Single-Cell RNA Sequencing Reveals an Immune Landscape of CD4+ T Cells in Coronary Culprit Plaques With Acute Coronary Syndrome in Humans-Brief Report.

BACKGROUND: Acute coronary syndrome (ACS) involves plaque-related thrombosis, causing primary ischemic cardiomyopathy or lethal arrhythmia. We previously demonstrated a unique immune landscape of myeloid cells in the culprit plaques causing ACS by using single-cell RNA sequencing. Here, we aimed to characterize T cells in a single-cell level, assess clonal expansion of T cells, and find a therapeutic target to prevent ACS. METHODS: We obtained the culprit lesion plaques from 4 patients with chronic coronary syndrome (chronic coronary syndrome plaques) and the culprit lesion plaques from 3 patients with ACS (ACS plaques) who were candidates for percutaneous coronary intervention with directional coronary atherectomy. Live CD45+ immune cells were sorted from each pooled plaque samples and applied to the 10× platform for single-cell RNA sequencing analysis. We also extracted RNA from other 3 ACS plaque samples and conducted unbiased TCR (T-cell receptor) repertoire analysis. RESULTS: CD4+ T cells were divided into 5 distinct clusters: effector, naive, cytotoxic, CCR7+ (C-C chemokine receptor type 7) central memory, and FOXP3 (forkhead box P3)+ regulatory CD4+ T cells. The proportion of central memory CD4+ T cells was higher in the ACS plaques. Correspondingly, dendritic cells also tended to express more HLAs (human leukocyte antigens) and costimulatory molecules in the ACS plaques. The velocity analysis suggested the differentiation flow from central memory CD4+ T cells into effector CD4+ T cells and that from naive CD4+ T cells into central memory CD4+ T cells in the ACS plaques, which were not observed in the chronic coronary syndrome plaques. The bulk repertoire analysis revealed clonal expansion of TCRs in each patient with ACS and suggested that several peptides in the ACS plaques work as antigens and induced clonal expansion of CD4+ T cells. CONCLUSIONS: For the first time, we revealed single cell-level characteristics of CD4+ T cells in patients with ACS. CD4+ T cells could be therapeutic targets of ACS. REGISTRATION: URL: https://upload.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000046521; Unique identifier: UMIN000040747.

Efficacy of Native T1 Mapping for Patients With Non-Ischemic Cardiomyopathy and Ventricular Functional Mitral Regurgitation Undergoing Transcatheter Edge-to-Edge Repair.

BACKGROUND: We investigated the efficacy of left ventricular (LV) myocardial damage by native T1mapping obtained with cardiac magnetic resonance (CMR) for patients undergoing transcatheter edge-to-edge repair (TEER).Methods and Results: We studied 40 symptomatic non-ischemic heart failure (HF) patients and ventricular functional mitral regurgitation (VFMR) undergoing TEER. LV myocardial damage was defined as the native T1Z-score, which was converted from native T1values obtained with CMR. The primary endpoint was defined as HF rehospitalization or cardiovascular death over 12 months after TEER. Multivariable Cox proportional hazards analysis showed that the native T1Z-score was the only independent parameter associated with cardiovascular events (hazard ratio 3.40; 95% confidential interval 1.51-7.67), and that patients with native T1Z-scores <2.41 experienced significantly fewer cardiovascular events than those with native T1Z-scores ≥2.41 (P=0.001). Moreover, the combination of a native T1Z-score <2.41 and more severe VFMR (effective regurgitant orifice area [EROA] ≥0.30 cm2) was associated with fewer cardiovascular events than a native T1Z-score ≥2.41 and less severe VFMR (EROA <0.30 cm2; P=0.002). CONCLUSIONS: Assessment of baseline LV myocardial damage based on native T1Z-scores obtained with CMR without gadolinium-based contrast media is a valuable additional parameter for better management of HF patients and VFMR following TEER.

Antithrombotic Therapy for Patients With Atrial Fibrillation and Bioprosthetic Valves　- Real-World Data From the Multicenter, Prospective, Observational BPV-AF Registry.

