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Aims Heart failure with preserved LV ejection fraction (HFpEF) is a serious health problem worldwide, as no effective therapy is yet available. We have previously demonstrated that our low-intensity pulsed ultrasound (LIPUS) therapy is effective and safe for angina and dementia. In this study, we aimed to examine whether the LIPUS therapy also ameliorates cardiac diastolic dysfunction in mice. Methods and results Twelve-weeks-old obese diabetic mice (db/db) and their control littermates (db/+) were treated with either the LIPUS therapy (1.875 MHz, 32 cycles, Ispta (spatial peak temporal average intensity) 117-162 mW/cm2, 0.25 W/cm2) or placebo procedure 2 times a week for 4 weeks. At 20-week-old, transthoracic echocardiography and invasive hemodynamic analysis showed that cardiac diastolic function parameters, such as e', E/e', end-diastolic pressure-volume relationship, Tau, and dP/dt min, were all deteriorated in placebo-treated db/db mice compared with db/+ mice, while systolic function was preserved. Importantly, these cardiac diastolic function parameters were significantly ameliorated in the LIPUS-treated db/db mice. We also measured the force (F) and intracellular Ca2+ ([Ca2+]i) in trabeculae dissected from ventricles. We found that relaxation time and [Ca2+]i decay (Tau) were prolonged during electrically stimulated twitch contractions in db/db mice, both of which were significantly ameliorated in the LIPUS-treated db/db mice, indicating that the LIPUS therapy also improves relaxation properties at tissue level. Functionally, exercise capacity was also improved in the LIPUS-treated db/db mice. Histologically, db/db mice displayed progressed cardiomyocyte hypertrophy and myocardial interstitial fibrosis, while those changes were significantly suppressed in the LIPUS-treated db/db mice. Mechanistically, Western blot showed that the eNOS-NO-cGMP-PKG pathway and Ca2+-handling molecules were up-regulated in the LIPUS-treated heart. Conclusions These results indicate that the LIPUS therapy ameliorates cardiac diastolic dysfunction in db/db mice through improvement of eNOS-NO-cGMP-PKG pathway and cardiomyocyte Ca2+-handling system, suggesting its potential usefulness for the treatment of HFpEF patients. Translational perspective Although HFpEF is a serious health problem worldwide, no effective treatment is yet available. We have previously demonstrated that our low-intensity pulsed ultrasound (LIPUS) therapy is effective and safe in animal models of angina and dementia. In this study, we examined whether our LIPUS therapy is also effective to improve cardiac diastolic dysfunction in mice. We found that the LIPUS therapy ameliorated myocardial structures and Ca2+-handling proteins, resulting in the improvement of cardiac diastolic functions and exercise tolerance in a mouse model of HFpEF. These results suggest that the LIPUS therapy is useful for the treatment of HFpEF in humans.

Since the treatment window of thrombolytic therapy for stroke is limited, new therapy remains to be developed. We have recently developed low-intensity pulsed ultrasound (LIPUS) therapy to improve cognitive dysfunction in mouse models of vascular dementia and Alzheimer’s disease. Here, we further aimed to examine whether our LIPUS therapy improves neurological recovery from ischemic stroke, and if so, to elucidate the mechanisms involved. In a mouse model of middle cerebral artery occlusion (MCAO), we applied LIPUS (32 cycles, 193 mW/cm2) to the whole brain 3 times in the first week (days 1, 3, and 5) after MCAO. We evaluated neurological functions using behavioral tests and performed histological analyses. Furthermore, to elucidate how LIPUS works within the injured brain, we also tested the effects of LIPUS in endothelial nitric oxide synthase (eNOS)-deficient (eNOS−/−) mice. In wild-type mice, the LIPUS therapy markedly improved neurological functions in the tightrope and rotarod tests at 28 days after MCAO. Histological analyses showed that the LIPUS therapy significantly increased the numbers of CD31-positive blood vessels in the perifocal lesion and doublecortin (DCX)-positive neurons in the ischemic striatum, indicating the angio-neurogenesis effects of the therapy. Importantly, these beneficial effects of the LIPUS therapy were totally absent in eNOS−/− mice. No adverse effects of the LIPUS therapy were noted. These results indicate that the LIPUS therapy improves neurological functions after stroke through enhanced neuro-angiogenesis in mice in vivo in an eNOS-dependent manner, suggesting that it could a novel and non-invasive therapeutic option for stroke.

