Registry for Evaluating Healthy Life Expectancy and Long-Term Outcomes after Catheter Ablation of Atrial Fibrillation in the Very Elderly (REHEALTH AF) study: rationale and design of a prospective, multicentre, observational, comparative study.

INTRODUCTION: Data are lacking on the extent to which patients with non-valvular atrial fibrillation (AF) who are aged ≥80 years benefit from ablation treatment. The question pertains especially to patients' postablation quality of life (QoL) and long-term clinical outcomes. METHODS AND ANALYSIS: We are initiating a prospective, registry-based, multicentre observational study that will include patients aged ≥80 years with non-valvular AF who choose to undergo treatment by catheter ablation and, for comparison, such patients who do not choose to undergo ablation (either according to their physician's advice or their own preference). Study subjects are to be enrolled from 52 participant hospitals and three clinics located throughout Japan from 1 June 2022 to 31 December 2023, and each will be followed up for 1 year. The planned sample size is 660, comprising 220 ablation group patients and 440 non-ablation group patients. The primary endpoint will be the composite incidence of stroke/transient ischaemic attack (TIA) or systemic embolism (SE), another cardiovascular event, major bleeding and/or death from any cause. Other clinical events such as postablation AF recurrence, a fall or bone fracture will be recorded. We will collect standard clinical background information plus each patient's Clinical Frailty Scale score, AF-related symptoms, QoL (Five-Level Version of EQ-5D) scores, Mini-Mental State Examination (optional) score and laboratory test results, including measures of nutritional status, on entry into the study and 1 year later, and serial changes in symptoms and QoL will also be secondary endpoints. Propensity score matching will be performed to account for covariates that could affect study results. ETHICS AND DISSEMINATION: The study conforms to the Declaration of Helsinki and the Ethical Guidelines for Clinical Studies issued by the Ministry of Health, Labour and Welfare, Japan. Results of the study will be published in one or more peer-reviewed journals. TRIAL REGISTRATION NUMBER: UMIN000047023.

Effect of Catheter Ablation for Atrial Fibrillation in Heart Failure With Mid-Range or Preserved Ejection Fraction　- Pooled Analysis of the AF Frontier Ablation Registry and Hokuriku-Plus AF Registry.

BACKGROUND: A recent randomized trial demonstrated that catheter ablation for atrial fibrillation (AF) in patients with heart failure with reduced ejection fraction (EF) is associated with a reduction in death or heart failure. However, the effect of catheter ablation for AF in patients with heart failure with mid-range or preserved EF is unclear.Methods and Results: We screened 899 AF patients (72.4% male, mean age 68.4 years) with heart failure and left ventricular EF ≥40% from 2 Japanese multicenter AF registries: the Atrial Fibrillation registry to Follow the long-teRm Outcomes and use of aNTIcoagulants aftER Ablation (AF Frontier Ablation Registry) as the ablation group (525 patients who underwent ablation) and the Hokuriku-Plus AF Registry as the medical therapy group (374 patients who did not undergo ablation). Propensity score matching was performed in these 2 registries to yield 106 matched patient pairs. The primary endpoint was a composite of cardiovascular death and hospitalization for heart failure. At 24.6 months, the ablation group had a significantly lower incidence of the primary endpoint (hazard ratio 0.32; 95% confidence interval 0.13-0.70; P=0.004) than the medical therapy group. CONCLUSIONS: Compared with medical therapy, catheter ablation for AF in patients with heart failure and mid-range or preserved EF was associated with a significantly lower incidence of cardiovascular death or hospitalization for heart failure.

Impact of sinus rhythm maintenance on major adverse cardiac and cerebrovascular events after catheter ablation of atrial fibrillation: insights from AF frontier ablation registry.