BACKGROUND: Although bioprosthetic valve (BPV) replacements are becoming more common within our aging society, there are limited prospective data on the appropriate antithrombotic therapy for East Asian patients with atrial fibrillation (AF) and BPV replacement. Antithrombotic therapy and thrombotic and hemorrhagic event rates in Japanese patients with AF and BPV replacement are investigated.Methods and Results:This multicenter, prospective, observational study enrolled patients with BPV replacement and AF. The primary efficacy outcome was stroke or systemic embolism, and the primary safety outcome was major bleeding. Of the 894 patients analyzed, 54.7%, 29.4%, and 9.6%, were treated with warfarin-based therapy, direct oral anticoagulant (DOAC)-based therapy, or antiplatelet therapy without anticoagulants, respectively; 6.3% did not receive any antithrombotic drugs. The mean observation period was 15.3±4.0 months. The event rates for stroke or systemic embolism and major bleeding were 1.95%/year and 1.86%/year, respectively. The multivariate adjusted hazard ratios for DOAC vs. warfarin were 1.02 (95% confidence intervals [CI], 0.30-3.41 [P=0.979]) for systemic embolic events and 0.96 (95% CI, 0.29-3.16 [P=0.945]) for major bleeding. CONCLUSIONS: Approximately 30% of patients with AF and BPV replacement were treated with DOAC. The risks of major bleeding and stroke or systemic embolism were similar between warfarin- and DOAC-treated patients with AF who had BPV replacement. Treatment with DOACs could be an alternative to warfarin in this population.

Comparison of Direct Oral Anticoagulants and Warfarin in Patients With Atrial Fibrillation and an Aortic Bioprosthetic Valve.

BACKGROUND: Current guidelines equally recommend direct oral anticoagulants (DOACs) and warfarin for atrial fibrillation (AF) patients with a bioprosthetic valve (BPV); however, there are limited data comparing DOACs and warfarin in AF patients with an aortic BPV.Methods and Results: This post-hoc subgroup analysis of a multicenter, prospective, observational registry (BPV-AF Registry) aimed to compare DOACs and warfarin in AF patients with an aortic BPV. The primary outcome was a composite of stroke, systemic embolism, major bleeding, heart failure requiring hospitalization, all-cause death, or BPV reoperation. The analysis included 479 patients (warfarin group, n=258; DOAC group, n=221). Surgical aortic valve replacement was performed in 74.4% and 36.7% of patients in the warfarin and DOAC groups, respectively. During a mean follow up of 15.5 months, the primary outcome occurred in 45 (17.4%) and 32 (14.5%) patients in the warfarin and DOAC groups, respectively. No significant difference was found in the primary outcome between the 2 groups (adjusted hazard ratio: 0.88, 95% confidence interval: 0.51-1.50). No significant multiplicative interaction was observed between the anticoagulant effects and type of aortic valve procedure (P=0.577). CONCLUSIONS: Among AF patients with an aortic BPV, no significant difference was observed in the composite outcome of adverse clinical events between patients treated with warfarin and those treated with DOACs, suggesting that DOACs can be used as alternatives to warfarin in these patients.

Real-world clinical outcomes of percutaneous transluminal septal myocardial ablation for patients with drug-refractory hypertrophic obstructive cardiomyopathy: results from a retrospective multicenter registry of non-high-volume centers.

