Aims: Measurement of protein S (PS) activity in patients taking direct oral anticoagulants (DOACs) using reagents based on a clotting assay results in falsely high PS activity, thus masking inherited ...PS deficiency, which is most frequently seen in the Japanese population. In this study, we investigated the effect of factor Xa (FXa) inhibitors on PS activity using the reagent on the basis of the chromogenic assay, which was recently developed in Japan.Methods: The study enrolled 152 patients (82 males and 70 females; the average age: 68.5±14.0 years) receiving three FXa inhibitors (rivaroxaban, edoxaban, and apixaban). PS activity was measured using the reagents on the basis of the clotting and chromogenic assays.Results: PS activity measured by the clotting assay reagents exhibited falsely high values depending on the plasma concentrations of FXa inhibitors in patients taking either rivaroxaban or edoxaban. However, none of the three FXa inhibitors affected PS activity when measured using the chromogenic assay. Conclusion: In patients taking rivaroxaban or edoxaban, inherited PS deficiency is likely missed because the levels of PS activity measured using the reagents based on the clotting assay are falsely high. However, we report that three FXa inhibitors do not affect PS activity measured by the chromogenic assay. When measuring the levels of PS activity in patients undergoing DOACs, the principles of each reagent should be understood. Furthermore, plasma samples must be collected at the time when plasma concentrations of DOACs are lowest or the DOAC-Stop reagent should be used.
Introduction
A novel real‐time lesion size index (LSI) that incorporates contact force (CF), time, and power has been developed for safe and effective catheter ablation. The optimal LSI was evaluated ...to eliminate gap formation during pulmonary vein isolation (PVI).
Methods and Results
Consecutive patients were enrolled, who underwent their first PVI using a fiber‐optic CF‐sensing catheter for atrial fibrillation between December 2016 and October 2017. The CF parameters, force‐time integral (FTI), and LSI for 3095 ablation points in 34 patients were evaluated. The FTI and LSI in the lesions with gaps or dormant conduction (gaps/DC) were significantly lower than those in the lesion without gaps/DC (FTI: 140.5 ± 54.5 and 232.4 ± 121.4 g s, P < 0.0001; LSI: 4.0 ± 0.6 and 4.7 ± 0.9, P < 0.0001, respectively). On receiver operating characteristic curve analysis, the optimal LSI threshold was 4.05 (sensitivity, 63.4%; specificity, 76.3%). The LSI of <5.25 predicted a gap or DC with a high sensitivity (sensitivity, 97.6%; specificity, 25.7%). In the posterior wall, which was 37% thinner than the nonposterior wall, a lower LSI of <3.95 showed a relatively high sensitivity (92.3%) and specificity (65.6%).
Conclusions
The LSI can be used to predict gaps/DC during the PVI procedure. An LSI of 5.2 may be a suitable target for effective lesion formation. An LSI of 4.0 may be acceptable in the posterior wall, especially in areas adjacent to the esophagus.
Selenoprotein P (SeP), a liver-derived secretory protein, functions as a selenium supply protein in the body. SeP has been reported to be associated with insulin resistance in humans through serial ...analysis of gene expression. Recently, SeP has been found to inhibit vascular endothelial growth factor-stimulated cell proliferation in human umbilical vein endothelial cells, and impair angiogenesis in a mouse hind limb model. In this study, the role of SeP in ischemia/reperfusion (I/R) injury has been investigated. SeP knockout (KO) and littermate wild-type (WT) mice were subjected to 30 min of myocardial ischemia followed by 24 h of reperfusion. The myocardial infarct area/area at risk (IA/AAR), evaluated using Evans blue (EB) and 2,3,5-triphenyltetrazolium chloride (TTC) staining, was significantly smaller in SeP KO mice than in WT mice. The number of terminal de-oxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive nuclei was significantly lower in SeP KO mice than in WT mice. In addition, caspase-3 activation was reduced in SeP KO mice compared to that in WT mice. Furthermore, phosphoinositide 3-kinase/Akt and Erk levels were examined for the reperfusion injury salvage kinase (RISK) pathway. Interestingly, SeP KO significantly increased the phosphorylation of IGF-1, Akt, and Erk compared to that in WT mice after I/R. Finally, I/R-induced myocardial IA/AAR was significantly increased in SeP KO mice overexpressing SeP in the liver compared to other SeP KO mice. These results, together, suggest that inhibition of SeP protects the heart from I/R injury through upregulation of the RISK pathway.