The impact of catheter ablation for atrial fibrillation (AF) on cardiovascular events and mortality is controversial. We investigated the impact of sinus rhythm maintenance on major adverse cardiac and cerebrovascular events after AF ablation from a Japanese multicenter cohort of AF ablation. We investigated 3326 consecutive patients (25.8% female, mean age 63.3 ± 10.3 years) who underwent catheter ablation for AF from the atrial fibrillation registry to follow the long-term outcomes and use of anti coagulants after ablation (AF frontier ablation registry). The primary endpoint was a composite of stroke, transient ischemic attack, cardiovascular events, and all-cause death. During a mean follow-up of 24.0 months, 2339 (70.3%) patients were free from AF after catheter ablation, and the primary composite endpoint occurred in 144 (4.3%) patients. The AF nonrecurrence group had a significantly lower incidence of the primary endpoint (1.8 per 100 person-years) compared with the AF recurrence group (3.0 per 100 person-years, p = 0.003). The multivariate analysis revealed that freedom from AF (hazard ratio 0.61, 95% confidence interval 0.44-0.86, p = 0.005) was independently associated with the incidence of the composite event. In the multicenter cohort of AF ablation, sinus rhythm maintenance after catheter ablation was independently associated with lower rates of major adverse cardiac and cerebrovascular events.

Different Determinants of the Recurrence of Atrial Fibrillation and Adverse Clinical Events in the Mid-Term Period After Atrial Fibrillation Ablation.

BACKGROUND: It is unclear whether there are differences in the clinical factors between atrial fibrillation (AF) recurrence and adverse clinical events (AEs), including stroke/transient ischemic attack (TIA), major bleeding, and death, after AF ablation.Methods and Results:We examined the data from a retrospective multicenter Japanese registry conducted at 24 cardiovascular centers between 2011 and 2017. Of the 3,451 patients (74.1% men; 63.3±10.3 years) who underwent AF ablation, 1,046 (30.3%) had AF recurrence and 224 (6.5%) suffered AEs (51 strokes/TIAs, 71 major bleeding events, and 36 deaths) over a median follow-up of 20.7 months. After multivariate adjustment, female sex, persistent and long-lasting persistent AF (vs. paroxysmal AF), and stepwise increased left atrial diameter (LAd) quartiles were significantly associated with post-ablation recurrences. A multivariate analysis revealed that an age ≥75 years (vs. <65 years), body weight <50 kg, diabetes, vascular disease, left ventricular (LV) ejection fraction <40% (vs. ≥50%), Lad ≥44 mm (vs. <36 mm), and creatinine clearance <50 mL/min were independently associated with AE incidences, but not with recurrences. CONCLUSIONS: This study disclosed different determinants of post-ablation recurrence and AEs. Female sex, persistent AF, and enlarged LAd were determinants of post-ablation recurrence, whereas an old age, comorbidities, and LV and renal dysfunction rather than post-ablation recurrence were AEs determinants. These findings will help determine ablation indications and post-ablation management.

Clinical outcomes of ablation versus non-ablation therapy for atrial fibrillation in Japan: analysis of pooled data from the AF Frontier Ablation Registry and SAKURA AF Registry.

Whether ablation for atrial fibrillation (AF) is, in terms of clinical outcomes, beneficial for Japanese patients has not been clarified. Drawing data from 2 Japanese AF registries (AF Frontier Ablation Registry and SAKURA AF Registry), we compared the incidence of clinically relevant events (CREs), including stroke/transient ischemic attack (TIA), major bleeding, cardiovascular events, and death, between patients who underwent ablation (n = 3451) and those who did not (n = 2930). We also compared propensity-score matched patients (n = 1414 in each group). In propensity-scored patients who underwent ablation and those who did not, mean follow-up times were 27.2 and 35.8 months, respectively. Annualized rates for stroke/TIA (1.04 vs. 1.06%), major bleeding (1.44 vs. 1.20%), cardiovascular events (2.15 vs. 2.49%) were similar (P = 0.96, 0.39, and 0.35, respectively), but annualized death rates were lower in the ablation group than in the non-ablation group (0.75 vs.1.28%, P = 0.028). After multivariate adjustment, the risk of CREs was statistically equivalent between the ablation and non-ablation groups (hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.71-1.11), but it was significantly low among patients who underwent ablation for paroxysmal AF (HR 0.68 [vs. persistent AF], 95% CI 0.49-0.94) and had a CHA2DS2-VASc score < 3 (HR 0.66 [vs. CHA2DS2-VASc score ≥ 3], 95% CI 0.43-0.98]). The 2-year risk reduction achieved by ablation may be small among Japanese patients, but AF ablation may benefit those with paroxysmal AF and a CHA2DS2-VASc score < 3.

