Does atrial fibrillation ablation worsen preexisting anemia? Another anemia paradox in DOAC era.

BACKGROUND: There is a concern about worsening anemia after atrial fibrillation (AF) ablation in anemic patients. We aimed to clarify whether or not patients with anemia who are on an oral anticoagulant therapy are more likely to lose blood after AF ablation. METHODS: We studied AF patients in 3 cardiovascular centers who skipped a single dose of a direct oral anticoagulant prior to the ablation, and compared the drop in the hemoglobin level 24 hours after the procedure and bleeding complications between the patients with and without preexisting anemia. RESULTS: We identified 183 (15.7%) patients with anemia at baseline out of 1163 patients. The reduction in the hemoglobin level (-0.39±0.71 vs. -0.93±0.9 g/dL; p<0.001) was smaller in the anemic than non-anemic patients. A fall in the hemoglobin level of ≥2 g/dL, which is a guideline-defined significant hemoglobin drop, was less common in anemic patients (1.6% vs. 11.3%; p<0.001). A female gender [odds ratio (OR) 1.62, confidence interval (CI) 1.07-2.45; p=0.02], persistent or long-standing persistent versus paroxysmal AF (OR 1.67, CI 1.13-2.49; p=0.01), ORBIT score ≥3 (OR 3.5, CI 1.34-8.94; p=0.01), and preexisting anemia (OR 0.02, CI 0.004-0.14; p<0.001) were independently associated with the fall in the hemoglobin level of ≥2 g/dL. No difference was noted in the rate of major bleeding complications (1.6% vs. 1.2%; p=0.72). CONCLUSIONS: Paradoxically, patients with preexisting anemia may be less likely to lose blood following AF ablation.

Six recurrences of myocarditis in 3 years: A case report.

A recent study revealed that recurrence of myocarditis occurs in a significant proportion of patients, but multiple recurrences of myocarditis have rarely been reported. The pathophysiology and best treatments for multiple recurrences of myocarditis remain unclear. A 60-year-old man presented to our emergency department with fever and chest pain. Physical examination, imaging, and laboratory findings were consistent with fulminant myocarditis. Paired titers confirmed adenovirus infection. The patient was treated with intra-aortic balloon pump and percutaneous cardiopulmonary support for 7 days and was discharged with near-normal electrocardiographic and echocardiographic findings on day 26. Over the subsequent 3 years, the patient experienced six episodes of recurrence of myocarditis with a progressive decrease in his ability to perform activities of daily living. At the time of his sixth recurrence, he died of ventricular fibrillation. Autopsy revealed mild enlargement of the left ventricle, extensive inflammatory cell infiltration, and mild interstitial fibrosis, suggesting left ventricle remodeling because of repetitive myocarditis. We have presented a case of multiple recurrences of myocarditis. This is the largest number of recurrences in a single patient reported to date. Further studies are needed to elucidate the underlying pathogenesis and best treatment of this condition. .

Intra-procedural anticoagulation and post-procedural hemoglobin fall in atrial fibrillation ablation with minimally interrupted direct oral anticoagulants: comparisons across 4 drugs.

PURPOSE: Thromboembolic or hemorrhagic complications related to atrial fibrillation (AF) ablation are rare, and thus, it is difficult to compare their frequency across different direct oral anticoagulants (DOACs). We aimed to compare the intra-ablation blood coagulability and post-procedural hemoglobin fall as alternatives to those complications across 4 DOACs. METHODS: We enrolled AF patients younger than 65 years old in 3 cardiovascular centers who skipped a single dose of apixaban, dabigatran, edoxaban, and rivaroxaban, prior to the ablation. Endpoints included the activated clotting time (ACT), heparin requirement during the ablation, and drop in the hemoglobin level 24 h after the procedure. RESULTS: The time-course curves of the ACT differed significantly across the patients with apixaban (N = 113), dabigatran (N = 130), edoxaban (N = 144), and rivaroxaban (N = 81), with its highest level in the dabigatran group (P < 0.001). The average ACT was greater in the dabigatran group than in the other groups (312.3 ± 34, 334.4 ± 44, 308.1 ± 41, and 305.8 ± 34.7 s; P < 0.001). A significant difference was noted in total heparin requirement across the patient groups (3990.2 ± 1167.9, 3890.4 ± 955.3, 4423.8 ± 1051.6, and 3972 ± 978.7 U/m2/h; P < 0.001), with its greatest amount in the edoxaban group. The reduction in the hemoglobin level was similar (- 0.93 ± 0.92, - 0.88 ± 0.79, - 0.89 ± 0.97, - 0.95 ± 1.23 g/dL; P = 0.94). No inter-group difference was noted in the rate of major or minor bleedings (0.9%, 2.3%, 1.4%, and 3.7%; P = 0.51), and no thromboembolic events were encountered. CONCLUSION: A difference in DOACs may have an impact on intra-ablation anticoagulation; however, it may not be on the procedural blood loss in the setting of a single skip.