Introduction
Optimal radiofrequency‐generated thermal energy applications have not been established for hot balloon ablation (HBA) systems. We investigated the feasibility of real‐time monitoring of ...pulmonary vein (PV) potentials and optimal time‐to‐isolation (TTI)‐guided application strategies in HBAs.
Methods and Results
Real‐time monitoring of PV potentials was performed using a four‐electrode unidirectional catheter in 34 consecutive patients. Acute isolation was achieved when PV potentials disappeared during HBAs and were undetected by high‐resolution mapping. The TTI, the difference between TTI and the time to reach target temperature (TTRT), and ablation time after isolation were examined for 177 applications in 136 PVs. Real‐time monitoring of PV activity was obtained in 167 out of 177 applications (94.3%) and acute isolation was achieved in 97 out of 177 (54.8%) applications. TTI‐TTRT was significantly shorter, and ablation times after isolation were significantly longer in the acute isolation group than in the other groups. TTI‐TTRT <4.5 seconds and TTIs <33.5 seconds predicted acute isolation (sensitivity 74.2%, specificity 88.4%; sensitivity 76.3%, specificity 76.7%, respectively). Ablation time after isolation >148.5 seconds (sensitivity 93.6%, specificity 51.7%) and >120.5 seconds (sensitivity 84.0%, specificity 78.6%) predicted acute isolation in superior PVs and inferior PVs, respectively.
Conclusions
Real‐time assessment of PV isolation can be achieved during HBAs with single‐shot techniques. (TTI‐TTRT)s <4.5 seconds and TTIs <33.5 seconds predicted for acute isolation. Ablation time after isolation >148.5 seconds in superior PVs and >120.5 seconds in inferior PVs were effective application durations.
fQRS Predicts Myocardial Fibrosis in HCM
Introduction
Myocardial fibrosis in patients with hypertrophic cardiomyopathy (HCM) usually shows a patchy distribution, which may not be detected by ...pathological Q waves on 12‐lead ECGs. Fragmented QRS complexes (fQRS) reflect intraventricular conduction delay and can be a marker of myocardial fibrosis. We assessed whether fQRS show better correlation with myocardial fibrosis than pathological Q waves in HCM.
Methods and Results
This cross‐sectional study included 108 patients with HCM who underwent 12‐lead ECG and cardiac magnetic resonance imaging with late gadolinium enhancement (LGE‐CMR). The number of leads with pathological Q waves was not correlated with the extent of LGE measured at any different standard deviations (SDs) (2, 4, 6, 8, and 10 SD), whereas the number of leads with fQRS showed the best correlation with LGE at 6 SD (r = 0.32, P = 0.0008). Further, the number of leads with fQRS was an independent predictor for the extent of LGE at 6 SD. fQRS showed higher accuracy for detecting myocardial fibrosis defined by LGE at 6 SD than pathological Q waves; the overall sensitivity, specificity, and accuracy of fQRS were 40%, 80%, and 64%, respectively, whereas those of pathological Q waves were 7%, 97%, and 60%, respectively. fQRS in lateral leads showed the highest accuracy (75%), followed by inferior leads (59%) and anterior leads (57%), for detecting LGE at 6 SD in the corresponding left ventricular segment.
Conclusions
These findings suggest that fQRS may have a substantially higher sensitivity and diagnostic accuracy compared with pathological Q waves for detecting myocardial fibrosis in HCM.