Percutaneous transluminal septal myocardial ablation (PTSMA) is a well-established interventional therapy for drug-refractory hypertrophic obstructive cardiomyopathy (HOCM) as an alternative to surgical myectomy. Although guidelines recommend that PTSMA should be performed in institutions with extensive experience, it is not centralized to such high-volume centers in real-world clinical practice. Thus, this study aimed to assess the feasibility of PTSMA in non-high-volume centers. We retrospectively examined patients with HOCM who underwent PTSMA between August 2012 and May 2020 at four institutions that experienced fewer than 20 cases of PTSMA procedures. The primary clinical endpoint was a composite of safety (all-cause death, electrical defibrillation for ventricular tachycardia or fibrillation, cardiac tamponade, permanent pacemaker implantation, and repeated interventions) and efficacy endpoints (repeated interventions [PTSMA or surgical myectomy]). Fifty-eight consecutive patients were enrolled. During the 30-day follow-up, no major clinical adverse events were noted except three patients (5.2%) requiring permanent pacemaker implantation for complete atrioventricular block. The percentage of patients with New York Heart Association functional class 1 or 2 significantly increased from 8.6 to 100% (p < 0.001). In the Cox proportional hazard model, left ventricular outflow tract pressure gradient at rest ≥ 30 mmHg (hazard ratio [HR] 6.56; 95% confidence interval [CI] 1.44-29.90; p = 0.015) and mitral regurgitation grade ≥ 3 (HR 10.75; 95% CI 1.81-63.79; p = 0.009) at the 30-day follow-up were associated with a composite of major clinical adverse events. The current study demonstrated that 58 patients who underwent PTSMA in non-high-volume centers had favorable 30-day clinical outcomes, with a primary composite endpoint rate of 5.2%. A prospective study with a larger sample size and longer follow-up is warranted to verify the safety and efficacy of PTSMA in non-high-volume centers.

The impact of vildagliptin on the daily glucose profile and coronary plaque stability in impaired glucose tolerance patients with coronary artery disease: VOGUE-A multicenter randomized controlled trial.

BACKGROUND: The impact of reduction in glycemic excursion on coronary plaques remains unknown. This study aimed to elucidate whether a dipeptidyl peptidase 4 inhibitor could reduce the glycemic excursion and stabilize the coronary plaques compared with conventional management in coronary artery disease (CAD) patients with impaired glucose tolerance (IGT). METHODS: This was a multicenter, randomized controlled trial including CAD patients with IGT under lipid-lowering therapy receiving either vildagliptin (50 mg once a day) or no medication (control group) regarding glycemic treatment. The primary endpoint was changes in the minimum fibrous cap thickness and lipid arc in non-significant native coronary plaques detected by optical coherence tomography at 6 months after intervention. Glycemic variability expressed as the mean amplitude of glycemic excursion (MAGE) measured with a continuous glucose monitoring system was evaluated before and 6 months after intervention. RESULTS: A total of 20 participants with 47 lesions were allocated to either the vildagliptin group (10 participants, 22 lesions) or the control group (10 participants, 25 lesions). The adjusted difference of mean changes between the groups was - 18.8 mg/dl (95% confidence interval, - 30.8 to - 6.8) (p = 0.0064) for the MAGE (vildagliptin, - 20.1 ± 18.0 mg/dl vs. control, 2.6 ± 12.7 mg/dl), - 22.8° (- 40.6° to - 5.1°) (p = 0.0012) for the mean lipid arc (vildagliptin, - 9.0° ± 25.5° vs. control, 15.8° ± 16.8°), and 42.7 µm (15.3 to 70.1 µm) (p = 0.0022) for the minimum fibrous cap thickness (vildagliptin, 35.7 ± 50.8 µm vs. control, - 15.1 ± 25.2 µm). CONCLUSIONS: Vildagliptin could reduce the MAGE at 6 months and may be associated with the decreased lipid arc and increased minimum FCT of the coronary plaques in CAD patients with IGT as compared with the control group. These findings may represent its potential stabilization effect on coronary plaques, which are characteristic in this patient subset. Trial registration Registered in the UMIN clinical trial registry (UMIN000008620), Name of the registry: VOGUE trial, Date of registration: Aug 6, 2012, URL: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000010058.

Rationale and Design of the Multicenter Trial on Japan Working Group on the Effects of Angiotensin Receptor Blockers Selection (Azilsartan vs. Candesartan) on Diastolic Function in the Patients Suffering from Heart Failure with Preserved Ejection Fraction: J-TASTE Trial.

