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Objectives Microscopic polyangiitis (MPA) affects various organs. However, echocardiographic findings of MPA are unclear. We aimed to evaluate the echocardiographic features of acute-phase MPA in Japanese patients. Methods This single-centre retrospective study included 15 patients with MPA who underwent echocardiography within 2 weeks of commencing steroid therapy for induction or reinduction. The echocardiography parameters of thetients were compared with those of 30 age- and sex-matched controls. Results No significant differences in left ventricular (LV) diameter, LV ejection fraction, or e’ were observed between the two groups. However, the MPA group showed a significantly higher left atrial (LA) diameter and LA volume index, as well as higher early diastolic filling velocity, diastolic pulmonary venous flow velocity, and trans-tricuspid pressure gradient, and a shorter deceleration time (DCT). Serum C-reactive protein levels were positively correlated with E wave, E/A, and DCT. These results may indicate that increased LV stiffness, rather than impairment of LV relaxation, contributed to LV diastolic function, resulting in LA enlargement. Conclusions Patients with acute-phase MPA had LA dilatation associated with LV diastolic dysfunction. This finding indicates the importance of cardiac assessment in patients with MPA, especially in patients with a strong inflammatory reaction.

Aims Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been shown to induce aberrant Ca2+ release from the cardiac ryanodine receptor (RyR2) in various diseased hearts. However, the precise pathogenic mechanism remains to be elucidated. Here, we investigated the effect of dantrolene (DAN): a RyR2 stabilizer on local Ca2+ release, cardiac function, and lethal arrhythmia in CaMKIIδc transgenic (TG) mice. Methods and results The TG mice showed an increase in left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) with a reduction in LV fractional shortening (LVFS). The phosphorylation levels of Ser2814 in RyR2 and Thr287 in CaMKII increased in TG mice. In TG cardiomyocytes, peak cell shortening (CS) decreased, and the frequency of spontaneous Ca2+ transients (sCaTs) increased. Endogenous RyR2-associated calmodulin (CaM) markedly decreased in TG cardiomyocytes. After chronic DAN treatment for 1 month, LVESD (but not LVEDD) decreased with an increase in LVFS. In the chronic DAN-treated cardiomyocytes, CS increased, sCaTs decreased, and the endogenous CaM binding to RyR2 normally restored. The phosphorylation levels of Ser2814 in RyR2 and Thr287 in CaMKII remained elevated even after DAN treatment. Moreover, in TG mice, chronic DAN treatment prevented sustained ventricular tachycardia induced by epinephrine. Conclusions Defective association of CaM with RyR2 is most likely to be involved in the pathogenesis of CaMKII-mediated cardiac dysfunction and lethal arrhythmia.

Introduction: Transesophageal echocardiography (TEE) is the gold standard modality for detecting a thrombus in the left atrium (LA) and the left atrial appendage (LAA) prior to pulmonary vein isolation (PVI) for the treatment of atrial fibrillation. Although TEE is has a good safety profile, it was recently reported that TEE preceding PVI can cause esophageal mucosal injury (EMI). However, the detailed data and mechanism of EMI by TEE remain to be elucidated. Herein, we investigated the incidence and risk factors of TEE-related EMI in patients who underwent PVI for AF. Methods: This study included 262 consecutive patients who underwent PVI with preoperative TEE using a 3D TEE probe and postoperative esophagogastroduodenoscopy. The cause of EMI was classified by an experienced gastroenterologist. Results: TEE-related EMI was found in 16 (6.1%) patients, whereas PVI-related EMI was found in 5 (1.9%) patients. Only one patient with TEE-related EMI experienced mild chest discomfort. In the multivariate analysis, advanced age was an independent risk factor for TEE-related EMI (odds ratio, 1.08 per 1-year increment; 95% confidence interval, 1.01-1.16; p = 0.0274). Conclusions: The incidence of TEE-related EMI, for which advanced age could be a significant risk factor, using a 3D TEE probe was relatively high in patients who underwent PVI. This study suggests that attention should be paid to the indications of TEE before performing PVI, especially in elderly patients, and other modalities for ruling out LA and LAA thrombus should also be considered.