Clinical Outcomes of Off-Label Underdosing of Direct Oral Anticoagulants After Ablation for Atrial Fibrillation.

Direct oral anticoagulants (DOACs) are sometimes prescribed at off-label under-doses for patients who have undergone ablation for atrial fibrillation (AF). This practice may be an attempt to balance the risk of bleeding against that of stroke or AF recurrence.We examined outcomes of 1163 patients who continued use of a DOAC after ablation. The patients were enrolled in a large (3530 patients) multicenter registry in Japan. The study patients were classified as 749 (64.4%) appropriate standard-dose DOAC users, 216 (18.6%) off-label under-dose DOAC users, and 198 (17.0%) appropriate low-dose DOAC users.Age and CHA2DS2-VASc scores differed significantly between DOAC dosing regimens, with patients given an appropriate standard-dose being significantly younger (63.3 ± 9.4 versus 64.8 ± 9.5 versus 73.2 ± 6.8 years, P < 0.0001) and lower (2.1 ± 1.5 versus 2.4 ± 1.6 versus 3.4 ± 1.4, P < 0.0001) than those given an off-label under-dose or an appropriate low-dose. During the median 19.0-month follow-up period, the AF recurrence rate was similar between the appropriate standard-dose and off-label under-dose groups but relatively low in the appropriate low-dose group (42.5% versus 41.2% versus 35.4%, P = 0.08). Annualized rates of thromboembolic events, major bleeding, and death from any cause were 0.47%, 0.70%, and 0.23% in the off-label under-dose group, while those rates were 0.74%, 0.73%, and 0.65% in the appropriate standard-dose, and 1.58%, 2.12%, and 1.57% in the appropriate low-dose groups.In conclusion, the clinical adverse event rates for patients on an off-label under-dose DOAC regimen after ablation, predicated on careful patient evaluations, was not high as seen with that of patients on a standard DOAC dosing regimen.

Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases.

AIMS: The genetic cause of cardiac conduction system disease (CCSD) has not been fully elucidated. Whole-exome sequencing (WES) can detect various genetic variants; however, the identification of pathogenic variants remains a challenge. We aimed to identify pathogenic or likely pathogenic variants in CCSD patients by using WES and 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines as well as evaluating the usefulness of functional studies for determining them. METHODS AND RESULTS: We performed WES of 23 probands diagnosed with early-onset (<65 years) CCSD and analysed 117 genes linked to arrhythmogenic diseases or cardiomyopathies. We focused on rare variants (minor allele frequency < 0.1%) that were absent from population databases. Five probands had protein truncating variants in EMD and LMNA which were classified as 'pathogenic' by 2015 ACMG standards and guidelines. To evaluate the functional changes brought about by these variants, we generated a knock-out zebrafish with CRISPR-mediated insertions or deletions of the EMD or LMNA homologs in zebrafish. The mean heart rate and conduction velocities in the CRISPR/Cas9-injected embryos and F2 generation embryos with homozygous deletions were significantly decreased. Twenty-one variants of uncertain significance were identified in 11 probands. Cellular electrophysiological study and in vivo zebrafish cardiac assay showed that two variants in KCNH2 and SCN5A, four variants in SCN10A, and one variant in MYH6 damaged each gene, which resulted in the change of the clinical significance of them from 'Uncertain significance' to 'Likely pathogenic' in six probands. CONCLUSION: Of 23 CCSD probands, we successfully identified pathogenic or likely pathogenic variants in 11 probands (48%). Functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants in patients with CCSD. SCN10A may be one of the major genes responsible for CCSD.

