Two-Year Clinical Outcome of MitraClip Transcatheter Edge-to-Edge Repair From the J-MITRA Registry Data.

BACKGROUND: The introduction of transcatheter edge-to-edge repair for moderate-to-severe or severe mitral regurgitation (MR) utilizing the MitraClip system became reimbursed and clinically accessible in Japan in April 2018. This study presents the 2-year clinical outcomes of all consecutively treated patients who underwent MitraClip implantation in Japan and were prospectively enrolled in the Japanese Circulation Society-oriented J-MITRA registry.Methods and Results: Analysis encompassed 2,739 consecutive patients enrolled in the J-MITRA registry with informed consent (mean age: 78.3±9.6 years, 1,550 males, STS risk score 11.7±8.9), comprising 1,999 cases of functional MR, 644 of degenerative MR and 96 in a mixed group (DMR and FMR). The acute procedure success rate was 88.9%. After MitraClip implantation, >80% exhibited an MR grade ≤2+ and the trend was sustained over the 2 years. Within this observation period, the mortality rate was 19.3% and the rate of heart failure readmissions was 20.6%. The primary composite endpoint, inclusive of cardiovascular death and heart failure readmission, was significantly higher in patients with functional MR than in with degenerative MR (32.0% vs. 17.5%, P<0.001). CONCLUSIONS: The 2-year clinical outcomes after MitraClip implantation were deduced from comprehensive data within an all-Japan registry.

Non-invasive assessment of left ventricular filling pressure in aortic stenosis.

BACKGROUND: The assessment of left ventricular (LV) filling pressure (FP) is important for the management of aortic stenosis (AS) patients. Although, it is often restricted for predict LV FP in AS because of mitral annular calcification and a certain left ventricular hypertrophy. Thus, we tested the predictive ability of the algorithm for elevated LV FP in AS patients and also applied a recently-proposed echocardiographic scoring system of LV FP, visually assessed time difference between the mitral valve and tricuspid valve opening (VMT) score. METHODS: We enrolled consecutive 116 patients with at least moderate AS in sinus rhythm who underwent right heart catheterization and echocardiography within 7 days. Mean pulmonary artery wedge pressure (PAWP) was measured as invasive parameter of LV FP. LV diastolic dysfunction (DD) was graded according to the ASE/EACVI guidelines. The VMT score was defined as follows: time sequence of opening of mitral and tricuspid valves was scored to 0-2 (0: tricuspid valve first, 1: simultaneous, 2: mitral valve first). When the inferior vena cava was dilated, one point was added and VMT score was finally calculated as 0-3. RESULTS: Of the 116 patients, 29 patients showed elevated PAWP. Ninety patients (93%) and 67 patients (63%) showed increased values for left atrium volume index (LAVI) and E/e', respectively when the cut-off values recommended by the guidelines were applied and thus the algorism predicted elevated PAWP with a low specificity and positive predictive value (PPV). VMT ≥ 2 predicted elevated PAWP with a sensitivity of 59%, specificity of 90%, PPV of 59%, and negative predictive value of 89%. An alternative algorithm that applied tricuspid regurgitation velocity and VMT scores was tested, and its predictive ability was markedly improved. CONCLUSION: VMT score was applicable for AS patients. Alternative use of VMT score improved diagnostic accuracy of guideline-recommended algorism.

Optogenetic termination of atrial tachyarrhythmias by brief pulsed light stimulation.

AIMS: The most efficient way to acutely restore sinus rhythm from atrial fibrillation (AF) is electrical cardioversion, which is painful without adequate sedation. Recent studies in various experimental models have indicated that optogenetic termination of AF using light-gated ion channels may provide a myocardium-specific and potentially painless alternative future therapy. However, its underlying mechanism(s) remain(s) incompletely understood. As brief pulsed light stimulation, even without global illumination, can achieve optogenetic AF termination, besides direct conduction block also modulation of action potential (AP) properties may be involved in the termination mechanism. We studied the relationship between optogenetic AP duration (APD) and effective refractory period (ERP) prolongation by brief pulsed light stimulation and termination of atrial tachyarrhythmia (AT). METHODS AND RESULTS: Hearts from transgenic mice expressing the H134R variant of channelrhodopsin-2 in atrial myocytes were explanted and perfused retrogradely. AT induced by electrical stimulation was terminated by brief pulsed blue light stimulation (470 nm, 10 ms, 16 mW/mm2) with 68% efficacy. The termination rate was dependent on pulse duration and light intensity. Optogenetically imposed APD and ERP changes were systematically examined and optically monitored. Brief pulsed light stimulation (10 ms, 6 mW/mm2) consistently prolonged APD and ERP when light was applied at different phases of the cardiac action potential. Optical tracing showed light-induced APD prolongation during the termination of AT. CONCLUSION: Our results directly demonstrate that cationic channelrhodopsin activation by brief pulsed light stimulation prolongs the atrial refractory period suggesting that this is one of the key mechanisms of optogenetic termination of AT.