Transesophageal echocardiography (TEE) is the gold standard for detecting thrombi in the left atrium (LA) and left atrial appendage (LAA) prior to pulmonary vein isolation (PVI) for the treatment of atrial fibrillation (AF). Although TEE has a good safety profile, it was recently reported that TEE preceding PVI can cause esophageal mucosal injuries (EMIs). The exact mechanism remains to be elucidated. In the present study, we investigated the incidence and risk factors of TEE-related EMI (TEE-EMI) among patients who underwent PVI for AF.This study included 262 consecutive patients who underwent PVI with preoperative TEE using a 3D TEE probe and postoperative esophagogastroduodenoscopy. TEE-EMIs were observed in 16 (6.1%) patients (18 lesions), whereas PVI-related EMIs were found in 5 (1.9%) patients (8 lesions). All TEE-EMIs were observed in the upper or middle esophagus and occurred more frequently in the right region of the upper esophagus and the left anterior region of the middle esophagus; only one patient experienced mild chest discomfort. In the multivariate analysis, advanced age was an independent risk factor for TEE-EMIs (odds ratio 1.08, 95% confidence interval 1.01-1.16; P = 0.0274).The incidence of TEE-EMIs with 3D TEE probes was relatively high in the upper or middle esophagus, anatomically close to the LA, among patients who underwent PVI. Advanced age could pose a significant risk. These findings may warrant consideration of other methods to rule out LA/LAA thrombi, especially in elderly patients.

In this study, we propose a projection mapping using a rotating volumetric display. In this proposal, a light source synchronized with the object of projection including its position and shape is dynamically generated by a simple structure of a rotating volume display. The light is projected onto a moving object using a recursive through optical systems. In this paper, we verify the applicability to projection mapping by implementing a prototype.

Background: Echocardiographic transaortic jet velocity (Vmax), mean pressure gradient (mPG), and aortic valve area (AVA) are routinely measured for severity of aortic stenosis (AS). Additionally, prolonged ejection time (ET), acceleration time (AT), and its ratio AT/ET are also known as indexes of AS severity. However, acoustic window dependency of AT/ET is not well studied. Methods: Eighty-one patients with AS assessed by transaortic jet tracing of all of three approaches (apical 3-chamber (3C), apical 5-chamber (5C), and right parasternal (R)) were included in this study. ET, AT, and AT/ET were measured on continuous Doppler recordings obtained by 3C, 5C, and R approaches. Also, ET and AT were corrected by dividing by (R-R interval)1/2, and they were named as cET and cAT. Results: No differences were observed in cET among 3 approaches. However, cAT was significantly longer in R (115+23 msec: p

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease that causes heart failure and/or sudden cardiac death. Several desmosomal genes (DSC2, PKG, PKP2, DSP, and RyR2) are thought to be the causative gene involved in ARVC. Out of them, DSC2 mutations account for 2% of ARVC genetic abnormalities. This study aimed to clarify the effect of G790del mutation in DSC2 on the arrhythmogenic mechanism and cardiac function in a mouse model. Result Neither the heterozygous +/G790del nor homozygous G790del/G790del mice showed structural and functional defects in the right ventricle (RV) or lethal arrhythmia. The homozygous G790del/G790del 6-month-old mice slightly showed left ventricular (LV) dysfunction. Cell shortening decreased with prolongation of intracellular Ca2+ transient in cardiomyocytes isolated from the homozygous G790del/G790del mice, and spontaneous Ca2+ transients were frequently observed in response to isoproterenol. Conclusions G790del mutation in DSC2 was not relevant to the pathogenesis of ARVC, but showed a slight contractile dysfunction and Ca2+ dysregulation in the LV., Highlights • We successfully established the DSC2 KI mice of G790del. • Both heterozygous +/G790del and homozygous G790del/G790del mice showed no signs of ARVC. • Homozygous G790del/G790del mice revealed a slight LV dysfunction with aberrant Ca2+ release. • The G790del mutation in DSC2 alone is insufficient to develop ARVC in a mouse model..

CaThe TG mice showed an increase in left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) with a reduction in LV fractional shortening (LVFS). The phosphorylation levels of Ser2814 in RyR2 and Thr287 in CaMKII increased in TG mice. In TG cardiomyocytes, peak cell shortening (CS) decreased, and the frequency of spontaneous CaDefective association of CaM with RyR2 is most likely to be involved in the pathogenesis of CaMKII-mediated cardiac dysfunction and lethal arrhythmia.