Background Heart failure (HF) promotes atrial fibrillation (AF) and AF worsens HF. This study aimed to investigate the long-term clinical outcomes after AF ablation in patients with HF. Methods and results A total of 106 consecutive HF patients, including 51 (48.1%) with a reduced left ventricular ejection fraction (LVEF) (HFrEF) and 55 (51.9%) with a preserved LVEF (HFpEF), underwent AF ablation. All patients underwent successful pulmonary vein antrum isolation, and substrate modification was added in 38 (35.8%). The mean follow-up period was 32.4 ± 18.6 months, and mean number of procedures was 1.4 ± 0.5 per patient. Low-dose antiarrhythmic drugs were combined in 29 (27.3%) patients. Freedom from recurrent atrial arrhythmias (ATa), HF-related hospitalizations, and the composite endpoint (all-cause death, stroke, HF-related hospitalizations) at 3 years was 88.7%, 97.6%, and 97.6% in HFrEF patients, and 79.3%, 96.2%, and 91.8% in HFpEF patients, respectively. LVEF normalization (≥50%) was observed in 37 (72.5%) HFrEF patients post-ablation, and a smaller LV diastolic diameter (LVDd) was the sole predictor [odds ratio (OR) = 0.863; 95% confidence interval (CI) = 0.779–0.955, p = 0.005]. Shortening of the LVDd (≥5 mm) was observed in 16 (29.1%) HFpEF patients post-ablation, and no recurrence after the initial procedure was the sole predictor (OR = 6.229; 95% CI = 1.524–25.469, p = 0.011). Conclusions Catheter ablation of AF could be one of the important therapeutic options in the management of patients with HF combined with AF regardless of the type of HF.

Persistent iatrogenic atrial septal defects (iASDs) can be observed after intervention requiring a left atria (LA) access, including pulmonary vein isolation (PVI) of atrial fibrillation (AF). We investigated the incidence of iASDs post-second-generation cryoballoon ablation and the pre-procedural predictors. Eighty-three paroxysmal AF patients underwent PVI using second-generation cryoballoons. The LA was accessed with single 15-Fr steerable sheaths following a radiofrequency transseptal puncture, and the iASD was evaluated with transthoracic echocardiography (TTE), a median of 9.3 (7.1–13.3) months post-procedure. All patients underwent pre-procedural contrast-enhanced multi-detector computed tomography (CT) to evaluate the LA and PV anatomy. iASDs were detected by TTE in 7 (8.4%) patients, a median of 15.5 (6.8–17.3) months post-procedure. Patients with iASDs had significantly larger LA volumes and smaller atrial septal angles, defined as the angle between the atrial septum and sagittal line on the horizontal section at the height of the fossa ovalis, which could be the transseptal puncture site measured on CT, and more likely hypertension than those without. Multivariate analyses revealed that the atrial septal angle was the sole predictor of iASDs [odds ratio 0.764, 95% confidence interval (CI) 0.624–0.935, p = 0.009], and the optimal cut-off value was 57.5° (sensitivity 85.7%, specificity 88.2%, 95% CI 0.873–0.995, p

Little is known regarding the association between chronological out-stent vessel remodeling and in-stent tissue characteristics of drug-eluting stent (DES) failure. We aimed to evaluate the relationship between serial vessel remodeling after DES implantation and neoatherosclerosis (NA) assessed by optical coherence tomography (OCT) in patients with DES failure.Forty-eight patients with late and very late stent failure after DES implantation, who underwent intravascular ultrasound (IVUS) at both the initial percutaneous coronary intervention and the time of stent failure and OCT imaging at the time of stent failure, were retrospectively investigated. NA on OCT was defined as neointimal formation with the presence of lipids or calcification inside the stents. Lesions were divided into two groups: those with NA and those without NA (NA: n=21; non-NA: n=27). From the serial IVUS examinations, external elastic membrane (EEM) volume and out-stent plaque volume were normalized by stent length and their changes were compared between the two groups.The NA group showed older stent age [median, 5.1 years (IQR, 4.8-8.3) vs 1.4 years (IQR, 0.8-4.5); p0.01] and more prevalent sirolimus-eluting stents (SES; 81.0% vs. 29.6%; p0.01). IVUS findings of the NA group showed a greater serial increase in both normalized EEM volume and normalized out-stent plaque volume (OSPVI) [1.05 (0.41-1.90) vs. 0.11 (-0.64 to 0.80) mmNA in late and very late DES failure was associated with out-stent positive vessel remodeling. In addition to SES, out-stent progressive positive remodeling may help predict NA in late and very late DES failure.