Empagliflozin attenuates arrhythmogenesis in diabetic cardiomyopathy by normalizing intracellular Ca2+ handling in ventricular cardiomyocytes.

Diabetic cardiomyopathy has been reported to increase the risk of fatal ventricular arrhythmia. The beneficial effects of the selective sodium-glucose cotransporter-2 inhibitor have not been fully examined in the context of antiarrhythmic therapy, especially its direct cardioprotective effects despite the negligible SGLT2 expression in cardiomyocytes. We aimed to examine the antiarrhythmic effects of empagliflozin (EMPA) treatment on diabetic cardiomyocytes, with a special focus on Ca2+ handling. We conducted echocardiography and hemodynamic studies and studied electrophysiology, Ca2+ handling, and protein expression in C57BLKS/J-leprdb/db mice (db/db mice) and their nondiabetic lean heterozygous Leprdb/+ littermates (db/+ mice). Preserved systolic function with diastolic dysfunction was observed in 16-wk-old db/db mice. During arrhythmia induction, db/db mice had significantly increased premature ventricular complexes (PVCs) than controls, which was attenuated by EMPA. In protein expression analyses, calmodulin-dependent protein kinase II (CaMKII) Thr287 autophosphorylation and CaMKII-dependent RyR2 phosphorylation (S2814) were significantly increased in diabetic hearts, which were inhibited by EMPA. In addition, global O-GlcNAcylation significantly decreased with EMPA treatment. Furthermore, EMPA significantly inhibited ventricular cardiomyocyte glucose uptake. Diabetic cardiomyocytes exhibited increased spontaneous Ca2+ events and decreased sarcoplasmic reticulum (SR) Ca2+ content, along with impaired Ca2+ transient, all of which normalized with EMPA treatment. Notably, most EMPA-induced improvements in Ca2+ handling were abolished by the addition of an O-GlcNAcase (OGA) inhibitor. In conclusion, EMPA attenuated ventricular arrhythmia inducibility by normalizing the intracellular Ca2+ handling, and we speculated that this effect was, at least partly, due to the inhibition of O-GlcNAcylation via the suppression of glucose uptake into cardiomyocytes.NEW & NOTEWORTHY SGLT2is are known to improve cardiovascular outcomes regardless of the presence of diabetes and decrease traditional cardiovascular risk factors. We demonstrated, for the first time, that EMPA inhibited PVCs by normalizing Ca2+ handling in diabetic mice. Our data suggest that the effects of SGLT2is on calcium handling may occur because of suppression of O-GlcNAcylation through inhibition of glucose uptake and not because of NHE inhibition, as previously suggested.

Impact of right ventricular reserve on exercise capacity and quality of life in patients with left ventricular assist device.

Although measuring right ventricular (RV) function during exercise is more informative than assessing it at rest, the relationship between RV reserve function, exercise capacity, and health-related quality of life (HRQoL) in patients with left ventricular assist devices (LVAD) remains unresolved. We aimed to investigate whether RV reserve assessed by the change in RV stroke work index (RVSWI) during exercise is correlated with exercise capacity and HRQoL in patients with LVAD. We prospectively assessed 24 consecutive patients with LVAD who underwent invasive right heart catheterization in the supine position. Exercise capacity and HRQoL were assessed using the 6-min walk distance (6 MWD) and peak oxygen consumption (V̇o2) in cardiopulmonary exercise testing, and the EuroQol visual analog scale (EQ-VAS), respectively. The patients were divided into two groups according to the median ΔRVSWI (change from rest to peak exercise). Patients with lower ΔRVSWI had significantly lower changes in cardiac index and absolute value of RV dP/dt than those with higher ΔRVSWI. The ΔRVSWI was positively correlated with 6 MWD (r = 0.59, P = 0.003) and peak V̇o2 (r = 0.56, P = 0.006). In addition, ΔRVSWI was positively correlated with the EQ-VAS (r = 0.44, P = 0.030). In contrast, there was no significant correlation between RVSWI at rest and 6 MWD (r = -0.34, P = 0.88), peak V̇o2 (r = 0.074, P = 0.74), or EQ-VAS (r = 0.127, P = 0.56). Our findings suggest that the assessment of RV reserve function is useful for risk stratification in patients with LVAD.NEW & NOTEWORTHY The change in right ventricular stroke work index (RVSWI) during exercise, not RVSWI at rest, was associated with exercise capacity and HRQoL. Our findings suggest that the assessment of change in RVSWI during exercise as a surrogate of RV reserve function may aid in risk stratification of patients with LVAD.