A case of long-term dasatinib-induced proteinuria and glomerular injury.

A 52-year-old woman was diagnosed with chronic myeloid leukemia. Treatment with dasatinib, a second-generation Bcr-Abl tyrosine kinase inhibitor, was initiated, and complete cytogenetic remission was achieved. Two years later, proteinuria occurred, and the urinary protein level increased gradually in the next 3 years. Moreover, the serum creatinine level increased mildly during this period. The urinary protein level reached 2.18 g/gCr; hence, a renal biopsy was conducted. Light microscopy revealed mild proliferation of mesangial cells, and immunofluorescence analysis revealed IgG and C3 depositions in the mesangial area. Electron microscopy revealed electron-dense deposition in the paramesangial area, partial podocyte foot process effacement, and segmental endothelial cell swelling with a slight expansion of the subendothelial space. Dasatinib was discontinued, and within 3 weeks, the proteinuria disappeared, with improvements in her renal function. After switching to bosutinib, a new second-generation of tyrosine kinase inhibitor, the proteinuria remained negative. The rapid cessation of proteinuria following dasatinib discontinuation indicated that proteinuria was induced by the long-term administration of dasatinib. Proteinuria and renal function should be regularly monitored during dasatinib therapy.

Bidirectional loop-snare technique for adherent inferior vena cava filter retrieval.

Placement of a Günther Tulip Inferior Vena Cava (IVC) Filter™ (Cook, Bloomington, IN, USA) is an alternative treatment option to prevent pulmonary embolism in patients in whom anticoagulation therapy is contraindicated. Most patients require filter placement for only short periods, after which it can be retrieved. IVC filter retrieval becomes more difficult as the indwelling time increases. We developed a new method to retrieve the Günther Tulip IVC Filter™, namely, the bidirectional loop-snare technique (BLT). The key to the BLT procedure is to use 2 snares from both the jugular and femoral access routes. The jugular snare catches the filter hook and the femoral snare relieves the adhesion between the filter leg and IVC wall. Pulling from both the jugular and femoral ends increases the power to retrieve the IVC filter, and leads to successful filter retrieval. .

A case of acute and late coronary events after blunt chest trauma: Attention to the late onset angina.

Mechanisms of acute myocardial infarction caused by traumatic coronary artery injury have been reported. However, late-onset coronary artery stenosis associated with trauma is less well known. We experienced a case in which acute myocardial infarction of the right coronary artery occurred at the time of blunt chest trauma (BCT) caused by a traffic accident and an increase in coronary artery stenosis in the left anterior descending artery (LAD) branch about 1 year later. A comparison of a volume-rendering image created from enhanced-contrast computed tomography at the time of trauma and coronary angiography revealed that the trauma site and the stenotic lesion in the LAD were in very close proximity, suggesting to us that traumatic coronary artery injury without flow limitation may have developed into high-grade stenosis in the LAD 1 year later. In this case we were able to demonstrate a causal relationship between BCT and delayed coronary artery stenosis. After BCT, it is necessary to be aware of the possibility of delayed coronary artery stenosis even if coronary injury is absent in the acute phase. .

Design and synthesis of novel δ opioid receptor agonists with an azatricyclodecane skeleton for improving blood-brain barrier penetration.