Current Status and Clinical Outcomes of Oral Anticoagulant Discontinuation After Ablation for Atrial Fibrillation in Japan　- Findings From the AF Frontier Ablation Registry.

BACKGROUND: The safety of discontinuing oral anticoagulant (OAC) after ablation for atrial fibrillation (AF) in Japanese patients has not been clarified.Methods and Results:A study based on the Atrial Fibrillation registry to Follow the long-teRm Outcomes and use of aNTIcoagulants aftER Ablation (AF Frontier Ablation Registry) was conducted. Data were collected from 3,451 consecutive patients (74.1% men; age, 63.3±10.3 years) who had undergone AF ablation at any of 24 cardiovascular centers in Japan between August 2011 and July 2017. During a 20.7-month follow-up period, OAC therapy was discontinued in 1,836 (53.2%) patients; 51 patients (1.5%) suffered a stroke/transient ischemic attack (TIA), 71 (2.1%) suffered major bleeding, and 36 (1.0%) died. Patients in whom OAC therapy was discontinued were significantly younger than those in whom OACs were continued, and their CHA2DS2-VASc scores were significantly lower. The incidences of stroke/TIA, major bleeding, and death were significantly lower among these patients. Upon multivariate adjustment, stroke events were independently associated with relatively high baseline CHA2DS2-VASc scores but not with OAC status. CONCLUSIONS: Although the incidences of stroke/TIA, major bleeding, and death were relatively low among patients for whom OAC therapy was discontinued, stroke/TIA occurrence was strongly associated with a high baseline stroke risk rather than with OAC status. Thus, discontinuation of OAC therapy requires careful consideration, especially in patients with a high baseline stroke risk.

Acute flaccid myelitis associated with enterovirus D68 in a non-epidemic setting.

Acute flaccid myelitis (AFM) is a recently defined clinical disease accompanied by the national outbreak of enterovirus D68 (EV-D68) in the United States during the late summer/fall of 2014; 258 cases of EV-D68 and 59 cases of AFM were reported in Japan during the late summer/fall of 2015. Subsequently, there have been no epidemics of AFM or EV-D68. However, we encountered a patient who had AFM associated with EV-D68 in 2017. This is the first case of AFM caused by EV-D68 after the 2015 epidemic, and the only reported case in 2017. This report indicates that AFM caused by EV-D68 can arise even in non-epidemic situations. If a patient presents with paralysis, AFM caused by EV-D68 should be included in the differential diagnosis, regardless of the absence of an epidemic of EV-D68 infection.

Pial arteriovenous fistula of the spine in a child with hemiplegia.

Pial arteriovenous fistula (AVF) is an extremely rare disease in children. When a child presents with sudden onset of hemiparesis and headache, it is very important to perform spinal magnetic resonance imaging (MRI) scanning for early diagnosis and treatment.

Impact of Distal Protection with Filter-Type Device on Long-term Outcome after Percutaneous Coronary Intervention for Acute Myocardial Infarction: Clinical Results with Filtrap®.

AIM: Although distal embolization during percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) deteriorates cardiac function, whether distal protection (DP) can improve prognosis is still controversial. We investigated whether a filter-type DP device, Filtrap®, could improve long-term outcomes after PCI for AMI. METHOD: We studied 164 patients (130 men, mean age: 65.7 years) who underwent PCI. Patients were divided into two groups based on the use of Filtrap®. The occurrence of congestive heart failure (CHF) and major adverse cardiac events (MACE) defined as cardiac death, recurrent AMI, and target vessel revascularization were compared. RESULT: Between DP (n=53, 41 men, mean age: 65.5 years) and non-DP (n=111, 89 men, mean age: 65.8 years) groups, although there was significantly greater plaque area in the DP group than in the non-DP group, there were no significant differences in coronary reperfusion flow after PCI. Interestingly, patients with CHF in the non-DP group exhibited a higher CK level than those in the DP group. During a 2-year follow-up period, cumulative CHF was significantly lower in the DP group than in the non-DP group (log-rank p=0.018), and there was no significant difference in the MACE rate (log-rank p=0.238). The use of DP device could not predict MACE, but could predict CHF by multivariate analysis (odds ratio=0.099, 95% CI: 0.02-0.42, p=0.005). CONCLUSION: These results demonstrate that favorable clinical outcomes could be achieved by the filter-type DP device in AMI, particularly in patients with CHF.