Background Ryanodine receptor (RyR2) is known to be a causal gene of catecholaminergic polymorphic ventricular tachycardia (CPVT), an important inherited disease. Some of the human CPVT-associated mutations have been found in a domain (4026-4172) that has EF hand motifs, the so-called calmodulin (CaM)-like domain (CaMLD). Objective The purpose of this study was to investigate the underlying mechanism by which CPVT is induced by a mutation at CaMLD. Methods A new N4103K/+ knock-in (KI) mice model was generated. Results Sustained ventricular tachycardia was frequently observed after infusion of caffeine plus epinephrine in KI mice. Endogenous CaM bound to RyR2 decreased even at baseline in isolated KI cardiomyocytes. Ca 2+ spark frequency (CaSpF) was much higher in KI cells than in wild-type cells. Addition of GSH-CaM (higher affinity CaM to RyR2) significantly decreased CaSpF. In response to isoproterenol, spontaneous Ca 2+ transient (SCaT) was frequently observed in intact KI cells. Incorporation of GSH-CaM into intact KI cells using a protein delivery kit decreased SCaT significantly. An assay using a quartz crystal microbalance technique revealed that mutated CaMLD peptide showed higher binding affinity to CaM binding domain (CaMBD) peptide. Conclusion In the N4103K mutant, CaM binding affinity to RyR2 was significantly reduced regardless of beta-adrenergic stimulation. We found that this was caused by an abnormally tight interaction between CaMBD and mutated CaM-like domain (N4103K-CaMBD). Thus, CaMBD–CaMLD interaction may be a novel therapeutic target for treatment of lethal arrhythmia.

Aims Cardiac Troponin T (TnT) mutation-linked familial hypertrophic cardiomyopathy (FHC) is known to cause sudden cardiac death at a young age. Here, we investigated the role of the Ca2+ release channel of the cardiac sarcoplasmic reticulum (SR), ryanodine receptor (RyR2), in the pathogenic mechanism of lethal arrhythmia in FHC-related TnT-mutated transgenic mice (TG; TnT-delta160E). Methods and results In TG cardiomyocytes, the Ca2+ spark frequency (SpF) was much higher than that in non-TG cardiomyocytes. These differences were more pronounced in the presence of isoproterenol (ISO; 10 nM). This increase in SpF was largely reversed by a CaMKII inhibitor (KN-93), but not by a protein kinase A inhibitor (H89). CaMKII phosphorylation at Ser2814 in RyR2 was increased significantly in TG. Spontaneous Ca2+ transients (sCaTs) after cessation of a 1–5 Hz pacing, frequently observed in ISO-treated TG cardiomyocytes, were also attenuated by KN-93, but not by H89. The RyR2 stabilizer dantrolene attenuated Ca2+ sparks and sCaTs in ISO-treated TG cardiomyocytes, indicating that the mutation-linked aberrant Ca2+ release is mediated by destabilized RyR2. Conclusions In FHC-linked TnT-mutated hearts, RyR2 is susceptible to CaMKII-mediated phosphorylation, presumably because of a mutation-linked increase in diastolic [Ca2+]i, causing aberrant Ca2+ release leading to lethal arrhythmia.

The aim of this study was to evaluate the association of functional mitral regurgitation (FMR), preserved or reduced ejection fraction (EF), and ischemic or nonischemic origin with outcomes in patients discharged alive after hospitalization for acute decompensated heart failure (HF). Of the 4,842 patients enrolled in the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, 3,357 patients were evaluated to assess the association of FMR, preserved or reduced EF, and ischemic or nonischemic origin with the primary end point (all-cause death and readmission for HF after discharge). At the time of discharge, FMR was assessed semiquantitatively (classified as none, mild, or moderate to severe) by color Doppler analysis of the regurgitant jet area. According to multivariable analysis, in the ischemic group, either mild or moderate to severe FMR in patients with a preserved EF had a significantly higher risk of the primary end point than patients without FMR (hazard ratio [HR] 1.60; 95% confidence interval [CI] 1.12 to 2.29; p = 0.010 and HR 1.98; 95% CI 1.30 to 3.01; p = 0.001, respectively). In patients with reduced EF with an ischemic origin, only moderate to severe FMR was associated with a significantly higher risk of the primary end point (HR 1.67; 95% CI 1.11 to 2.50; p = 0.014). In the nonischemic group, there was no significant association between FMR and the primary end point in patients with either a preserved or reduced EF. In conclusion, among patients with acute decompensated HF with a preserved or reduced EF, the association of FMR with adverse outcomes may differ between patients who had an ischemic or nonischemic origin of HF.