We designed and synthesized novel δ opioid receptor (DOR) agonists 3a-i with an azatricyclodecane skeleton, which was a novel structural class of DOR agonists. Among them, 3b exhibited high values of binding affinity and potent agonistic activity for the DOR that were approximately equivalent to those of 2 which bore an oxazatricyclodecane skeleton. In vitro assays using the blood-brain barrier (BBB) permeability test kit supported the idea that 3b achieved an excellent BBB permeability by converting an oxygen atom of 2 to a carbon atom (methylene group) in the core skeleton. As a result, 3b showed potent antinociceptive effects.

Novel delta opioid receptor agonists with oxazatricyclodecane structure showing potent agonistic activities.

We recently reported oxazatricyclodecane derivatives 1 as δ opioid receptor (DOR) agonists having a novel chemotype, but their DOR agonistic activities were relatively low. Based on the working hypothesis that the dioxamethylene moiety in 1 may be an accessory site and that it may interfere with the sufficient conformational change of the receptor required for exerting the full agonistic responses, we designed and synthesized new oxazatricyclodecane derivatives 2-4 lacking the dioxamethylene moiety. As we expected, the designed compounds 2-4 showed pronouncedly improved agonistic activities for the DOR. Compound 2a with the 17-cyclopropylmethyl substituent was a potent agonist with the highest selectivity for the DOR and was expected to be a lead compound for novel and selective DOR agonists.

Risk stratification of ventricular fibrillation in Brugada syndrome using noninvasive scoring methods.

BACKGROUND: Risk stratification for ventricular fibrillation (VF) in patients with Brugada syndrome (BrS) remains controversial. OBJECTIVE: The purpose of this study was to construct a novel prediction model for VF risk in BrS patients using noninvasive parameters. METHODS: A total of 143 Japanese BrS patients with VF (n = 35) and without VF (n = 108) were retrospectively enrolled. We built a logistic regression model predicting VF occurrence and evaluated it by cross-validation. RESULTS: Frequencies of history of syncope and spontaneous type 1 ECG, r-J interval in V1, QRS duration in V6, and LAS40, Tpeak-Tend dispersion, and max T-wave alternans were significantly associated with VF occurrence in univariate analyses. The history of syncope, r-J interval in V1, QRS duration in V6, and Tpeak-Tend dispersion were identified as independent predictors by multivariate logistic regression analysis. The predictive model was constructed using all these parameters with good discrimination of VF occurrence (area under the curve 0.869 with 97.1% sensitivity and 65.7% specificity). The area under the curve based on leave-one-out cross-validation was 0.845, with 97.1% sensitivity and 63.0% specificity suggesting good performance of the model. Retrospective survival analysis revealed that the cumulative VF event rate was significantly higher in patients at high risk than in those with low risk using the log rank test (P = 2.97 × 10(-8)). Notably, no BrS patient below the cutoff value developed a subsequent VF event. CONCLUSION: This novel prediction method may effectively assesses VF risk in BrS patients, especially when determining implantable cardioverter-defibrillator placement for asymptomatic BrS patients.

Increased left atrial pressure in non-heart failure patients with subclinical hypothyroidism and atrial fibrillation.

BACKGROUND: The impact of subclinical hypothyroidism on the cardiovascular risk is still debated. We aimed to measure the relationship between subclinical hypothyroidism and the left atrial (LA) pressure. METHODS: The LA pressures and thyroid function were measured in consecutive patients undergoing atrial fibrillation (AF) ablation, who did not have any known heart failure, structural heart disease, or overt thyroid disease. RESULTS: Subclinical hypothyroidism (4.5≤ thyroid-stimulating hormone <19.9 mIU/L) was present in 61 (13.0%) of the 471 patients included. More subclinical hypothyroidism patients than euthyroid patients (55.7% vs 40.2%; P=0.04).'euthyroid patients had persistent or long-standing persistent AF (55.7% vs 40.2%; P = 0.04). The mean LA pressure (10.9 ± 4.7 vs 9.1 ± 4.3 mmHg; P = 0.002) and LA V-wave pressure (17.4 ± 6.5 vs 14.3 ± 5.9 mmHg; P < 0.001) were, respectively, higher in the patients with subclinical hypothyroidism than in the euthyroid patients. After an adjustment for potential confounders, the LA pressures remained significantly higher in the subclinical hypothyroidism patients. A multiple logistic regression model showed that subclinical hypothyroidism was independently associated with a mean LA pressure of >18 mmHg (odds ratio 3.94, 95% CI 1.28 11.2; P = 0.02). CONCLUSIONS: Subclinical hypothyroidism may increase the LA pressure in AF patients.