BACKGROUND: Previous studies suggest that the pathophysiology of heart failure with preserved ejection fraction (HFpEF) is characterized not only by high ventricular stiffness, but also by vascular stiffness. Azilsartan has higher vascular affinity compared with other angiotensin II receptor blockers (ARBs), which were proven to have no beneficial effects on clinical outcomes in patients with HFpEF in earlier clinical trials. We aimed to test the hypothesis that azilsartan may improve left ventricular diastolic function in HFpEF patients with hypertension in this trial. METHODS: The Effects of Angiotensin Receptor Blockers on Diastolic Function in Patients Suffering from Heart Failure with Preserved Ejection Fraction: J-TASTE trial is a multicenter, randomized, open-labeled, and assessor(s)-blinded, active controlled using candesartan, parallel-group clinical trial, to compare changes in left ventricular (LV) diastolic dysfunction between HFpEF patients with hypertension who have received candesartan or azilsartan for 48 weeks. The primary endpoint is the change in early diastolic wave height/early diastolic mitral annulus velocity (E/e') assessed by echocardiography from the baseline to the end of the study (48 weeks). A total of 190 patients will be recruited into the study. CONCLUSIONS: The design of the J-TASTE trial will provide data on whether differences between the effects of the two tested drugs on LV diastolic function exist in HFpEF patients with hypertension and will improve understanding of the pathophysiological role of vascular stiffness on diastolic function.

Hemorrhagic and Thromboembolic Complications after Hepato-Biliary-Pancreatic Surgery in Patients Receiving Antithrombotic Therapy.

BACKGROUND: Perioperative management for patients receiving long-term anticoagulant (AC) and antiplatelet (AP) therapy is a great concern for surgeons. This single-center retrospective study evaluated the risks of hemorrhage and thromboembolism after hepato-biliary-pancreatic (HBP) surgery in such patients. METHODS: Between 2009 and 2014, 886 patients underwent HBP surgery. Patients were categorized into the AC (n = 39), AP (n = 77), or control (n = 770) group according to the administration of antithrombotic drugs. Perioperative management of AC and AP therapies followed the guidelines of the Japanese Circulation Society. The incidences of hemorrhage and thromboembolism were compared among groups. We used 1:1 propensity score matching and compared the incidences between the matched pairs. RESULTS: There were 0, 1 (1.3%), and 26 (3.4%) hemorrhagic complications in the AC, AP, and control groups, respectively (p = 0.16). There were 0, 1 (1.3%), and 6 (0.8%) thromboembolic complications in the AC, AP, and control groups, respectively (p = 0.66). There was no significant difference in hemorrhagic and thromboembolic complications between the propensity-matched pairs. CONCLUSION: The incidences of hemorrhage and thromboembolism after HBP surgery in patients receiving long-term AC and AP therapies are within acceptable ranges.

Effects of 6-month eicosapentaenoic acid treatment on postprandial hyperglycemia, hyperlipidemia, insulin secretion ability, and concomitant endothelial dysfunction among newly-diagnosed impaired glucose metabolism patients with coronary artery disease. An open label, single blinded, prospective randomized controlled trial.

BACKGROUND: Recent experimental studies have revealed that n-3 fatty acids, such as eicosapentaenoic acid (EPA) regulate postprandial insulin secretion, and correct postprandial glucose and lipid abnormalities. However, the effects of 6-month EPA treatment on postprandial hyperglycemia and hyperlipidemia, insulin secretion, and concomitant endothelial dysfunction remain unknown in patients with impaired glucose metabolism (IGM) and coronary artery disease (CAD). METHODS AND RESULTS: We randomized 107 newly diagnosed IGM patients with CAD to receive either 1800 mg/day of EPA (EPA group, n = 53) or no EPA (n = 54). Cookie meal testing (carbohydrates: 75 g, fat: 28.5 g) and endothelial function testing using fasting-state flow-mediated dilatation (FMD) were performed before and after 6 months of treatment. The primary outcome of this study was changes in postprandial glycemic and triglyceridemic control and secondary outcomes were improvement of insulin secretion and endothelial dysfunction. After 6 months, the EPA group exhibited significant improvements in EPA/arachidonic acid, fasting triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C). The EPA group also exhibited significant decreases in the incremental TG peak, area under the curve (AUC) for postprandial TG, incremental glucose peak, AUC for postprandial glucose, and improvements in glycometabolism categorization. No significant changes were observed for hemoglobin A1c and fasting plasma glucose levels. The EPA group exhibited a significant increase in AUC-immune reactive insulin/AUC-plasma glucose ratio (which indicates postprandial insulin secretory ability) and significant improvements in FMD. Multiple regression analysis revealed that decreases in the TG/HDL-C ratio and incremental TG peak were independent predictors of FMD improvement in the EPA group. CONCLUSIONS: EPA corrected postprandial hypertriglyceridemia, hyperglycemia and insulin secretion ability. This amelioration of several metabolic abnormalities was accompanied by recovery of concomitant endothelial dysfunction in newly diagnosed IGM patients with CAD. Clinical Trial Registration UMIN Registry number: UMIN000011265 ( https://www.upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000013200&language=E ).