BACKGROUND Little is known about the pattern of isotope accumulation in the heart on 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography in patients with cardiac sarcoidosis (CS) complicated by ventricular aneurysm (VA).Methods and Results:We prospectively enrolled 82 consecutive patients with CS; 54 patients with active CS (presence of abnormal 18F-FDG accumulation in the heart) were subdivided into VA (n=17) and non-VA groups (n=37). Strong 18F-FDG accumulation surrounding the VA and its disappearance in the VA center was observed in all patients with VA, probably because of scar formation at the VA. Peak standardized uptake value was higher around the VA than in the VA center (5.1±2.1 vs. 2.2±0.6, P=0.0003) and the VA center had no 18F-FDG accumulation (VA center: 2.2±0.6 vs. control area: 2.1±0.6, P=0.37). On the other hand, in non-VA patients with LV wall thinning (n=28), 18F-FDG accumulation was significantly high, even in the area of LV wall thinning (LV wall thinning area: 3.1±0.8 vs. control area: 2.0±0.6, P=0.00002). CONCLUSIONS A pattern of strong 18F-FDG accumulation surrounding the VA and its disappearance in the VA center might be characteristic in patients with CS complicated by VA. Careful attention to FDG uptake would further elucidate CS pathophysiology and aid in the early treatment of VA.

Aberrant Ca2+ release from cardiac ryanodine receptors (RyR2) has been shown to be one of the most important causes of lethal arrhythmia in various types of failing hearts. We previously showed that dantrolene, a specific agent for the treatment of malignant hyperthermia, inhibits Ca2+ leakage from the RyR2 by correcting the defective inter-domain interaction between the N-terminal (1-619 amino acids) and central (2000-2500 amino acids) domains of the RyR2 and allosterically enhancing the binding affinity of calmodulin to the RyR2 in diseased hearts. In this study, we examined whether dantrolene inhibits this Ca2+ leakage, thereby preventing the pharmacologically inducible ventricular tachycardia in ventricular pressure-overloaded failing hearts. Ventricular tachycardia (VT) was easily induced after an injection of epinephrine in mice after 8 weeks of transverse aortic constriction-induced pressure-overload. Pretreatment with dantrolene almost completely inhibited the pharmacologically inducible VT. In the presence of dantrolene, the occurrence of both Ca2+ sparks and spontaneous Ca2+ transients was inhibited, which was associated with enhanced calmodulin binding affinity to the RyR2. These results suggest that dantrolene could be a new potent agent in the treatment of lethal arrhythmia in cases of acquired heart failure.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by a single point mutation in the cardiac type 2 ryanodine receptor (RyR2). Using knock-in mouse (KI) model (R2474S/+), we previously reported that a single point mutation within the RyR2 sensitizes the channel to agonists, primarily mediated by defective inter-domain interaction within the RyR2 molecule and subsequent dissociation of calmodulin (CaM) from the RyR2. Here, we examined whether CPVT can be genetically rescued by enhancing the binding affinity of CaM to the RyR2. We first determined whether there is a possible amino-acid substitution at the CaM-binding domain in the RyR2 (3584-3603) that can enhancethe binding affinity of CaM, and found that V3599K substitution showed the highest binding affinity of CaM to CaM-binding domain. Hence, we generated a heterozygous KI mouse model (V3599K/+) with a single amino acid substitution in the CaM-binding domain of the RyR2, and crossbred it with the heterozygous CPVT -associated R2474S/+ KI mouse to obtain a double heterozygous R2474S/V3599K KI mouse. The CPVT phenotypes—bidirectional or polymorphic ventricular tachycardia, spontaneous Ca2+ transients, and Ca2+ sparks—were all inhibited in the R2474S/V3599K mice. Thus, enhancement of the CaM binding affinity of the RyR2 is essential to prevent CPVT-associated arrhythmogenesis.

Myelodysplastic syndromes (MDSs) are blood disorders characterized by dysfunction in blood cell production in the bone marrow. Approximately 10–30% of MDS cases are associated with autoimmune disea...

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by a single point mutation in the cardiac type 2 ryanodine receptor (RyR2). Using a knockin (KI) mouse model (R2474S/+), we previously reported that a single point mutation within the RyR2 sensitizes the channel to agonists, primarily mediated by defective interdomain interaction within the RyR2 and subsequent dissociation of calmodulin (CaM) from the RyR2. Here, we examined whether CPVT can be genetically rescued by enhancing the binding affinity of CaM to the RyR2. We first determined whether there is a possible amino acid substitution within the CaM-binding domain in the RyR2 (3584–3603 residues) that can enhance its binding affinity to CaM and found that V3599K substitution showed the highest binding affinity of CaM to the CaM-binding domain. Hence, we generated a heterozygous KI mouse model (V3599K/+) with a single amino acid substitution in the CaM-binding domain of the RyR2 and crossbred it with the heterozygous CPVT-associated R2474S/+-KI mouse to obtain a double-heterozygous R2474S/V3599K-KI mouse model. The CPVT phenotypes — bidirectional or polymorphic ventricular tachycardia, spontaneous Ca(2+) transients, and Ca(2+) sparks — were all inhibited in the R2474S/V3599K mice. Thus, enhancement of the CaM-binding affinity of the RyR2 is essential to prevent CPVT-associated arrhythmogenesis.