Liver stiffness assessed by magnetic resonance elastography predicts clinical outcomes in patients with heart failure and without chronic liver disease.

OBJECTIVES: Evaluation of liver stiffness (LS) by magnetic resonance elastography (MRE) is useful for estimating right atrial pressure (RAP) in patients with heart failure (HF). However, its prognostic implications are unclear. We sought to investigate whether LS measured by MRE (LS-MRE) could predict clinical outcomes in patients with HF. METHODS: We prospectively examined 207 consecutive HF patients between April 2018 and May 2021 after excluding those with organic liver disease. All patients underwent 3.0-T MRE. The primary outcome of interest was the composite of all-cause death and hospitalisation for HF. RESULTS: During a median follow-up period of 720 (interquartile range [IQR] 434-1013) days, the primary outcome occurred in 44 patients (21%), including 15 (7%) all-cause deaths and 29 (14%) hospitalisations for HF. The patients were divided into two groups according to median LS-MRE of 2.54 (IQR 2.34-2.82) kPa. Patients with higher LS-MRE showed a higher incidence of the primary outcome compared to those with lower LS-MRE (p < 0.001). Multivariable Cox regression analyses revealed that LS-MRE value was independently associated with the risk of adverse events (hazard ratio 2.49, 95% confidence interval 1.46-4.24). In multivariable linear regression, RAP showed a stronger correlation with LS-MRE (ß coefficient = 0.31, p < 0.001) compared to markers related to liver fibrosis. CONCLUSIONS: In patients without chronic liver disease and presenting with HF, elevated LS-MRE was independently associated with worse clinical outcomes. Elevated LS-MRE may be useful for risk stratification in patients with HF and without chronic liver disease. KEY POINTS: • Magnetic resonance elastography (MRE) is an emerging non-invasive imaging technique for evaluating liver stiffness (LS) which can estimate right atrial pressure. • Elevated LS-MRE, which mainly reflects liver congestion, was independently associated with worse clinical outcomes in patients with heart failure. • The assessment of LS-MRE would be useful for stratifying the risk of adverse events in heart failure patients without chronic liver disease.

Differences in blood flow dynamics between balloon- and self-expandable valves in patients with aortic stenosis undergoing transcatheter aortic valve replacement.

BACKGROUND: The differences in pre- and early post-procedural blood flow dynamics between the two major types of bioprosthetic valves, the balloon-expandable valve (BEV) and self-expandable valve (SEV), in patients with aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR), have not been investigated. We aimed to investigate the differences in blood flow dynamics between the BEV and SEV using four-dimensional flow cardiovascular magnetic resonance (4D flow CMR). METHODS: We prospectively examined 98 consecutive patients with severe AS who underwent TAVR between May 2018 and November 2021 (58 BEV and 40 SEV) after excluding those without CMR because of a contraindication, inadequate imaging from the analyses, or patients' refusal. CMR was performed in all participants before (median interval, 22 [interquartile range (IQR) 4-39] days) and after (median interval, 6 [IQR 3-6] days) TAVR. We compared the changes in blood flow patterns, wall shear stress (WSS), and energy loss (EL) in the ascending aorta (AAo) between the BEV and SEV using 4D flow CMR. RESULTS: The absolute reductions in helical flow and flow eccentricity were significantly higher in the SEV group compared in the BEV group after TAVR (BEV: - 0.22 ± 0.86 vs. SEV: - 0.85 ± 0.80, P < 0.001 and BEV: - 0.11 ± 0.79 vs. SEV: - 0.50 ± 0.88, P = 0.037, respectively); there were no significant differences in vortical flow between the groups. The absolute reduction of average WSS was significantly higher in the SEV group compared to the BEV group after TAVR (BEV: - 0.6 [- 2.1 to 0.5] Pa vs. SEV: - 1.8 [- 3.5 to - 0.8] Pa, P = 0.006). The systolic EL in the AAo significantly decreased after TAVR in both the groups, while the absolute reduction was comparable between the groups. CONCLUSIONS: Helical flow, flow eccentricity, and average WSS in the AAo were significantly decreased after SEV implantation compared to BEV implantation, providing functional insights for valve selection in patients with AS undergoing TAVR. Our findings offer valuable insights into blood flow dynamics, aiding in the selection of valves for patients with AS undergoing TAVR. Further larger-scale studies are warranted to confirm the prognostic significance of hemodynamic changes in these patients.