Usefulness of non-contrast-enhanced MRI with two-dimensional balanced steady-state free precession for the acquisition of the pulmonary venous and left atrial anatomy pre catheter ablation of atrial fibrillation: Comparison with contrast enhanced CT in clinical cases.

BACKGROUND: To investigate the feasibility of substituting non-contrast-enhanced MR (non-CE-MR) imaging with a two-dimensional (2D) balanced steady-state free precession (b-SSFP) sequence for contrast-enhanced computed tomography (CE-CT) for atrial fibrillation (AF) ablation. METHODS: Fifty-four patients that underwent AF ablation under the guidance of a 3D electro-anatomical mapping system with CE-CT (n = 27) or non-CE-MR images (n = 27) were studied. Procedural results were compared between the two groups. Furthermore, in 22 patients who underwent both CE-CT and non-CE-MRI, two cardiologists independently scored the multiplanar reformatted images on a scale of 1 to 4 (from 1, poor, to 4, excellent). RESULTS: The image score was nearly 0.5 point higher with the CE-CT method. However, the procedural results such as the surface registration error (1.0 [0.8-1.6] mm versus 1.0 [0.8-1.35] mm, P = 0.88) and procedure time (185 [159-199] min versus 185 [142-221] min, P = 0.86) did not significantly differ between the CE-CT and non-CE-MR groups. CONCLUSION: The non-CE-MR method with a 2D-b-SSFP sequence can give us adequate information on AF ablation without any radiation exposure or contrast medium usage

Distribution of Ventricular Fibrosis Associated With Life-Threatening Ventricular Tachyarrhythmias in Patients With Nonischemic Dilated Cardiomyopathy.

BACKGROUND: Current guidelines recommend the implantation of an implantable cardioverter-defibrillator (ICD) for primary prevention of sudden cardiac death (SCD) in a subgroup of patients with nonischemic cardiomyopathy (NICM) who have a left ventricular ejection fraction (LVEF) ≤ 30-35%, and are NYHA functional class II or III. However, the majority of patients with an ICD implantation for primary prevention did not receive appropriate ICD therapy. The purpose of this study was to evaluate the association between myocardial fibrosis detected by cardiovascular magnetic resonance (CMR) imaging and life-threatening ventricular arrhythmic events in NICM patients. METHODS: One hundred and seventy-five NICM patients with an LVEF ≦ 35 % and NYHA functional class II or III, (60 ± 15 years, LVEF 29 ± 5.4%) were studied. Myocardial fibrosis was identified with a late gadolinium enhancement (LGE) on CMR. Clinical events were defined as SCD or life-threatening ventricular arrhythmic events and were followed up for 5.1 ± 3.3 years. RESULTS: The presence of an LGE was detected in 122 patients (70%). No life-threatening ventricular arrhythmia events occurred in patients with the absence of an LGE. A total of 18 ventricular tachycardia and 8 ventricular fibrillation events were found in patients with the presence of an LGE (P < 0.01). Sensitivity, specificity, and positive and negative predictive value of LGE in predicting life-threatening ventricular arrhythmia events were 100%, 34%, and 15% and 100%, respectively. Multivariate analysis showed that the presence of both septal and lateral mid-wall LGE was associated with life-threatening ventricular arrhythmic events (hazard ratio 23.1 CI; 2.88-184.9, P = 0.003). CONCLUSIONS: The absence of an LGE predicts a low potential risk of SCD and life-threatening ventricular arrhythmia events in the near future. CMR may be a useful tool for selecting suitable patients for primary ICD implantations in NICM patients.