Common Variant Near HEY2 Has a Protective Effect on Ventricular Fibrillation Occurrence in Brugada Syndrome by Regulating the Repolarization Current.

BACKGROUND: Risk stratification of Brugada syndrome (BrS) remains controversial and the majority of patients with BrS have no genetic explanation. We investigated relationships between genotypes of 3 single-nucleotide polymorphisms reported in a recent genome-wide association study and BrS phenotypes. METHODS AND RESULTS: SCN10A (rs10428132), SCN5A (rs11708996), and downstream from HEY2 (rs9388451) single-nucleotide polymorphisms were genotyped and compared between 95 Japanese patients with BrS and 1978 controls. Relationships between the single-nucleotide polymorphisms and clinical characteristics, 12-lead ECG findings, signal-averaged ECG findings, and electrophysiological parameters were also examined in patients with BrS. Both rs10428132 and rs9388451 were significantly associated with BrS (P=2.7×10(-14); odds ratio, 3.0; P=9.2×10(-4); odds ratio, 1.7, respectively). Interestingly, the HEY2 risk allele C was less frequent in BrS patients with ventricular fibrillation than in those without (59% versus 74%; P=4.1×10(-2); odds ratio, 0.5). A significant linear correlation was found between HEY2 genotypes and QTc interval (CC: 422±27 ms; CT: 408±21 ms; and TT: 381±27 ms; P= 4.0×10(-4)). The HEY2 mRNA expression level in the right ventricular specimens from patients with BrS (n=20) was significantly lower in patients with CC genotype than the other genotypes (P=0.04). Additionally, during 63±28 months follow-up periods after implantable cardioverter defibrillator implantation (n=90), Kaplan-Meier event-free survival curves revealed that the cumulative rate of ventricular fibrillation events was significantly lower in cases with HEY2 CC genotype (P=0.04). CONCLUSIONS: Our findings suggest that HEY2 CC genotype may be a favorable prognostic marker for BrS, protectively acting to prevent ventricular fibrillation presumably by regulating the repolarization current.

Inhibition of Inflammatory and Neuropathic Pain by Targeting a Mu Opioid Receptor/Chemokine Receptor5 Heteromer (MOR-CCR5).

Chemokine release promotes cross-talk between opioid and chemokine receptors that in part leads to reduced efficacy of morphine in the treatment of chronic pain. On the basis of the possibility that a MOR-CCR5 heteromer is involved in such cross-talk, we have synthesized bivalent ligands (MCC series) that contain mu opioid agonist and CCR5 antagonist pharmacophores linked through homologous spacers (14-24 atoms). When tested on lipopolysaccharide-inflamed mice, a member of the series (MCC22; 3e) with a 22-atom spacer exhibited profound antinociception (i.t. ED50 = 0.0146 pmol/mouse) that was 2000× greater than morphine. Moreover, MCC22 was ~3500× more potent than a mixture of mu agonist and CCR5 antagonist monovalent ligands. These data strongly suggest that MCC22 acts by bridging the protomers of a MOR-CCR5 heteromer having a TM5,6 interface. Molecular simulation studies are consistent with such bridging. This study supports the MOR-CCR5 heteromer as a novel target for the treatment of chronic pain.

Mechanical and substrate abnormalities of the left atrium assessed by 3-dimensional speckle-tracking echocardiography and electroanatomic mapping system in patients with paroxysmal atrial fibrillation.