Background The intrinsic cardiac autonomic nervous system (ANS) plays a significant role in atrial fibrillation(AF) mechanisms. This study evaluated the incidence and impact of intra-procedural vagal reactions and ANS modulation by pulmonary vein isolation (PVI) using second-generation cryoballoons on outcomes. Methods One hundred three paroxysmal AF patients underwent PVI with one 28-mm second-generation balloon. The median follow-up was 15.0[12.0-18.0] months. ANS modulation was defined as a >20% cycle length decrease on 3-minute resting electrocardiograms at 1, 3, 6, and 12 months post-index procedure relative to baseline if sinus rhythm was maintained. Results Marked sinus arrests/bradycardia and AV block (intra-procedural vagal reaction) occurred in 14 and 2 patients, and all sinus arresst/bradycardia occurred in 44 patients with left superior PVs targeted before right PVs. ANS modulation was identified in 66/95(69.5%) patients, and it persisted 12-month post-procedure in 36(37.9%) patients. Additional beta-blocker administration was required in 9 patients for sinus tachycardia. ANS modulation was similarly observed in patients with and without intra-procedural vagal reactions (p = 0.443). Forty-eight(46.6%) patients experienced early recurrences, and the single procedure success at 12 months was 72.7%. Neither intra-procedural vagal reactions nor ANS modulation predicted AF freedom within or after the blanking period. Thirty-three patients underwent second procedures, and reconnections were detected in 39/130(30.0%) PVs among 23(69.7%) patients. The incidence of reconnections was similar in patients with and without ANS modulation. Conclusions Increased heart rate persisted in 37.9% of patients even at 12-month post-second-generation cryoballoon PVI. Neither intra-procedural vagal reactions nor increased heart rate predicted a single procedure clinical outcome. This article is protected by copyright. All rights reserved

The reverse CART technique provides the potential to modify the retrograde procedure by improving the controlled movement of the retrograde wire and improve the success rates of percutaneous coronary intervention (PCI) of chronic total occlusion (CTO). Development of interventricular hematoma is a rare complication of CTO PCI. A 63-year-old man with effort angina with a right coronary artery CTO lesion underwent PCI by retrograde approach from the LAD to a septal branch. A contrast “stain” was demonstrated surrounding the septal collateral channel used for the retrograde approach at the end of the procedure without symptom. Echocardiography indicated an increased interventricular septum thickness with low echo signals region and decreased contractility. Cardiac magnetic resonance (CMR) imaging using gadolinium showed a diffusely thickened septum with a low signal fusiform neocavitation delimited by an enhanced-signal ring suggesting intraventricular septal dissecting hematoma. After conservative treatment, follow-up echocardiogram and CMR showed the resolution of the hematoma without clinical events. This case highlights the potentially lethal complication of septal perforator dissection and hematoma that may cause severe myocardial injury caused by retrograde approach for CTO PCI.

Background Atrial fibrillation ablation is associated with substantial risks of silent cerebral events (SCEs) or silent cerebral lesions. We investigated which procedural processes during cryoballoon procedures carried a risk. Methods and Results Forty paroxysmal atrial fibrillation patients underwent pulmonary vein isolation using second-generation cryoballoons with single 28-mm balloon 3-minute freeze techniques. Microembolic signals (MESs) were monitored by transcranial Doppler throughout all procedures. Brain magnetic resonance imaging was obtained pre- and post-procedure in 34 patients (85.0%). Of 158 pulmonary veins, 152 (96.2%) were isolated using cryoablation, and 6 required touch-up radiofrequency ablation. A mean of 5.0±1.2 cryoballoon applications was applied, and the left atrial dwell time was 76.7±22.4 minutes. The total MES counts/procedures were 522 (426–626). Left atrial access and Flexcath sheath insertion generated 25 (11–44) and 34 (24–53) MESs. Using radiofrequency ablation for transseptal access increased the MES count during transseptal punctures. During cryoapplications, MES counts were greatest during first applications (117 [81–157]), especially after balloon stretch/deflations (43 [21–81]). Pre– and post–pulmonary vein potential mapping with Lasso catheters generated 57 (21–88) and 61 (36–88) MESs. Reinsertion of once withdrawn cryoballoons and subsequent applications produced 205 (156–310) MESs. Touch-up ablation generated 32 (19–62) MESs, whereas electric cardioversion generated no MESs. SCEs and silent cerebral lesions were detected in 11 (32.3%) and 4 (11.7%) patients, respectively. The patients with SCEs were older than those without; however, there were no significant factors associated with SCEs. Conclusions A significant number of MESs and SCE/silent cerebral lesion occurrences were observed during second-generation cryoballoon ablation procedures. MESs were recorded during a variety of steps throughout the procedure; however, the majority occurred during phases with a high probability of gaseous emboli.