Impact of thin-cap fibroatheroma on predicting deteriorated coronary flow during interventional procedures in acute as well as stable coronary syndromes: insights from optical coherence tomography analysis.

The occurrence of deteriorated coronary flow associated with distal embolization during percutaneous coronary intervention results in impaired myocardial perfusion and worsens the clinical prognosis. This study aimed to examine the impact of optical coherence tomography (OCT)-determined coronary plaque morphology on the prediction of deteriorated coronary flow after stent implantation in acute as well as stable coronary syndromes (ACS and SAP, respectively). We studied 126 patients who underwent OCT during stenting for ACS (n = 44) and SAP (n = 82) with a de novo lesion. Angiographic deteriorated coronary flow was defined as the deterioration of TIMI flow grade after mechanical dilatation in the absence of a mechanical obstruction on angiograms. Patients could be divided into the deteriorated flow group (n = 21) and the reflow group (n = 105). Under these conditions, the presence of thin-cap fibroatheroma (TCFA) was more frequently observed in the deteriorated flow group than in the reflow group in both ACS and SAP. A multivariable logistic regression model revealed that TCFA was an independent predictor of deteriorated coronary flow (hazard ratio: 12.32; 95 % confidence interval: 3.02-50.31; p = 0.0005). These results demonstrate that TCFA detected by OCT could be a strong predictor of the occurrence of deteriorated coronary flow during stent implantation in ACS as well as SAP.

Comparison of sirolimus-eluting, paclitaxel-eluting, and bare-metal stents in a patient with angina pectoris: histopathological autopsy findings of the third month.

A 67-year-old man with a more than 15-year-old history of hypertension, dyslipidemia, and glucose intolerance presented at our hospital with exertional angina. Coronary angiography showed considerable stenosis of 3 vessels. A diffuse calcified lesion in the left anterior descending coronary artery was pre-treated using rotational atherectomy followed by sirolimus-eluting stent (SES) implantation. A lesion in the proximal right coronary artery was treated by bare-metal stent (BMS) implantation, and the tandem lesion in the left circumflex artery was treated using paclitaxel-eluting stent (PES) implantation. All the procedures were performed within 1 month of the initial presentation and yielded good angiographic results. 3 months after the final stenting, the patient was re-admitted because of congestive heart failure (CHF). While recovering from CHF, he suddenly developed cardiopulmonary arrest and died during hospitalization. Autopsy examination of the coronary arteries showed that both drug-eluting stents (DESs: SES and PES) and the BMS had characteristic histopathological features. Inflammatory responses in the neointima were greater in both the DESs than in the BMS. SES and PES showed different inflammatory infiltration pattern or fibrin deposition status; these histopathological differences observed in the DES environments have implication to cause adverse clinical events such as late stent thrombosis or late catch-up phenomena.

Therapeutic Efficacy and Safety of GH in Japanese Children with Down Syndrome Short Stature Accompanied by GH Deficiency.

In this study, we investigated the effects of GH treatment in children with Down syndrome who had been diagnosed with GH deficiency (GHD). A total of 20 subjects were investigated in this study. Fourteen Down syndrome children (5 boys and 9 girls) with short stature due to GHD were treated with GH at Okayama Red Cross General Hospital, and 6 Down syndrome children (4 boys and 2 girls) with short stature due to GHD were registered in the Pfizer International Growth Database (KIGS). Height SD score (SDS) increased throughout the three-year GH treatment period. The overall mean height SDS increased from -3.5 at baseline to -2.5 after 3 yr of treatment. The mean change in height SDS during these 3 yr was 1.1. In addition, height assessment of SD score based on Down syndrome-specific growth data in the Japanese population revealed that the height SDS (Down syndrome) also increased across the 3-yr GH treatment period. The mean change in height SDS (Down syndrome) during these three years was 1.3. GH therapy was effective for Down syndrome short stature accompanied by GHD, and no new safety concerns were found in this study.