BACKGROUND: Left atrial (LA) remodeling progresses to electrical remodeling, contractile remodeling, and subsequently structural remodeling. Little is known about the relationship between LA electrical and anatomical remodeling and LA mechanical function. OBJECTIVES: We aimed to clarify the relationship between LA mechanical function using 3-dimensional speckle-tracking echocardiography (3D-STE) and LA electrical remodeling using an electroanatomic mapping system (CARTO 3) and to estimate atrial fibrillation (AF) substrate in patients with paroxysmal AF (PAF). METHODS: A total of 52 patients with PAF (41 (79%) men; mean age 61 ± 11 years) undergoing their initial pulmonary vein isolation (PVI) were examined. The standard deviation of the time to peak strain in each LA segment (%SD-TPS) was analyzed as an index of LA dyssynchrony using 3D-STE before PVI. Contact LA bipolar voltage and activation maps were constructed during sinus rhythm before PVI using CARTO 3. The LA total activation time was measured and low-voltage zones (LVZs) were determined with a local bipolar electrogram amplitude of <0.5 mV. The patients were divided into those with an LVZ (LVZ group; n = 23) and those without an LVZ (non-LVZ group; n = 29). RESULTS: The %SD-TPS was significantly higher (14.1 ± 5.7 vs 8.0 ± 5.1; P=.0002) in the LVZ group than in the non-LVZ group and was an independent determinant of the LVZ (odds ratio 1.21; 95% confidence interval 1.04-1.49; P=.01). In addition, the LA total activation time was weakly correlated with the %SD-TPS. CONCLUSION: LA dyssynchrony and conduction delay exist in patients with PAF. The 3D-STE enabled noninvasive estimation of LA electrical remodeling and AF substrate.

Design, synthesis, and structure-activity relationship of novel opioid κ receptor selective agonists: α-iminoamide derivatives with an azabicyclo[2.2.2]octene skeleton.

The α-iminoamide derivative, 4b was designed and synthesized as a novel agonist selective for the opioid κ receptor. The amide was constrained to an orientation horizontal to the F-ring of the azabicyclo[2.2.2]octane skeleton, which remarkably improved its affinity, selectivity, and agonistic activity for the κ receptor. This finding was newly established by chemical modification of the nitrogen atom at the 8-position in the azabicyclo[2.2.2]octane skeleton. This modification would never have been found with KNT-63, a derivation of oxabicyclo[2.2.2]octane. These results may provide valuable information for the future development of novel κ selective agonists.

Time-domain T-wave alternans is strongly associated with a history of ventricular fibrillation in patients with Brugada syndrome.

AIMS: T-wave alternans (TWA) is an indicator of vulnerability to ventricular arrhythmias and is useful for predicting sudden cardiac death (SCD) in patients with various structural heart diseases. We evaluated whether high levels of time-domain TWA on ambulatory ECG (AECG) are associated with a history of ventricular fibrillation (VF) in Brugada syndrome (BrS) patients. METHODS AND RESULTS: We examined the associations among VF history, family history of SCD, spontaneous type 1 electrocardiogram (ECG), late potentials, VF induction by programmed electrical stimulation, and TWA in 45 BrS patients (44 males; mean age, 45 ± 15 years). TWA analyzed from 24-h AECG recordings using the modified moving average method was positive in 13 of 43 patients (30%). Patients with a history of VF had a significantly higher incidence of a positive TWA test (82% vs. 13%; P < 0.001) and spontaneous type 1 ECG (92% vs. 38%; P = 0.007) than those without VF history. Multivariate analysis indicated that positive TWA (OR 7.217; 95% CI 2.503-35.504; P = 0.002) and spontaneous type 1 ECG (OR 5.530; 95% CI 1.651-34.337; P = 0.020) were closely associated with VF history. Spontaneous type 1 ECG had high sensitivity (92%) but low specificity (63%). Positive TWA was a reliable marker with high sensitivity and specificity (82% and 88%, respectively). CONCLUSION: Elevated time-domain TWA on AECG confirms arrhythmia risk in symptomatic BrS patients without the need for provocative stimuli.

Incomplete cure of tachycardia-induced cardiomyopathy secondary to rapid atrial fibrillation by heart rate control without sinus conversion.

