrosis. We hypothesized that voltage reduction in the atria is a diffuse process associated with fibrosis and that the presence of LVAs reflects a global voltage reduction. Methods and Results We examined 140 patients with atrial fibrillation and 13 patients with a left accessory pathway (controls). High-density bipolar voltage mapping was performed using a grid-mapping catheter during high right atrial pacing. Global left atrial (LA) voltage (VGLA) in the whole LA and regional LA voltage (VRLA) in 6 anatomic regions were evaluated with the mean of the highest voltage at a sampling density of 1 cm2. Patients with atrial fibrillation were categorized into quartiles by VGLA. LVAs were evaluated at voltage cutoffs of 0.1, 0.5, 1.0, and 1.5 mV. Twenty-eight patients with atrial fibrillation also underwent right atrial septum biopsy, and the fibrosis extent was quantified. Voltage at the biopsy site (Vbiopsy) was recorded. VGLA results by category were Q1 (<4.2 mV), Q2 (4.2-5.6 mV), Q3 (5.7-7.0 mV), and Q4 (≥7.1 mV). VRLA at any region was reduced as VGLA decreased. VGLA and VRLA did not differ between Q4 and controls. The presence of LVAs increased as VGLA decreased at any voltage cutoff. Biopsies revealed 11±6% fibrosis, which was inversely correlated with both Vbiopsy and VGLA (r=-0.71 and -0.72, respectively). Vbiopsy was correlated with VGLA (r=0.82). Conclusions Voltage reduction in the LA is a diffuse process associated with fibrosis. Presence of LVAs reflects diffuse voltage reduction of the LA.

Reduction of bleeding complications on puncture site after percutaneous coronary intervention using a 6.5-French sheathless guiding catheter.

BACKGROUND: Reducing complications at the puncture site after percutaneous coronary intervention (PCI) is important. The diameter of a 6.5-French (Fr) sheathless guiding catheter (GC) is smaller by approximately 2-Fr compared to a 6-Fr conventional sheath. In the present study, we investigated the post-PCI puncture site complications of a transradial approach in each gender while using a 6.5-Fr sheathless GC. METHODS AND RESULTS: Our study consisted of 332 patients who underwent transradial coronary intervention (TRI) between August 2017 and July 2019. We classified the patients into either the 6.5-Fr sheathless GC (Asahi, Intecc, Aichi, Japan) Group (Sheathless group: n = 182 males, 58 females) or the 6-Fr sheathed GC Group (Sheathed group: n = 150 males, 36 females). We determined the complications at the puncture site: oozing, subcutaneous hemorrhage, formation of hematoma, pseudoaneurysms, and peripheral neuropathy. The body mass index of the patients was greater in the sheathless GC group compared to the sheathed GC group (24.5 ± 3.5 kg/m2 vs. 23.6 ± 3.7 kg/m2, p = 0.02). In males, there was no significant difference in the complication rate at the puncture site between the sheathless GC and sheathed GC groups (19.3% vs. 18.6%, p = 0.88). However, the complication rate at the puncture site in females was higher in the sheathed GC group than in the sheathless GC group (36% vs. 15.5%, p = 0.02). A multiple logistic regression analysis revealed that the use of a 6.5-Fr sheathless GC independently reduced the complications in female patients (p = 0.006). CONCLUSION: The use of the 6.5-Fr sheathless GC system in a transradial approach reduced the complications at the puncture site in female patients. The 6.5-Fr sheathless GC system may be a safe option for them compared to the conventional sheath system.

Proposal criteria of paradoxical low-flow low-gradient aortic stenosis for predicting prognosis in patients undergoing transcatheter aortic valve implantation.

BACKGROUND: Paradoxical low-flow, low-gradient (PLF-LG) aortic stenosis (AS) is associated with poor prognosis in patients undergoing transcatheter aortic valve implantation (TAVI). This study aimed to verify the conventional criteria of PLF-LG AS (left ventricular ejection fraction [LVEF] > 50%, mean aortic valve pressure gradient [AVPG] < 40 mm Hg and stroke volume index [SVI] < 35 ml/m2 by measuring Doppler method) compatible for predicting prognosis in patients undergoing TAVI. MATERIALS AND METHODS: A total of 128 consecutive patients who underwent TAVI for AS with LVEF > 50% were enrolled. The primary endpoint was the hospital readmission due to heart failure (HRHF) and the secondary endpoint was all-cause mortality after hospital discharge. The patients were classified by both the conventional criteria of PLF-LG AS and the proposal criteria of PLF-LG AS if mean aortic valve pressure gradient (AVPG) < 40 mmHg and SVI by measuring Simpson's method < cut off value based on the ROC curve for predicting HRHF. RESULTS: According to the conventional criteria, only 6 patients were diagnosed with PLF-LG AS. However, according to the proposal criteria, 16 patients were diagnosed with PLF-LG AS. Fourteen patients developed HRHF during the follow-up period after TAVI. Based on the ROC curves, SVI by measuring Simpson's method (cut off value = 25 ml/m2) had higher sensitivity and specificity for predicting HRHF (AUC = 0.74, p = 0.0013) than SVI by measuring Doppler method (AUC = 0.63, p = 0.045). The multivariate analysis revealed that PLF-LG AS defined by the proposal criteria (HR: 5.25; 95% CI: 1.60-17.16; p = 0.0073) but not by the conventional criteria was independently associated with HRHF. PLF-LG AS defined by the conventional criteria and the proposal criteria were not associated with all-cause mortality in the univariate analysis. CONCLUSIONS: Our results demonstrated that new criteria of PLF-LG AS defined as SVI < 25 ml/m2 measured by Simpson's method could predict HRHF in patients with severe AS who underwent TAVI.