Genetic testing for inherited arrhythmias and discriminating pathogenic or benign variants from variants of unknown significance (VUS) is essential for gene-based medicine. KCNQ1 is a causative gene ...of type 1 long QT syndrome (LQTS), and approximately 30% of the variants found in type 1 LQTS are classified as VUS. We studied the role of zebrafish cardiac arrhythmia model in determining the clinical significance of KCNQ1 variants. We generated homozygous kcnq1 deletion zebrafish (kcnq1del/del) using the CRISPR/Cas9 and expressed human Kv7.1/MinK channels in kcnq1del/del embryos. We dissected the hearts from the thorax at 48 h post-fertilization and measured the transmembrane potential of the ventricle in the zebrafish heart. Action potential duration was calculated as the time interval between peak maximum upstroke velocity and 90% repolarization (APD90). The APD90 of kcnq1del/del embryos was 280 ± 47 ms, which was significantly shortened by injecting KCNQ1 wild-type (WT) cRNA and KCNE1 cRNA (168 ± 26 ms, P < 0.01 vs. kcnq1del/del). A study of two pathogenic variants (S277L and T587M) and one VUS (R451Q) associated with clinically definite LQTS showed that the APD90 of kcnq1del/del embryos with these mutant Kv7.1/MinK channels was significantly longer than that of Kv7.1 WT/MinK channels. Given the functional results of the zebrafish model, R451Q could be reevaluated physiologically from VUS to likely pathogenic. In conclusion, functional analysis using in vivo zebrafish cardiac arrhythmia model can be useful for determining the pathogenicity of loss-of-function variants in patients with LQTS.
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•Homozygous mutant zebrafish with deletion of the kcnq1 gene (kcnq1del/del) was created.•The ventricular APD90 of kcnq1del/del embryos was significantly longer.•It was shortened by co-injecting human KCNQ1 cRNA with human KCNE1 cRNA.•Injecting cRNA of pathogenic KCNQ1 variants did not rescue the prolonged APD90.•Injecting cRNA of KCNQ1 VUS, R451Q identified from a patient with LQTS did not rescue the prolonged APD90 either.
Abstract Background Although an increased epicardial adipose tissue (EAT) volume around the left atrium (LA) is related to the atrial fibrillation (AF) burden, the role of EAT inflammation in AF is ...unclear. We investigated the association between AF and inflammation of the EAT around the LA. Methods We retrospectively identified regions of EAT around the LA and measured the density of these areas using computed tomography (CT). Results A total of 32 patients who underwent their first catheter ablation for paroxysmal AF (PAF) were enrolled (mean age 62.5 ± 11.1 years). Patients without a history of AF ( n = 32), but who underwent cardiac CT and were matched by age, sex, and metabolic risk factors, were enrolled in the control group (62.2 ± 12.1 years). The mean EAT density around the LA was significantly higher in the PAF group than in the control group (−108.1 ± 6.7 vs. −111.6 ± 5.5 Hounsfield units; p = 0.02), while the densities of subcutaneous adipose tissue (SAT) in the abdomen and thorax did not differ between the two groups. In a multiple logistic regression analysis, a higher EAT density was significantly associated with the presence of PAF after adjusting for other risk factors (odds ratio: 1.25; 95% confidence interval: 1.08–1.45, p = 0.003). Conclusions This study supports the hypothesis that inflammation of EAT around the LA, but not SAT, is related to the presence of PAF.