BACKGROUND: It is uncertain whether rate or rhythm control is more favorable for patients experiencing tachycardia-induced cardiomyopathy (TIC) secondary to rapid atrial fibrillation (AF). METHODS AND RESULTS: We compared the electrophysiological and hemodynamic properties and outcome after AF ablation in 20 patients with a history of decompensated TIC who maintained sinus rhythm or had paroxysmal AF (group 1), 32 with a history of decompensated TIC who had persistent or longstanding persistent AF (group 2), 377 without TIC who had paroxysmal AF (group 3), and 225 without TIC who had persistent or longstanding persistent AF (group 4). The corrected sinus node recovery time was more prolonged in group 2 than in groups 1, 3, or 4 (1,066 ± 946 vs. 416 ± 188, 450 ± 322 and 590 ± 329 milliseconds; P < 0.001, respectively). The mean left atrial pressure in group 2 was greater than that in groups 1, 3, or 4 (13.9 ± 6.5 vs. 7.5 ± 3.1, 8.2 ± 4.1 and 10.8 ± 4.2 mmHg; P < 0.001, respectively). The left ventricular ejection fraction assessed after the recovery from the decompensation was more decreased in group 2 than in group 1; however, it almost returned to normal if sinus rhythm was maintained after the AF ablation in group 2. The presence of a history of TIC did not predict an AF recurrence after the ablation. CONCLUSIONS: Heart rate control during AF without sinus conversion may result in an incomplete cure of TIC, suggesting the advantages of rhythm control with ablation in patients with TIC.

Deterioration of the circadian variation of heart rate variability in Brugada syndrome may contribute to the pathogenesis of ventricular fibrillation.

AIMS: Abnormal sympathetic innervation triggers ventricular fibrillation (VF). We examined the circadian variation of autonomic nervous system and its relevance to risk stratification of VF in patients with Brugada syndrome (Brs). METHODS: We enrolled 12 male Brs patients with documented VF (Brs-S; mean age, 42±4 years), 17 without documented VF (Brs-N; mean age 48±4 years), and 16 age- and gender-matched controls. The clinical data, 12-lead electrocardiography (ECG), signal-averaged ECG, electrophysiological study (EPS), and heart rate variability from 24h Holter ECG were compared between the groups. RESULTS: The low frequency components (LF) in Brs-S and Brs-N and high frequency components (HF) in Brs-S patients were significantly lower than in the controls (409.8±128.6ms(2), 329.5±108ms(2) vs. 945.3±111.3ms(2); 135.1±73.8ms(2) vs. 391.8±63.9ms(2), respectively). The circadian variation of the LF and LF/HF decreased in the Brs patients, the standard deviation (SD) of LF/HF (<2.5) and SD of LF (<400ms(2)) had sufficiently high sensitivity (96.6%) and specificity (92.9%) for the diagnosis of Brs. Most of the Brs-S patients (83.3%) were located under the line formed by the SD/mean of HF=SD/mean of LF in the scatter plots. CONCLUSION: Lack of the circadian variation of autonomic function occurs in Brs, and this may contribute to the pathogenesis of VF.

Prediction of atrial fibrillation after off-pump coronary artery bypass grafting using preoperative total atrial conduction time determined on tissue Doppler imaging.

BACKGROUND: Postoperative atrial fibrillation (POAF) is a common complication of cardiac surgery and results in increased health-care utilization. This study identified new transthoracic echocardiographic predictors of POAF using an index of the total atrial conduction time derived on tissue Doppler imaging (PA-TDI duration) in patients undergoing off-pump coronary artery bypass grafting (OPCAB). METHODS AND RESULTS: A total of 88 patients undergoing isolated OPCAB were enrolled. They were examined preoperatively on transthoracic echocardiography with tissue Doppler evaluations and monitored postoperatively with continuous electrocardiographic telemetry for 7 days. POAF occurred in 35 patients (39.8%). Patients with POAF had a significantly longer duration of hospital stay than those without (44.9±6.2 vs. 37.3±3.3 days, P=0.04). Multivariate analysis showed that PA-TDI duration (odds ratio [OR], 1.11; 95% confidence interval [CI]: 1.06-1.16; P=0.0001) and left atrial volume index (LAVI; OR, 1.11; 95% CI: 1.02-1.20; P=0.01) were independent predictors of POAF. Moreover, PA-TDI duration was more reliable, given an area under the receiver operating characteristic curve of 0.85 (sensitivity, 74.3%; specificity, 86.8%). CONCLUSIONS: PA-TDI duration was an independent predictor of POAF following OPCAB. Awareness of risk of POAF may lead to the prevention of POAF, a rapid response to POAF, shortened hospital stay, and improved prognosis.