In cardiac myocytes Calmodulin (CaM) bound to the ryanodine receptor (RyR2) constitutes a large pool of total myocyte CaM, but the CaM-RyR2 affinity is reduced in pathological conditions. Knock-in mice expressing RyR2 unable to bind CaM also developed hypertrophy and early death. However, it is unknown whether CaM released from this RyR2-bound pool participates in pathological cardiac hypertrophy. We found that angiotensin II (AngII) or phenylephrine (PE) both cause CaM to dissociate from the RyR2 and translocate to the nucleus. To test whether this nuclear CaM accumulation depends on CaM released from RyR2, we enhanced CaM-RyR2 binding affinity (with dantrolene), or caused CaM dissociation from RyR2 (using suramin). Dantrolene dramatically reduced AngII- and PE-induced nuclear CaM accumulation. Conversely, suramin enhanced nuclear CaM accumulation. This is consistent with nuclear CaM accumulation coming largely from the CaM-RyR2 pool. CaM lacks a nuclear localization signal (NLS), but G-protein coupled receptor kinase 5 (GRK5) binds CaM, has a NLS and translocates like CaM in response to AngII or PE. Suramin also promoted GRK5 nuclear import, and caused nuclear export of histone deacetylase 5 (HDAC5). Dantrolene prevented these effects. After 2–8 weeks of pressure overload (TAC) CaM binding to RyR2 was reduced, nuclear CaM and GRK5 were both elevated and there was enhanced nuclear export of HDAC5. Stress (acute AngII or TAC) causes CaM dissociation from RyR2 and translocation to the nucleus with GRK5 with parallel HDAC5 nuclear export. Thus CaM dissociation from RyR2 may be an important step in driving pathological hypertrophic gene transcription.

Background: Tachycardia worsens cardiac performance in acute decompensated heart failure (ADHF). We investigated whether heart rate (HR) optimization by landiolol, an ultra-short-acting β1-selective blocker, in combination with milrinone improved cardiac function in patients with ADHF and rapid atrial fibrillation (AF). Methods and Results: We enrolled9 ADHF patients (New York Heart Association classification IV; HR, 138 ± 18 bpm; left ventricular [LV] ejection fraction, 28 ± 8%; cardiac index [CI], 2.1 ± 0.3 L/min–1/m–2; pulmonary capillary wedge pressure [PCWP], 24 ± 3 mm Hg), whose HRs could not be reduced using standard treatments, including diuretics, vasodilators, and milrinone. Landiolol (1.5–6.0 µg/kg–1/min–1, intravenous) was added to milrinone treatment to study its effect on hemodynamics. The addition of landiolol (1.5 µg/kg–1/min–1) significantly reduced HR by 11% without changing systolic blood pressure (BP) and resulted in a significant decrease in PCWP and a significant increase in stroke volume index (SVI), suggesting that HR reduction restores incomplete LV relaxation. Administration of more than 3.0 µg/kg–1/min–1 of landiolol decreased BP, CI, and SVI. Conclusion: The addition of landiolol at doses of

Cardiac Troponin T (TnT) mutation-linked familial hypertrophic cardiomyopathy (FHC) is known to cause sudden cardiac death at a young age. Here, we investigated the role of the CaIn TG cardiomyocytes, the CaIn FHC-linked TnT-mutated hearts, RyR2 is susceptible to CaMKII-mediated phosphorylation, presumably because of a mutation-linked increase in diastolic [Ca