Detection of fibrotic remodeling of epicardial adipose tissue in patients with atrial fibrillation: Imaging approach based on histological observation.

BACKGROUND: Fibrotic remodeling of epicardial adipose tissue (EAT) is crucial for proinflammatory atrial myocardial fibrosis, which leads to atrial fibrillation (AF). OBJECTIVES: We tested the hypothesis that the ratio of central to marginal adipocyte diameter in EAT represents its fibrotic remodeling. Based on a similar concept, we also tested whether the percent (%) change in EAT fat attenuation determined using computed tomographic (CT) images can detect this remodeling. METHODS: Left atrial appendages were obtained from 76 consecutive AF patients during cardiovascular surgery. EAT in the central area (central EAT: C-EAT) and that adjacent to the atrial myocardium (Marginal EAT: M-EAT) were evaluated histologically. CT images for all of the 76 patients were also analyzed. RESULTS: The adipocyte diameter was smaller, fibrotic remodeling of EAT (EAT fibrosis) was more severe, and infiltration of macrophages and myofibroblasts was more extensive in M-EAT than in C-EAT. EAT fibrosis was positively correlated with adipocyte diameter in C-EAT and negatively correlated in M-EAT, resulting in a positive correlation between EAT fibrosis and the ratio of central to marginal adipocyte diameter (C/M diameter ratio; r = 0.73, P < .01). The C/M diameter ratio was greater in patients with persistent AF than in those with paroxysmal AF. CT images demonstrated that the %change in EAT fat attenuation was positively correlated with EAT fibrosis. CONCLUSION: Our results suggest that the central-to-marginal adipocyte diameter ratio is tightly associated with fibrotic remodeling of EAT. In addition, the %change in EAT fat attenuation determined using CT imaging can detect remodeling noninvasively.

Disruption of actin dynamics regulated by Rho effector mDia1 attenuates pressure overload-induced cardiac hypertrophic responses and exacerbates dysfunction.

AIMS: Cardiac hypertrophy is a compensatory response to pressure overload, leading to heart failure. Recent studies have demonstrated that Rho is immediately activated in left ventricles after pressure overload and that Rho signalling plays crucial regulatory roles in actin cytoskeleton rearrangement during cardiac hypertrophic responses. However, the mechanisms by which Rho and its downstream proteins control actin dynamics during hypertrophic responses remain not fully understood. In this study, we identified the pivotal roles of mammalian homologue of Drosophila diaphanous (mDia) 1, a Rho-effector molecule, in pressure overload-induced ventricular hypertrophy. METHODS AND RESULTS: Male wild-type (WT) and mDia1-knockout (mDia1KO) mice (10-12 weeks old) were subjected to a transverse aortic constriction (TAC) or sham operation. The heart weight/tibia length ratio, cardiomyocyte cross-sectional area, left ventricular wall thickness, and expression of hypertrophy-specific genes were significantly decreased in mDia1KO mice 3 weeks after TAC, and the mortality rate was higher at 12 weeks. Echocardiography indicated that mDia1 deletion increased the severity of heart failure 8 weeks after TAC. Importantly, we could not observe apparent defects in cardiac hypertrophic responses in mDia3-knockout mice. Microarray analysis revealed that mDia1 was involved in the induction of hypertrophy-related genes, including immediate early genes, in pressure overloaded hearts. Loss of mDia1 attenuated activation of the mechanotransduction pathway in TAC-operated mice hearts. We also found that mDia1 was involved in stretch-induced activation of the mechanotransduction pathway and gene expression of c-fos in neonatal rat ventricular cardiomyocytes (NRVMs). mDia1 regulated the filamentous/globular (F/G)-actin ratio in response to pressure overload in mice. Additionally, increases in nuclear myocardin-related transcription factors and serum response factor were perturbed in response to pressure overload in mDia1KO mice and to mechanical stretch in mDia1 depleted NRVMs. CONCLUSION: mDia1, through actin dynamics, is involved in compensatory cardiac hypertrophy in response to pressure overload.

Baroreflex Sensitivity in Patients With Atrial Fibrillation.