Spontaneous healing of posttraumatic focal coronary aneurysm: a case report.

We report on the spontaneous healing of a posttraumatic focal coronary aneurysm in a previously healthy 61-year-old man after his involvement in a motor vehicle accident, resulting in blunt chest trauma that injured the anterior wall of his left ventricle. Left-sided cardiac catheterization and selective coronary angiography 1 month after the accident showed an aneurysm in the proximal part of the left anterior descending artery, and normal coronary arteries otherwise. Intravascular ultrasound revealed that the lesion was a pseudoaneurysm protruding toward the myocardium. Surgical removal of the aneurysm was not considered, and the patient was discharged after 2 months of uneventful hospitalization. Follow-up coronary angiography and intravascular ultrasound at 3 months and 1 year after the accident showed a total regression of the aneurysm. The patient has remained asymptomatic, with no residual ischemia 3 years after the accident. This case indicates that careful conservative treatment is a therapeutic option for posttraumatic coronary pseudoaneurysms.

Transition of the ST segment from a J wave to a coved-type elevation before ventricular fibrillation induced by coronary vasospasm in the precordial leads.

We describe the case of a 63-year-old man whose electrocardiogram showed transition of the ST segment from a J wave to a coved-type elevation in precordial leads before ventricular fibrillation induced by right coronary artery vasospasm. Simultaneously, the ST segment in inferior leads was gradually depressed with a J wave. Considering the sudden death of his son, induced ventricular fibrillation by programmed electrical stimulation, and modulations of the ST segment in the precordial and inferior leads by pilsicainide, some abnormalities in repolarization associated with Brugada syndrome or early repolarization syndrome might have caused these atypical ST-segment manifestations.

Growth of infants with osteogenesis imperfecta treated with bisphosphonate.

BACKGROUND: Osteogenesis imperfecta (OI) is a heritable bone disease characterized by bone brittleness and various degrees of growth disorder. Cyclic pamidronate therapy is reportedly useful to prevent bone fracture in OI and in infants with OI, but, it remains unclear how infants with OI grow during bisphosphonate therapy. METHODS: Height and weight measurements of OI infants treated with cyclic pamidronate therapy were taken before and every 6 months during therapy until 18 months. Vertebral morphometry and the concavity index were analyzed using X-ray films taken simultaneously. RESULTS: Among OI patients, those in the group for which the height z-score decreased tended to have more femur fractures than those of the group for which the height z-score increased. Morphometry of the lumbar spine showed that compression fractures occurred less during cyclic pamidronate therapy, by which the lumbar bone mineral density increased. CONCLUSIONS: Bisphosphonate preserved vertebral morphometry during 18 months after starting therapy in infants. Prevention of femur fracture during the infantile period might help prevent short stature; therapeutic strategies during infancy must better emphasize prevention of long bone fracture before the beginning of gait.

Flow uniformity in oxygenators with different outlet port design.

This study reports on evaluation of the optimum design of a blood outlet port structure for providing uniform flow by visualizing the blood flow in an extracapillary membrane oxygenator. We tested a cylindrical type extracapillary membrane oxygenator, HPO-20. The HPO-20 has a tangential blood outlet port and is thus referred to as "Tangential HPO-20." We engineered "Vertical HPO-20" with a vertical blood outlet port by modifying the Tangential HPO-20. To visualize the blood-side flow, a total of 120 insulated copper-wire electrodes were placed in the "Tangential" and the Vertical HPO-20s. The test solution flow was visualized by the dimensionless fluid arrival time reaching each electrode. The test solution flow in the Tangential HPO-20 was not uniform, particularly at the outside blood channel. The flow was more uniform in the Vertical HPO-20. The blood flow in an extracapillary membrane oxygenator with a vertical blood outlet port is well distributed so that it produces more uniform blood flow than that with a tangential outlet port because of the small stagnation and reduced channeling.