Background: We investigated the relationship between intraprocedural angiographic and echocardiographic AR severity after TAVI, and the clinical robustness of angiographic assessment. Methods and Results: In 74 consecutive patients, the echocardiographic circumferential extent (CE) of the paravalvular regurgitant jet was retrospectively measured and graded based on the VARC-2 cut-points; and angiographic post-TAVI AR was retrospectively quantified using contrast videodensitometry (VD) software that calculates the ratio of the contrast time-density integral in the LV outflow tract to that in the ascending aorta (LVOT-AR). Seventy-four echocardiograms immediately after TAVI were analyzable, while 51 aortograms were analyzable for VD. These 51 echocardiograms and VD were evaluated. Median LVOT-AR across the echocardiographic AR grades was as follows: none-trace, 0.07 (IQR, 0.05–0.11); mild, 0.12 (IQR, 0.09–0.15); and moderate, 0.17 (IQR, 0.15–0.22; Pmild AR patients compared with no-mild AR on intra-procedural echocardiography (41.5% vs. 12.4%, P=0.03) as well as in patients with LVOT-AR >0.17 compared with LVOT-AR ≤0.17 (59.5% vs. 16.6%, P=0.03). Conclusions: VD (LVOT-AR) has good intra-procedural inter-technique consistency and clinical robustness. Greater than mild post-TAVI AR, but not mild post-TAVI AR, is associated with late mortality.

Background— Recently, we reported that urinary 8-hydroxy-2′-deoxyguanosine (U-8-OHdG), an oxidative stress marker, reflected inflammatory activity in cardiac sarcoidosis (CS). Here, we investigated whether U-8-OHdG levels were associated with ventricular tachycardia (VT) in patients with CS. Methods and Results— This prospective cohort study enrolled 62 consecutive patients with CS, of whom 36 were diagnosed as having active CS based on abnormal 18 F-flurodeoxyglucose accumulation in the heart on positron-emission tomography/computed tomography. The 36 patients with active CS were subdivided as having CS with sustained VT (CS-VT group; n=18) or CS without sustained VT (CS-nVT group; n=18). Twenty-seven patients diagnosed with idiopathic dilated cardiomyopathy served as heart failure controls. U-8-OHdG, brain natriuretic peptide, cardiac function indices, and immunohistological data from subendomyocardial biopsy samples were compared across groups. Immunohistochemical examination of ventricle biopsy samples revealed that the anti-8-OHdG antibody-positive area of cardiac tissue was significantly greater in CS-VT than in CS-nVT or dilated cardiomyopathy and significantly correlated with U-8-OHdG levels (n=58; R =0.61; P P Conclusions— U-8-OHdG levels are associated with VT in patients with active CS diagnosed by 18 F-flurodeoxyglucose positron-emission tomography, providing additive and relevant information about the arrhythmia substrate.

We present the case of a 63-year-old woman presenting with a huge pelvic and retroperitoneal high flow arteriovenous malformation (AVM) causing high-output heart failure, who was treated with combined therapies, including transarterial embolization with n-butyl cyanoacrylate–iodized oil mixture (NBCA–lip) and coils for the right ovarian, both internal iliac, 3rd and 4th lumber arteries, venous sclerotherapy using coils and ethanolamine oleate (EO) for the right ovarian and both internal iliac veins with balloon-occluded retrograde transvenous obliteration technique, and direct percutaneous sclerotherapy using the NBCA–lip and EO for the large nidus of AVM under outflow control using occlusion balloon catheters.

Background Inflammation and oxidative stress play a crucial role in the pathogenesis of cardiac sarcoidosis (SAR). We investigated whether urinary (U) 8-hydroxy-2′-deoxyguanosine (8-OHdG)—an oxidative DNA damage marker—was related to SAR inflammatory activity. Methods U-8-OHdG levels were measured in 31 SAR patients, classified as active (n=17) or non-active (n=14) based on 18 F-fluorodeoxyglucose positron emission tomography–computed tomography ( 18 F-FDG-PET/CT), 28 dilated cardiomyopathy (DCM) patients, and 30 controls. In active SAR patients, U-8-OHdG levels were reexamined and compared with 18 F-FDG-PET/CT results at 6months after corticosteroid treatment to assess therapeutic response. Results Immunohistochemical examination of left ventricle (LV) autopsy samples from SAR patients revealed positive 8-OHdG staining in cardiomyocyte nuclei from LV sections showing 18 F-FDG accumulation on PET/CT, while serum 8-OHdG levels were significantly higher in the coronary sinus than in the aortic root only in active SAR patients. U-8-OHdG levels in SAR patients were higher than those in controls, and significantly higher in active SAR patients than in non-active SAR and DCM patients. U-8-OHdG was a powerful predictor of active SAR in receiver operating characteristic curve analysis (AUC, 0.98; 95% CI, 0.94–1.02; optimal cutoff value, 13.1ng/mg creatinine), with a sensitivity of 88.2% and a specificity of 92.9%. U-8-OHdG levels in responders significantly decreased at 6months after corticosteroid treatment initiation, in proportion with the decrease in the focal cardiac uptake of 18 F-FDG. Conclusions U-8-OHdG is a potentially clinically useful biomarker for evaluating inflammatory activity and monitoring the effectiveness of corticosteroid therapy in SAR patients.