Background It has been reported that atrial fibrillation (AF) may contribute to impairment of baroreflex sensitivity (BRS). However, the difference of BRS between patients with persistent AF (PeAF) and those with paroxysmal AF (PAF) is unknown. We tested the hypothesis that patients with PeAF have a more impaired BRS compared with those with PAF. Methods and Results From October 2015 onwards, a total of 67 patients (14 women [20.9%]; mean age 65.2±10.1 years) with PAF (n=46, 68.7%) and PeAF (n=21, 31.3%), who underwent catheter ablation, were prospectively enrolled. The baseline BRS was evaluated during sinus rhythm. The baseline BRS in patients with PeAF was significantly lower than those with PAF (2.97 [0.52-6.62] ms/mm Hg versus 4.70 [2.36-8.37] ms/mm Hg, P=0.047). The BRS was significantly depressed after catheter ablation in all the patients (4.66 [1.80-7.37] ms/mm Hg versus 0.55 [-0.15 to 1.22] ms/mm Hg, P<0.001). However, the depression of BRS because of catheter ablation appeared attenuated in patients with PeAF when compared with those with PAF. The number of patients who did not show depression of BRS was significantly greater, that is, patients with PeAF (3/12, 25%) than those with PAF (0/46, 0%, P<0.01). Conclusions Our findings demonstrated that the baseline BRS was more depressed in patients with PeAF compared with PAF. Catheter ablation depressed BRS irrespective of the type of AF, with a greater effect in patients with PAF than PeAF.

A traditional herbal medicine rikkunshito prevents angiotensin II-Induced atrial fibrosis and fibrillation.

BACKGROUND: Rikkunshito (RKT), a traditional herbal medicine, has been demonstrated to exert anti-inflammatory, anti-apoptotic, and anti-fibrotic effects in several organs. This study tested the hypothesis that RKT can suppress angiotensin II (AngII)-induced inflammatory atrial fibrosis and ameliorate enhanced vulnerability to atrial fibrillation (AF). METHODS: Eight-week-old male C57BL/6 mice were subcutaneously infused with either vehicle or AngII (2.0 mg/kg/day) for 2 weeks. Water or RKT at a dose of 1000 mg/kg/day were orally administered once daily for 2 weeks. Morphological, histological, and biochemical analyses were performed. AF was induced either by transesophageal burst pacing in vivo or by burst/extrastimuli in isolated perfused hearts using a Langendorff apparatus. RESULTS: RKT at a dose of 1000 mg/kg/day for 2 weeks attenuated atrial interstitial fibrosis and profibrotic and proinflammatory signals induced by continuous infusion of AngII. RKT attenuated AngII-induced enhanced vulnerability to AF in in vivo experiments and in isolated perfused hearts. Atractylodin, an active component of RKT, exhibited antifibrotic activity comparable to that of RKT. RKT reversed AngII-induced suppression of sirtuin 1 (Sirt1) translocation to the nuclei. RKT suppressed AngII-induced phosphorylation of IκB, overexpression of p53, and cellular apoptotic signals and apoptosis. All of the antagonizing effects of RKT against AngII were attenuated by a concomitant treatment with a growth hormone secretagogue receptor (GHSR)-inhibitor. CONCLUSION: Our results demonstrated that RKT prevented atrial fibrosis and attenuated enhanced vulnerability to AF induced by AngII. The results also suggested that potentiating the GHSR-Sirt1 pathway is involved in these processes.

Role of angiopoietin-like protein 2 in atrial fibrosis induced by human epicardial adipose tissue: Analysis using an organo-culture system.

BACKGROUND: We have recently reported that peri-left atrial epicardial adipose tissue (EAT) is associated with atrial myocardial fibrosis, in which angiopoietin-like protein 2 (Angptl2) protein content in EAT is associated with atrial myocardial fibrosis. OBJECTIVE: This study aimed to examine whether Angptl2 contained in peri-left atrial EAT can induce atrial myocardial fibrosis. METHODS: Human peri-left atrial EAT and abdominal subcutaneous adipose tissue (SAT) were collected from 9 autopsy cases. EAT- or SAT-conditioned medium was dropped onto the rat left atrial epicardial surface using an organo-culture system. Conditioned medium, recombinant Angptl2, and its antibody effects on organo-cultured rat atrial myocardial fibrosis were evaluated. Angptl2 effects on cultured neonatal rat fibroblasts were also investigated. RESULTS: EAT-conditioned medium induced atrial fibrosis in organo-cultured rat atrium with a progressive increase in the number of myofibroblasts. The profibrotic effect of EAT was greater than that of SAT. EAT in patients with atrial fibrillation induced a more significant atrial fibrosis than in those without. Treatment with human recombinant Angptl2 induced fibrosis in organo-cultured rat atrium, which was suppressed by the concomitant treatment with Angptl2 antibody. In cultured fibroblasts, Angptl2 upregulated the expression of α-smooth muscle actin, transforming growth factor-ß1, phospho-extracellular signal-regulated kinase,phospho-inhibitor of κBα, and phospho-p38 mitogen-activated protein kinase. CONCLUSION: This study demonstrated that Angptl2 contained in EAT played a crucial role in EAT-induced inflammatory atrial fibrosis. The results also suggested that antagonizing the expression of Angptl2 in EAT can be a novel therapeutic approach to prevent atrial fibrillation.