Background Despite a moderate correlation between angiographical stenosis and physiological significance, the mechanism of discordance has not been fully elucidated, particularly regarding the significance of microvascular function. This study sought to clarify whether microvascular function affects visual‐functional mismatch between quantitative coronary angiography ( QCA ) and fractional flow reserve ( FFR ). Methods and Results We assessed QCA , FFR , coronary flow reserve, and the index of microcirculatory resistance in 849 non‐left‐main coronary lesions with visually estimated intermediate stenoses from 532 patients. Clinical and lesion‐specific characteristics and physiological parameters associated with mismatch and reverse mismatch were studied. Coronary flow reserve and index of microcirculatory resistance showed a weak, but significant, correlation with FFR (R=0.306, P P QCA ‐ DS ] ≤50%) and 427 lesions were visually significant ( QCA ‐ DS >50%). Among visually nonsignificant lesions, FFR ≤0.80 (reverse mismatch) was observed in 129 lesions (30.6%). Among visually significant lesions, FFR >0.80 (mismatch) were observed in 179 lesions (41.9%). The significant predictors of reverse mismatch were male sex, nonculprit lesions of acute coronary syndrome, left anterior descending artery location, smaller QCA reference diameter, greater QCA ‐ DS , lower coronary flow reserve, and lower index of microcirculatory resistance. Mismatch was associated with right coronary artery location, greater QCA reference diameter, smaller QCA ‐ DS , lesion length, higher coronary flow reserve, and higher index of microcirculatory resistance. Conclusions There was a high prevalence of visual‐functional mismatches between QCA and FFR . The discrepancy was related to clinical characteristics, lesion‐specific factors, and microvascular resistance that was undistinguishable by coronary angiography, thus suggesting the importance of physiological lesion assessment.

From August 26th to 30th, the 2017 Annual Congress of the European Society of Cardiology (ESC 2017) was held in Barcelona, Spain. Despite the terrorism tradegy just before the ESC congress, the congress attracted many medical professionals from all over the world to discuss the recent topics in cardiovascular medicine in more than 500 sessions, including COMPASS (Cardiovascular OutcoMes for People using Anticoagulation StrategieS Trial), CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study), and ORION (which assessed the effect of a novel siRNA inhibitor to PCSK9 on reductions in low-density lipoprotein cholesterol). Japanese cardiologists and the Japanese Circulation Society greatly contributed to the congress. This report briefly introduces some late-breaking registry results, late-breaking clinical trials, and ESC Guidelines from the ESC 2017 Congress.

Percutaneous directional coronary atherectomy (DCA) is a plaque debulking method performed in Japan, and recently a renewed DCA device has been launched. We present a case with a tight left anterior descending lesion undergoing percutaneous coronary intervention with application of DCA. After several sessions of DCA, white plaques accompanied by green, stringed materials were obtained from the device; some materials were considerably long (approximately 15 mm in length). A drug-eluting stent was subsequently implanted, and the procedure was completed successfully without any complications. The extracted plaques and artificial materials were pathologically examined, and no inflammatory changes were detected on plaques adjacent to the material. Assessing pathological findings and structure of the DCA catheter, the obtained artificial materials were considered as peeled guidewire, possibly resulting from the friction between the guidewire and metallic bearing in the housing of DCA catheter. Of note, this phenomenon has been recognized even in other DCA cases in which guidewires of the other kind are used. We report this phenomenon for the first time, warning of theoretically possible distal embolization of artificial materials caused by any debulking devices.