Objective: Recently, we reported that low-dose landiolol (1.5 µg·kg-1·min-1), an ultra-short-acting β-blocker, safely decreased the heart rate (HR) in patients with acute decompensated heart failure (ADHF) and sinus tachycardia, thereby improving cardiac function. We investigated whether low-dose landiolol effectively decreased the HR in ADHF patients with rapid atrial fibrillation (AF). Methods: We enrolled 23 ADHF patients with rapid AF (HR ≥120 beats·min-1 and New York Heart Association class III-IV) and systolic heart failure (SHF: n = 12) or diastolic heart failure (DHF: n = 11) who received conventional therapy with diuretics, vasodilators, and/or low-dose inotropes. They were administered continuous intravenous infusion of low-dose landiolol (1.0-2.0 µg·kg-1·min-1), and their electrocardiograms and blood pressures were monitored for 24 h thereafter. Results: Two hours after starting landiolol, the HR was reduced significantly (22%), without a reduction in blood pressure, and remained constant thereafter. The HR reduction 2 h after landiolol administration was significantly greater in the DHF group than in the SHF group. No incidence of hypotension was recorded. Conclusions: Digitalis or amiodarone is currently recommended for HR control in ADHF patients with rapid AF. Our results showed that continuous infusion of low-dose landiolol may also be useful as first-line therapy in these patients.

Real-time three-dimensional transthoracic echocardiography (3DTTE) has been developed and provides detailed 3D information, noninvasively. However, the accuracy and usefulness of 3DTTE in the evaluation of aortic root geometry are still not clear. 2DTTE and 3DTTE were performed in 161 patients with various cardiac diseases. Multidetector computed tomography (MDCT) was performed in 35 of the 161 patients. The diameters and areas of the aortic annulus were evaluated by these three methods and compared. To evaluate the shape of the aortic annuli, eccentricity index (EI) (1 − minimum diameter/long-axis diameter) were calculated. Maximum dimensions of the aortic annulus measured by MDCT were significantly larger than those by 3DTTE and 2DTTE. The aortic annular areas measured by MDCT and 3DTTE were significantly larger than areas by 2DTTE. A good correlation (r = 0.85) was observed between the areas obtained by 3DTTE and MDCT; however, the correlation between the values by 2DTTE and MDCT was rough (r = 0.44). EI values in 46 % of the patients were greater than 0.1, i.e., the aortic annulus was elliptical. The images obtained by 3DTTE provided accurate values of the aortic annular area, which were equal to the values measured by MDCT. 3DTTE is a useful method to evaluate the aortic annular geometry.

Background Calmodulin (CaM) is a key modulator of the channel gating function of the ryanodine receptor (RyR). Objective The purpose of this study was to investigate the pathogenic role of RyR-bound CaM in diastolic Ca 2+ leakage from the sarcoplasmic reticulum and arrhythmogenesis in pressure-overloaded heart failure. Methods Pressure overload was induced in 12-week-old mice by transverse aortic constriction (TAC) using a 27-gauge needle. Results TAC operation for 8 weeks produced a significant increase in left ventricular end-diastolic diameter and frequent occurrence of lethal arrhythmias after infusion of epinephrine and caffeine in TAC mice. The amount of RyR-bound CaM decreased significantly in TAC mice compared with sham mice. The apparent affinity of CaM binding to RyR decreased in pressure-overloaded cells compared with sham cells and untreated cells. High-affinity calmodulin (HA-CaM; ie, CaM whose binding affinity to RyR was significantly increased) restored a normal level of CaM-RyR binding properties in pressure-overloaded cells. HA-CaM corrected abnormally increased Ca 2+ spark frequency in the pressure-overloaded cells to the level seen in the sham cells. The frequency of spontaneous Ca 2+ transients in TAC cells during and after 1–5 Hz of field stimulation was 44%, whereas it was significantly attenuated by HA-CaM but not with CaM. Conclusion Several disorders in the RyR channel function characteristic of pressure-overloaded cells (increased spontaneous Ca 2+ leakage, delayed afterdepolarization, triggered activity, Ca 2+ spark frequency, spontaneous Ca 2+ transients) are caused by deteriorated CaM binding to RyR2. These disorders could be rectified by restoring normal CaM binding to RyR2.