Classic electrocardiographic (ECG) voltage indexes have been applied to screen for left ventricular (LV) hypertrophy in hypertrophic cardiomyopathy (HC). However, it is unclear whether low ECG ...voltage reflects deteriorated electrical forces because of replacement of the myocardium by fibrotic tissues in HC. We investigated correlations between classic ECG voltage indexes (Cornell, total QRS voltage, and Sokolow-Lyon) and cardiac magnetic resonance (CMR) parameters focusing on the impact of low ECG voltage on the LV ejection fraction (LVEF) and myocardial fibrosis in HC. We studied 108 consecutive patients with HC who underwent CMR imaging with late gadolinium enhancement (LGE). Nineteen patients with complete right or left bundle branch block were excluded, leaving 89 patients for analysis (age 61.0 ± 13.9 years; 58 men). Of the 3 voltage indexes, the total QRS voltage and Sokolow-Lyon indexes were positively correlated with LVEF. For discriminating patients with end-stage HC (LVEF <50%) from patients with HC and preserved LVEF (≥50%), receiver-operating characteristic analysis revealed an excellent area under the curve of 0.87 for the total QRS voltage index and 0.90 for the Sokolow-Lyon index, whereas the area under the curve for the Cornell index was only 0.54 (p <0.01). Moreover, these 2 voltage indexes were negatively correlated with the extent of LGE-determined myocardial fibrosis when adjusted by the LV maximal wall thickness. In conclusion, low ECG voltage indexes may reflect increased myocardial fibrosis in patients with HC.
Background: Obstructive sleep apnea syndrome (OSAS) is associated with augmented sympathetic nerve activity and cardiovascular diseases. However, the interaction between coronary artery plaque ...characteristics and sympathetic nerve activity remains unclear. The purpose of this study was to clarify the relationships between coronary artery plaque characteristics, sleep parameters and single- and multi-unit muscle sympathetic nerve activity (MSNA) in OSAS patients. Methods and Results: A total of 32 OSAS patients who underwent full-polysomnography participated in this study. The coronary plaque volume was calculated with 320-slice coronary computed tomography (CT). Single- and multi-unit MSNA were obtained during the daytime within 1 week from full-polysomnography. Patients were divided into 2 groups according to their apnea-hypopnea index (AHI) score (mild-moderate group, AHI <30; and severe group, AHI ≥30). There were no group differences in risk factors for atherosclerosis; however, severe AHI patients showed significantly high single-unit MSNA, and low- and intermediate-attenuation plaque volumes. In regression analysis, the plaque volume of any CT value was not associated with single- or multi-unit MSNA; only AHI significantly correlated with low-attenuation plaque volume (R=0.52, P<0.05). Conclusions: Our findings provided the evidence that AHI is an independent predictor for low-attenuated, vulnerable plaque volume, but not daytime MSNA, in patients with OSAS.
The Rho/Rho-kinase pathway plays an important role in many cardiovascular diseases such as hypertension, atherosclerosis, heart failure, and myocardial infarction. Although previous studies have ...shown that Rho-kinase inhibitors reduce ischemia/reperfusion (I/R) injury and cytokine production, the role of Rho-kinase in leukocytes during I/R injury is not well understood. Mice were subjected to 30-min ischemia and reperfusion. Rho-kinase activity was significantly greater in leukocytes subjected to myocardial I/R compared to the sham-operated mice. Administration of fasudil, a Rho-kinase inhibitor, significantly reduced the I/R-induced expression of the proinflammatory cytokines interleukin (IL)-6, C-C motif chemoattractant ligand 2 (CCL2), and tumor necrosis factor (TNF)-α, in leukocytes, compared with saline as the vehicle. Furthermore, fasudil decreased I/R-induced myocardial infarction/area at risk (IA) and I/R-induced leukocyte infiltration in the myocardium. Interestingly, IA in fasudil-administered mice with leukocyte depletion was similar to that in fasudil-administered mice. I/R also resulted in remarkable increases in the mRNA expression levels of the proinflammatory cytokines TNF-α, IL-6, and CCL2 in the heart. Inhibition of Rho-kinase activation in leukocytes has an important role in fasudil-induced cardioprotective effects. Hence, inhibition of Rho-kinase may be an additional therapeutic intervention for the treatment of acute coronary syndrome.
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