Fragmented QRS on 12-lead electrocardiogram predicts long-term prognosis in patients with cardiac sarcoidosis.

Fragmented QRS (fQRS) on a 12-lead electrocardiogram is a known marker of fatal arrhythmias or cardiac adverse events in ischemic and non-ischemic cardiomyopathy patients. Nonetheless, the association between fQRS and clinical outcomes in patients with cardiac sarcoidosis (CS) remains unclear. Herein, we investigated whether fQRS is associated with long-term clinical outcomes in CS patients. A total of 78 patients who received immunosuppressive therapy (IST) for clinically diagnosed CS were retrospectively examined. Patients were classified into two groups according to the presence (n = 19) or absence (n = 59) of fQRS on electrocardiogram before IST. The primary outcome was the composite event of all-cause death, ventricular tachyarrhythmias (VTs), and hospitalization for heart failure. Results of late gadolinium enhancement on cardiac magnetic resonance imaging were also analyzed. During a median follow-up period of 3.7 years (interquartile range: 1.6-6.2 years), the primary outcome occurred more frequently in patients with fQRS than in those without (47% vs. 13%, log-rank p = 0.002). Multivariable Cox regression analyses showed that fQRS was an independent determinant of the primary outcome. The incidence of VTs, within 12 months of IST initiation, was comparable between the two groups; however, late-onset VTs, defined as those occurring ≥ 12 months after IST initiation, occurred more frequently in the fQRS group (21% vs. 2%, log-rank p = 0.002). The scar zone and scar border zone were greater in patients with fQRS than in those without it. In conclusion, our analysis suggests that fQRS is an independent predictor of adverse events, particularly late-onset VTs, in patients with CS.

Paradoxical increase in global longitudinal strain by handgrip exercise despite left ventricular diastolic dysfunction.

BACKGROUND: Although global longitudinal strain (GLS) is recognized as a sensitive marker of intrinsic left ventricular (LV) dysfunction, its afterload dependency has also been pointed. We hypothesized that decrease in GLS during handgrip exercise could be more sensitive marker of intrinsic myocardial dysfunction. METHODS: Handgrip exercise-stress echocardiography was performed in 90 cardiovascular disease patients with preserved LV ejection fraction. LV diastolic function was graded according to the guidelines. Diastolic wall stress (DWS) and ratio of left atrial (LA) volume index to late-diastolic mitral annular velocity (LAVI/a') were measured at rest as LV stiffness. As well, LA strains were measured to assess LA function. GLS was expressed as absolute value and significant changes in GLS by handgrip exercise was defined as changes over prespecified mean absolute test-retest variability (2.65%). RESULTS: While mean value of GLS did not change by the exercise, substantial patients showed significant changes in GLS: decreased (group I, n = 28), unchanged (group II, n = 34), and increased (group III, n = 28). Unexpectedly, patients in group I did not show any clinical and echocardiographic characteristics, while those in group III were characterized by elevated natriuretic peptide levels, blunted heart rate response to handgrip exercise, and advanced LV diastolic dysfunction. Multivariable analyses revealed that DWS, left atrial booster strain, and grade II or more diastolic dysfunction determined the increase in GLS even after adjustment for elevated natriuretic peptides and the changes in heart rate by the exercise. CONCLUSION: In contrast to our hypothesis, paradoxical increase in GLS by handgrip exercise could be associated with advanced LV diastolic dysfunction in cardiovascular patients with preserved LV ejection fraction. Our findings suggest that HG exercise for heart failure patients does not enhance the afterload straightforward, resulting in variable changes of GLS according to the individual conditions.

Increased Piezo1 expression in myofibroblasts in patients with symptomatic carotid atherosclerotic plaques undergoing carotid endarterectomy: A pilot study.

OBJECTIVES: We aimed to investigate Piezo1 expression in myofibroblasts in symptomatic and asymptomatic patients undergoing carotid endarterectomy and its relationship with atherosclerotic plaque formation. METHODS: This cross-sectional study analyzed carotid plaques of 17 randomly selected patients who underwent carotid endarterectomy from May 2015 to August 2017. In total, 51 sections (the most stenotic lesion, and the sections 5-mm proximal and distal) stained with hematoxylin-eosin and elastica-Masson were examined. Immunohistochemistry was performed using antibodies to Piezo1. The Piezo1 score of a section was calculated semiquantitatively, averaged across 30 randomly selected myofibroblasts in the fibrous cap of the plaque. RESULTS: Of 17 patients (mean age: 74.2 ± 7.1 years), 15 were men, 9 had diabetes mellitus, and 13 had hypertension. Symptomatic patients had higher mean Piezo1 score than asymptomatic patients (1.78 ± 0.23 vs 1.34 ± 0.17, p < .001). Univariate linear regression analyses suggested an association between plaque rupture, thin-cap fibroatheroma and microcalcifications and the Piezo1 score (p = .001, .008, and 0.003, respectively). CONCLUSIONS: Increased Piezo1 expression of myofibroblasts may be associated with atherosclerotic carotid plaque instability. Further study is warranted to support this finding.