Aims The channel function of the cardiac ryanodine receptor (RyR2) is modulated by calmodulin (CaM). However, the involvement of CaM in aberrant Ca2+ release in diseased hearts remains unclear. Here, we investigated the pathogenic role of defective CaM binding to the RyR2 in the channel dysfunction associated with heart failure. Methods and results The involvement of CaM in aberrant Ca2+ release was assessed in normal and pacing-induced failing canine hearts. The apparent affinity of CaM for RyR2 was considerably lower in failing sarcoplasmic reticulum (SR) compared with normal SR. Thus, the amount of CaM bound to RyR2 was markedly decreased in failing myocytes. Expression of the CaM isoform Gly-Ser-His-CaM (GSH-CaM), which has much higher binding affinity than wild-type CaM for RyR1, restored normal CaM binding to RyR2 in both SR and myocytes of failing hearts. The Ca2+ spark frequency (SpF) was markedly higher and the SR Ca2+ content was lower in failing myocytes compared with normal myocytes. The incorporation of GSH-CaM into the failing myocytes corrected the aberrant SpF and SR Ca2+ content to normal levels. Conclusion Reduced CaM binding to RyR2 seems to play a critical role in the pathogenesis of aberrant Ca2+ release in failing hearts. Correction of the reduced CaM binding to RyR2 stabilizes the RyR2 channel function and thereby restores normal Ca2+ handling and contractile function to failing hearts.

The time interval between the onset of early transmitral flow velocity (E) and that of early diastolic mitral annular velocity (e') (T(E-e')) is a good predictor of elevated left ventricular (LV) filling pressure in patients with sinus rhythm. Although the evaluation of LV filling pressure using E/e' has been challenging in atrial fibrillation (AF), the usefulness of T(E-e') is unknown.E and e' were simultaneously recorded using dual Doppler echocardiography in 45 AF patients (30 men; mean age, 69 ± 9 years). E/e' and T(E-e') were calculated and compared with the pulmonary capillary wedge pressure (PCWP), which was measured invasively. E/e' and T(E/e') correlated with PCWP (E/e', r=0.57, P0.001; T(E-e'), r=0.77, P0.001). Using receiver operating characteristic analysis, the optimal cut-off for T(E-e') was 34 ms (sensitivity, 95%; specificity, 88%) and that for E/e' was 14.6 (sensitivity, 50%; specificity, 84%) in order to predict12-mmHg PCWP. When the combined cut-offs of T(E-e')34 ms and E/e'14.6 were used, the sensitivity and specificity of predicting elevated PCWP were improved to 100% and 88%, respectively.In AF patients, the simultaneous recording of E and e' using dual Doppler echocardiography and the analysis of T(E-e'), in addition to E/e', improved the accuracy of evaluation of LV filling pressure.

Calcium (Ca2+) is known to be a key messenger in cardiac excitation-contraction coupling. Alterations in excitation-contraction coupling reportedly play a crucial role in the pathogenesis of heart failure and lethal arrhythmias, such as catecholaminergic polymorphic ventricular tachycardia (CPVT) [(

The presence of apex-to-base disparity in diastolic left ventricle (LV) endocardial lengthening, based on an electromechanical activation sequence, has been recognized as an important determinant of LV diastolic properties. However, the behavior of LV apical and basal diastolic lengthening and its relationship to LV filling in hypertrophic cardiomyopathy (HCM) are unknown.We obtained basal and apical LV short-axis views in 27 patients with non-obstructive HCM and 25 healthy volunteers. The patients with HCM were subdivided into two groups; those with apical hypertrophy [APH(+)] or those without apical hypertrophy [APH(-)]. Eight equiangular points on the endo-myocardium at end diastole were placed in each view, and the movements of these points were automatically tracked using a two-dimensional echocardiographic tissue tracking system. Time-LV internal diameter curves were obtained and averaged. The time intervals from the aortic valve closure to the point of the first 40% of peak diastolic lengthening (T 40) were measured in each view. The standard deviation of the time to peak systolic circumferential shortening at the base and apex were calculated to assess the heterogeneity of LV contraction.The time difference in the T 40 between the apex and base (dt-T 40) in the HCM-APH(+) and HCM-APH(-) groups was greater than that in the control group. The heterogeneities in LV apical systolic shortening in the HCM groups were greater than those in the control group. There were good linear correlations between the dt-T 40 and the LV early diastolic echo-parameters and the LV mass index.Delayed apical relaxation and filling in patients with HCM is related to LV diastolic dysfunction and systolic dyssynchronous contraction.