BACKGROUND The effect of prior use of aspirin (ASA) on the onset of acute coronary syndrome (ACS) has not been clarified. This study used optical coherence tomography (OCT) to investigate the morphological features of culprit lesions of ACS in patients with prior ASA use.Methods and Results:In total, 442 patients with their first ACS episode undergoing OCT for the culprit lesions were investigated. Clinical characteristics, OCT findings, and adverse events at 30 days were compared between patients with prior ASA use and ASA-naive patients (non-ASA). 67 patients (15.2%) had received ASA at presentation. The ASA group was older, had higher frequency of dyslipidemia and hypertension, and lower renal function than the non-ASA group. Non-ST-elevation ACS was more prevalent in the ASA than in the non-ASA group (79.1 vs. 53.6%, P

Backgrounds: The aim of the present study is to investigate the relationship between physiological coronary artery stenosis severity and lesion instability by Optical Coherence Tomography (OCT) in patients with stable angina pectoris (SAP). Methods and Results: We investigated 198 culprit lesions of 180 SAP patients who underwent OCT imaging and fractional flow reserve (FFR) measurement before PCI procedure. Physiological coronary stenosis severity was assessed by FFR analysis, and lesions were divided into two groups on the basis of FFR values; severe stenosis group (group S): FFR Conclusions: Lesions of physiologically severe coronary stenosis in SAP were associated with lesion instability assessed by OCT. These findings may challenge the concept that lesions responsible for acute coronary syndromes are mild in most cases provided that plaque rupture of TCFA evenly results in coronary events in the wide range of stenosis severity in patients with SAP.

Introduction Chronic left ventricular (LV) pressure overload causes relative ischemia with resultant LV dysfunction. We have recently demonstrated that low-intensity pulsed ultrasound (LIPUS) improves myocardial ischemia in a pig model of chronic myocardial ischemia through enhanced myocardial angiogenesis. In the present study, we thus examined whether LIPUS also ameliorates contractile dysfunction in LV pressure-overloaded hearts. Methods and results Chronic LV pressure overload was induced with transverse aortic constriction (TAC) in mice. LIPUS was applied to the whole heart three times in the first week after TAC and was repeated once a week for 7 weeks thereafter (n = 22). Animals in the control groups received the sham treatment without LIPUS (n = 23). At 8 weeks after TAC, LV fractional shortening was depressed in the TAC-Control group, which was significantly ameliorated in the TAC-LIPUS group (30.4±0.5 vs. 36.2±3.8%, P

Objectives Although diagnostic coronary angiography (CAG) is performed worldwide, procedure-related myocardial necrosis (PMN) following diagnostic catheter-based procedures has not been well investigated. The aim of this study was to determine clinical and procedural factors associated with PMN, using a high-sensitivity cardiac troponin I (hs-cTnI) assay, and to investigate the clinical implications of PMN. Methods Among 697 patients undergoing elective CAG and pre- and post-procedural hs-cTnI (pre-TnI, post-TnI, respectively) measurements, a total of 538 patients (124 female) were evaluated, with 2.2% lost during follow-up. Minor PMN was defined as post-TnI above the sex-specific upper reference limit (URL), with a 20% increase from the pre-TnI level. Major PMN was defined as post-TnI above 5x the URL. Clinical and procedural factors predicting PMN and the association between PMN and major adverse cardiac events (MACE) following CAG were examined. Results PMN of any type was detected in 178 patients (33.0%), while major PMN was observed in 32 patients (5.9%). Female sex, estimated glomerular filtration rate, procedural time, left ventricular end-diastolic pressure (LVEDP) and fractional flow reserve measurement independently predicted any PMN; whereas, only LVEDP and log-transformed N-terminal pro-brain natriuretic peptide independently predicted major PMN. The incidence of MACE was significantly associated with major PMN. Cox proportional-hazards models revealed that major PMN, pre-TnI, and the absence of statin use were independently associated with MACE. Conclusions Diagnostic cardiac catheteriation may highlight cardiomyocyte susceptibility to stress in patients with or without CAD. CAG-related major myocardial injury might be associated with future adverse cardiac events independently of the presence or absence of functional stenosis.

Background: Circulating high-sensitivity cardiac troponin-I (hs-cTnl) and N-terminal pro brain natriuretic peptide (NT-proBNP) are powerful predictors of adverse cardiac outcomes in patients with coronary artery disease (CAD). We investigated the association of plasma levels of hs-cTnI and NT-proBNP