Pharmacological nNOS inhibition modified small-conductance Ca2+-activated K+ channel without altering Ca2+ dynamics.

Atrial fibrillation (AF) is associated with electrical remodeling processes that promote a substrate for the maintenance of AF. Although the small-conductance Ca2+-activated K+ (SK) channel is a key factor in atrial electrical remodeling, the mechanism of its activation remains unclear. Regional nitric oxide (NO) production by neuronal nitric oxide synthase (nNOS) is involved in atrial electrical remodeling. In this study, atrial tachyarrhythmia (ATA) induction and optical mapping were performed on perfused rat hearts. nNOS is pharmacologically inhibited by S-methylthiocitrulline (SMTC). The influence of the SK channel was examined using a specific channel inhibitor, apamin (APA). Parameters such as action potential duration (APD), conduction velocity, and calcium transient (CaT) were evaluated using voltage and calcium optical mapping. The dominant frequency was examined in the analysis of AF dynamics. SMTC (100 nM) increased the inducibility of ATA and apamin (100 nM) mitigated nNOS inhibition-induced arrhythmogenicity. SMTC caused abbreviations and enhanced the spatial dispersion of APD, which was reversed by apamin. By contrast, conduction velocity and other parameters associated with CaT were not affected by SMTC or apamin administration. Apamin reduced the frequency of SMTC-induced ATA. In summary, nNOS inhibition abbreviates APD by modifying the SK channels. A specific SK channel blocker, apamin, mitigated APD abbreviation without alteration of CaT, implying an underlying mechanism of posttranslational modification of SK channels.NEW & NOTEWORTHY We demonstrated that pharmacological nNOS inhibition increased the atrial arrhythmia inducibility and a specific small-conductance Ca2+-activated K+ channel blocker, apamin, reversed the enhanced atrial arrhythmia inducibility. Apamin mitigated APD abbreviation without alteration of Ca2+ transient, implying an underlying mechanism of posttranslational modification of SK channels.

Hospitalization for Heart Failure in the United States, UK, Taiwan, and Japan: An International Comparison of Administrative Health Records on 413,385 Individual Patients.

BACKGROUND: Registries show international variations in the characteristics and outcome of patients with heart failure (HF), but national samples are rarely large, and case selection may be biased owing to enrolment in academic centers. National administrative datasets provide large samples with a low risk of bias. In this study, we compared the characteristics, health care resource use (HRU) and outcomes of patients with primary HF hospitalizations (HFH) using electronic health records (EHR) from 4 high-income countries (United States, UK, Taiwan, Japan) on 3 continents. METHODS AND RESULTS: We used electronic health record to identify unplanned HFH between 2012 and 2014. We identified 231,512, 10,991, 36,900, and 133,982 patients with a primary HFH from the United States, the UK, Taiwan, and Japan, respectively. HFH per 100,000 population was highest in the United States and lowest in Taiwan. Fewer patients in Taiwan and Japan were obese or had chronic kidney disease. The length of hospital stay was shortest in the United States (median 4 days) and longer in the UK, Taiwan, and Japan (medians of 7, 9, and 17 days, respectively). HRU during hospitalization was highest in Japan and lowest in UK. Crude and direct standardized in-hospital mortality was lowest in the United States (direct standardized rates 1.8, 95% confidence interval 1.7%-1.9%) and progressively higher in Taiwan (direct standardized rates 3.9, 95% CI 3.8%-4.1%), the UK (direct standardized rates 6.4, 95% CI 6.1%-6.7%), and Japan (direct standardized rates 6.7, 95% CI 6.6%-6.8%). The 30-day all-cause (25.8%) and HF (7.2%) readmissions were highest in the United States and lowest in Japan (11.9% and 5.1%, respectively). CONCLUSIONS: Marked international variations in patient characteristics, HRU, and clinical outcomes exist; understanding them might inform health care policy and international trial design.

Impact of Tweeting Summaries by the Japanese Circulation Society Official Account on Article Viewership　- Pilot Trial.