Variable procedural strategies adapted to anatomical characteristics in catheter ablation of the cavotricuspid isthmus using a preoperative multidetector computed tomography analysis.

OBJECTIVES: This study aimed to investigate the anatomical characteristics complicating cavotricuspid isthmus (CTI) ablation and the effectiveness of various procedural strategies. METHODS AND RESULTS: This study included 446 consecutive patients (362 males; mean age 60.5 ± 10.4 years) in whom CTI ablation was performed. A total of 80 consecutive patients were evaluated in a preliminary study. The anatomy of the CTI was evaluated by multidetector row-computed tomography (MDCT) prior to the procedure. A multivariate logistic regression analysis revealed that the angle and mean wall thickness of the CTI, a concave CTI morphology, and a prominent Eustachian ridge, were associated with a difficult CTI ablation (P < 0.01). In the main study, 366 consecutive patients were divided into 2 groups: a modulation group (catheter inversion technique for a concave aspect, prominent Eustachian ridge, and steep angle of the CTI or increased output for a thicker CTI) and nonmodulation group (conventional strategy). The duration and total amount of radiofrequency energy delivered were significantly shorter and smaller in the modulation group than those in the nonmodulation group (162.2 ± 153.5 vs 222.7 ± 191.9 seconds, P < 0.01, and 16,962.4 ± 11,545.6 vs 24,908.5 ± 22,804.2 J, P < 0.01, respectively). The recurrence rate of type 1 atrial flutter after the CTI ablation in the nonmodulation group was significantly higher than that in the modulation group (6.3 vs 1.7%, P = 0.02). CONCLUSION: Changing the procedural strategies by adaptating them to the anatomical characteristics improved the outcomes of the CTI ablation.

A nonsynonymous polymorphism in semaphorin 3A as a risk factor for human unexplained cardiac arrest with documented ventricular fibrillation.

Unexplained cardiac arrest (UCA) with documented ventricular fibrillation (VF) is a major cause of sudden cardiac death. Abnormal sympathetic innervations have been shown to be a trigger of ventricular fibrillation. Further, adequate expression of SEMA3A was reported to be critical for normal patterning of cardiac sympathetic innervation. We investigated the relevance of the semaphorin 3A (SEMA3A) gene located at chromosome 5 in the etiology of UCA. Eighty-three Japanese patients diagnosed with UCA and 2,958 healthy controls from two different geographic regions in Japan were enrolled. A nonsynonymous polymorphism (I334V, rs138694505A>G) in exon 10 of the SEMA3A gene identified through resequencing was significantly associated with UCA (combined P = 0.0004, OR 3.08, 95%CI 1.67-5.7). Overall, 15.7% of UCA patients carried the risk genotype G, whereas only 5.6% did in controls. In patients with SEMA3A(I334V), VF predominantly occurred at rest during the night. They showed sinus bradycardia, and their RR intervals on the 12-lead electrocardiography tended to be longer than those in patients without SEMA3A(I334V) (1031±111 ms versus 932±182 ms, P = 0.039). Immunofluorescence staining of cardiac biopsy specimens revealed that sympathetic nerves, which are absent in the subendocardial layer in normal hearts, extended to the subendocardial layer only in patients with SEMA3A(I334V). Functional analyses revealed that the axon-repelling and axon-collapsing activities of mutant SEMA3A(I334V) genes were significantly weaker than those of wild-type SEMA3A genes. A high incidence of SEMA3A(I334V) in UCA patients and inappropriate innervation patterning in their hearts implicate involvement of the SEMA3A gene in the pathogenesis of UCA.