BACKGROUND: The impact of promotional tweets from the official journal account (forCirculation JournalandCirculation Reports) on article viewership has not been thoroughly evaluated.Methods and Results:We retrospectively collected journal viewership data forCirculation JournalandCirculation Reportsfrom March 2021 to August 2021. We compared viewership between articles with (n=15) and without (n=250) tweets. After 1 : 4 propensity score matching (15 tweeted articles and 60 non-tweeted matched controls), journal viewership metrics within 7 days of the tweeting date (and the hypothetical tweeting date), was larger in tweeted articles than non-tweeted articles (median [interquartile range] Abstract page views 89 [60-104] vs. 18 [8-41]). CONCLUSIONS: This pilot study suggests a positive relationship between journal-posted promotional tweets and article viewership.

Myocardial T-Lymphocytes as a Prognostic Risk-Stratifying Marker of Dilated Cardiomyopathy　- Results of the Multicenter Registry to Investigate Inflammatory Cell Infiltration in Dilated Cardiomyopathy in Tissues of Endomyocardial Biopsy (INDICATE Study).

BACKGROUND: Dilated cardiomyopathy (DCM) associated with inflammation is diagnosed by endomyocardial biopsy; patients with this have a poorer prognosis than patients without inflammation. To date, standard diagnostic criteria have not been established.Methods and Results: This study analyzed clinical records and endomyocardial biopsy samples of 261 patients with DCM (201 males, median left ventricular ejection fraction; 28%) from 8 institutions in a multicenter retrospective study. Based on the European Society of Cardiology criteria and CD3 (T-lymphocytes) and CD68 (macrophages) immunohistochemistry, 48% of patients were categorized as having inflammatory DCM. For risk-stratification, we divided patients into 3 groups using Akaike Information Criterion/log-rank tests, which can determine multiple cut-off points: CD3+-Low, <13/mm2(n=178, 68%); CD3+-Moderate, 13-24/mm2(n=58, 22%); and CD3+-High, ≥24/mm2(n=25, 10%). The survival curves for cardiac death or left ventricular assist device implantation differed significantly among the 3 groups (10-year survival rates: CD3+-Low: 83.4%; CD3+-Moderate: 68.4%; CD3+-High: 21.1%; Log-rank P<0.001). Multivariate Cox analysis revealed CD3+count as a potent independent predictive factor for survival (fully adjusted hazard ratio: CD3+-High: 5.70, P<0.001; CD3+-Moderate: 2.64, P<0.01). CD3+-High was also associated with poor left ventricular functional and morphological recovery at short-term follow up. CONCLUSIONS: Myocardial CD3+T-lymphocyte infiltration has a significant prognostic impact in DCM and a 3-tiered risk-stratification model could be helpful to refine patient categorization.

Association of Low Body Weight with Clinical Outcomes in Elderly Atrial Fibrillation Patients Receiving Apixaban-J-ELD AF Registry Subanalysis.

PURPOSE: Although direct oral anticoagulants are effective and safe in preventing stroke in atrial fibrillation (AF) patients with low body weight, data remain limited in AF patients with extremely low body weight (<50 kg). We aimed to investigate the association of this body weight category with clinical outcomes in elderly AF patients receiving apixaban. METHODS: The J-ELD AF Registry is a large-scale, multicenter prospective observational study of Japanese non-valvular AF patients aged ≥ 75 years taking on-label doses of apixaban. The entire cohort (3025 patients from 110 institutions) was divided into three body weight subgroups: >60 kg (n = 1019, 33.7%), 50-60 kg (n = 1126, 37.2%), and <50 kg (n = 880, 29.1%). RESULTS: The event incidence rates (/100 person years) were 1.69, 1.82, and 1.23 for stroke or systemic embolism (P = 0.60); 1.37, 1.73, and 2.73 for bleeding requiring hospitalization (P = 0.154); 2.02, 2.67, and 4.92 for total death (P = 0.003); and 0.73, 0.95, and 1.23 for cardiovascular death (P = 0.57), respectively. After adjusting for confounders by Cox regression analysis, body weight <50 kg was not an independent risk for stroke or systemic embolism, bleeding requiring hospitalization, total death, or cardiovascular death. CONCLUSIONS: The incidence of events in each body weight group was comparable for stroke or systemic embolism and bleeding requiring hospitalization, and body weight <50 kg might not be an independent risk for death in Japanese non-valvular AF patients aged ≥ 75 years taking on-label doses of apixaban.

Prognostic value of an echocardiographic index reflecting right ventricular operating stiffness in patients with heart failure.

PURPOSE: We recently reported a noninvasive method for the assessment of right ventricular (RV) operating stiffness that is obtained by dividing the atrial-systolic descent of the pulmonary artery-RV pressure gradient (PRPGDAC) derived from the pulmonary regurgitant velocity by the tricuspid annular plane movement during atrial contraction (TAPMAC). Here, we investigated whether this parameter of RV operating stiffness, PRPGDAC/TAPMAC, is useful for predicting the prognosis of patients with heart failure (HF). METHODS: We retrospectively included 127 hospitalized patients with HF who underwent an echocardiographic examination immediately pre-discharge. The PRPGDAC/TAPMAC was measured in addition to standard echocardiographic parameters. Patients were followed until 2 years post-discharge. The endpoint was the composite of cardiac death, readmission for acute decompensation, and increased diuretic dose due to worsening HF. RESULTS: 58 patients (46%) experienced the endpoint during follow-up. Univariable and multivariable Cox regression analyses demonstrated that the PRPGDAC/TAPMAC was associated with the endpoint. In a Kaplan-Meier analysis, the event rate of the greater PRPGDAC/TAPMAC group was significantly higher than that of the lesser PRPGDAC/TAPMAC group. In a sequential Cox analysis for predicting the endpoint's occurrence, the addition of PRPGDAC/TAPMAC to the model including age, sex, NYHA functional classification, brain natriuretic peptide level, and several echocardiographic parameters including tricuspid annular plane systolic excursion significantly improved the predictive power for prognosis. CONCLUSION: A completely noninvasive index of RV operating stiffness, PRPGDAC/TAPMAC, was useful for predicting prognoses in patients with HF, and it showed an incremental prognostic value over RV systolic function.

Application of the proximal isovelocity surface area method for estimation of the effective orifice area in aortic stenosis.

Although the echocardiographic effective orifice area (EOA) calculated using the continuity equation is widely used for the assessment of severity in aortic stenosis (AS), the existence of high flow velocity at the left ventricular outflow tract (LVOT) potentially causes its overestimation. The proximal isovelocity surface area (PISA) method could be an alternative tool for the estimation of EOA that limits the influence of upstream flow velocity. EOA was calculated using the continuity equation (EOACont) and PISA method (EOAPISA), respectively, in 114 patients with at least moderate AS. The geometric orifice area (GOA) was also measured using the planimetry method in 51 patients who also underwent three-dimensional transesophageal echocardiography. Patients were divided into two groups according to the median LVOT flow velocity. EOAPISA could be obtained in 108 of the 114 patients (95%). Although there was a strong correlation between EOACont and EOAPISA (r = 0.78, P < 0.001), EOACont was statistically significantly larger than EOAPISA (0.86 ± 0.33 vs 0.75 ± 0.29 cm2, P < 0.001). Both EOACont and EOAPISA similarly correlated with GOA (r = 0.70, P < 0.001 and r = 0.77, P < 0.001, respectively). However, a fixed bias, which is hydrodynamically supposed to exist between EOA and GOA, was not observed between EOACont and GOA. In contrast, there was a negative fixed bias between EOAPISA and GOA with smaller EOAPISA than GOA. The difference between EOACont and GOA was significantly greater with a larger EOACont relative to GOA in patients with high LVOT flow velocity than in those without (0.16 ± 0.25 vs - 0.07 ± 0.10 cm2, P < 0.001). In contrast, the difference between EOAPISA and GOA was consistent regardless of the LVOT flow velocity (- 0.07 ± 0.12 vs - 0.07 ± 0.15 cm2, P = 0.936). The PISA method was applied to estimate EOA in patients with AS. EOAPISA could be an alternative parameter for AS severity grading in patients with high LVOT flow velocity in whom EOACont would potentially overestimate the orifice area.

Intrinsic anti-tachycardia pacing terminated ventricular tachycardia resistant to traditional anti-tachycardia pacing.

Implantable cardioverter-defibrillators (ICDs) serve to reduce the risk of sudden death; however, ICD shocks worsen patient prognosis. Therefore, attempts have been made to terminate life-threatening arrhythmias without ICD shocks. A 71-year-old man with non-ischemic cardiomyopathy, who previously underwent cardiac resynchronization therapy-defibrillator (CRT-D) placement, was hospitalized for ventricular tachyarrhythmia (VT) that was refractory to traditional anti-tachycardia pacing (ATP). Endocardial and epicardial ablation failed to prevent VT recurrence. Since the CRT-D battery was exhausted, it was replaced with a Cobalt™ XT HF CRT-D (Medtronic, Minneapolis, MN, USA), and the intrinsic ATP (iATP) algorithm was employed. Although VT recurred frequently, recurrent VTs were terminated by the iATP, which created a conduction block in the circuit without VT acceleration or shock. This is the first reported case wherein an iATP algorithm was effective against VT resistant to traditional anti-tachycardia pacing. This novel ATP algorithm has the potential to terminate refractory VT without ICD shocks and provide a better prognosis.

SK channel blockade prevents hypoxia-induced ventricular arrhythmias through inhibition of Ca2+/voltage uncoupling in hypertrophied hearts.

Ventricular arrhythmia (VA) is the major cause of death in patients with left ventricular (LV) hypertrophy and/or acute ischemia. We hypothesized that apamin, a blocker of small-conductance Ca2+-activated K+ (SK) channels, alters Ca2+ handling and exhibits anti-arrhythmic effects in ventricular myocardium. Spontaneous hypertensive rats were used as a model of LV hypertrophy. A dual optical mapping of membrane potential (Vm) and intracellular calcium (Cai) was performed during global hypoxia (GH) on the Langendorff perfusion system. The majority of pacing-induced VAs during GH were initiated by triggered activities. Pretreatment of apamin (100 nmol/L) significantly inhibited the VA inducibility. Compared with SK channel blockers (apamin and NS8593), non-SK channel blockers (glibenclamide and 4-AP) did not exhibit anti-arrhythmic effects. Apamin prevented not only action potential duration (APD80) shortening (-18.7 [95% confidence interval, -35.2 to -6.05] ms vs. -2.75 [95% CI, -10.45 to 12.65] ms, P = 0.04) but also calcium transient duration (CaTD80) prolongation (14.52 [95% CI, 8.8-20.35] ms vs. 3.85 [95% CI, -3.3 to 12.1] ms, P < 0.01), thereby reducing CaTD80 - APD80, which denotes "Cai/Vm uncoupling" (33.22 [95% CI, 22-48.4] ms vs. 6.6 [95% CI, 0-14.85] ms, P < 0.01). The reduction of Cai/Vm uncoupling was attributable to less prolonged Ca2+ decay constant and suppression of diastolic Cai increase by apamin. The inhibition of VA inducibility and changes in APs/CaTs parameters caused by apamin was negated by the addition of ouabain, an inhibitor of Na+/K+ pump. Apamin attenuates APD shortening, Ca2+ handling abnormalities, and Cai/Vm uncoupling, leading to inhibition of VA occurrence in hypoxic hypertrophied hearts.NEW & NOTEWORTHY We demonstrated that hypoxia-induced ventricular arrhythmias were mainly initiated by Ca2+-loaded triggered activities in hypertrophied hearts. The blockades of small-conductance Ca2+-activated K+ channels, especially "apamin," showed anti-arrhythmic effects by alleviation of not only action potential duration shortening but also Ca2+ handling abnormalities, most notably the "Ca2+/voltage uncoupling."

Blood flow dynamics with four-dimensional flow cardiovascular magnetic resonance in patients with aortic stenosis before and after transcatheter aortic valve replacement.

BACKGROUND: Pre- and post-procedural hemodynamic changes which could affect adverse outcomes in aortic stenosis (AS) patients who undergo transcatheter aortic valve replacement (TAVR) have not been well investigated. Four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) enables accurate analysis of blood flow dynamics such as flow velocity, flow pattern, wall shear stress (WSS), and energy loss (EL). We sought to examine the changes in blood flow dynamics of patients with severe AS who underwent TAVR. METHODS: We examined 32 consecutive severe AS patients who underwent TAVR between May 2018 and June 2019 (17 men, 82 ± 5 years, median left ventricular ejection fraction 61%, 6 self-expanding valve), after excluding those without CMR because of a contraindication or inadequate imaging from the analyses. We analyzed blood flow patterns, WSS and EL in the ascending aorta (AAo), and those changes before and after TAVR using 4D flow CMR. RESULTS: After TAVR, semi-quantified helical flow in the AAo was significantly decreased (1.4 ± 0.6 vs. 1.9 ± 0.8, P = 0.002), whereas vortical flow and eccentricity showed no significant changes. WSS along the ascending aortic circumference was significantly decreased in the left (P = 0.038) and left anterior (P = 0.033) wall at the basal level, right posterior (P = 0.011) and left (P = 0.010) wall at the middle level, and right (P = 0.012), left posterior (P = 0.019) and left anterior (P = 0.028) wall at the upper level. EL in the AAo was significantly decreased (15.6 [10.8-25.1 vs. 25.8 [18.6-36.2]] mW, P = 0.012). Furthermore, a significant negative correlation was observed between EL and effective orifice area index after TAVR (r = - 0.38, P = 0.034). CONCLUSIONS: In severe AS patients undergoing TAVR, 4D flow CMR demonstrates that TAVR improves blood flow dynamics, especially when a larger effective orifice area index is obtained.