The Speckle Tracking Imaging for the Assessment of Cardiac Resynchronization Therapy (START) study.

BACKGROUND: We sought to identify the feasibility of speckle tracking echocardiography (STE) to predict cardiac resynchronization therapy (CRT) responders in a prospective multicenter study. METHODS AND RESULTS: Patients who were newly implanted with a CRT device were enrolled. Time (T) from QRS to maximum peak radial and circumferential strain (CS) in 6 segments on the left ventricular (LV) short-axis plane, and to the maximum peak of longitudinal strain in 18 segments on 3 apical LV planes was measured (Tmax). In segments with multiple peaks on the time-strain curves, time to the first peak (Tfirst) was also assessed. Difference in T between the earliest and latest segment and standard deviation (SD) of T in each strain component were assessed. CRT responders were defined as having LV end-systolic volume reduction >15% at 6 months after CRT. Clinical outcomes were assessed with a composite endpoint of death from cardiac causes or unplanned hospitalization for heart failure. Among 180 patients, 109 patients were identified as responders. Tfirst-SD of CS >116 ms was selected as the best independent predictor of CRT responders (P<0.001, hazard ratio=9.83, 95% confidence interval 3.78-25.6). In addition, Tfirst-SD of CS was associated with the clinical endpoints. CONCLUSIONS: This prospective multicenter study revealed the high feasibility of dyssynchrony assessment by STE, which may improve the ability to predict CRT responders.

Novel Compression Tool to Prevent Hematomas and Skin Erosions After Device Implantation.

BACKGROUND: The incidence of hematoma formation following implantation of a cardiovascular implantable electronic device (CIED) is estimated to be 5% even if a pressure dressing is applied. It is unclear whether a pressure dressing can really compress the pocket in different positions. Furthermore, the adhesive tape for fixing pressure dressings can tear the skin. We developed a new compression tool for preventing hematomas and skin erosions. METHODS AND RESULTS: We divided 46 consecutive patients receiving anticoagulation therapy who underwent CIED implantation into 2 groups (Group I: conventional pressure dressing, Group II: new compression tool). The pressure on the pocket was measured in both the supine and standing positions. The incidence of hematomas was compared between the 2 groups. The pressure differed between the supine and standing positions in Group I, but not in Group II (Group I: 14.8±7.1 mmHg vs. 11.3±9.9 mmHg, P=0.013; Group II: 13.5±2.8 mmHg vs. 13.5±3.5 mmHg, P=0.99). The incidence of hematomas and skin erosions was documented in 2 (8.7%) and 3 (13%) Group I patients, respectively. No complications were documented in Group II. CONCLUSIONS: The new compression tool can provide adequate continuous pressure on the pocket, regardless of body position. This device may reduce the incidence of hematomas and skin erosions after CIED implantation.

Relationship of decreased accumulation of (99m)Tc-tetrofosmin on myocardial single-photon emission computed tomography images between QRS duration in dilated cardiomyopathy patient with left bundle branch block.

PURPOSE: This study aimed to clarify the relationship between severity of conduction delay in the left ventricle and myocardial uptake of (99m)Tc-tetrofosmin (TF) in dilated cardiomyopathy (DCM) patients with left bundle branch block (LBBB). METHODS AND RESULTS: Thirty-two DCM patients with LBBB underwent electrocardiography and (99m)Tc-TF myocardial single-photon emission computed tomography (SPECT). SPECT images were acquired at 30 min (early images) and 3 h (late images) after injection. We calculated the total defect score (TDS) using a 20-segment model with a 5-point scoring system. The TDS in early and late images was defined as the summed early score (SES) and summed late score (SLS), respectively. On early images, 29 of 32 patients (91%) had decreased tracer uptake in the septum. All patients showed a decreased tracer uptake in the septum on late images. A significant correlation was observed between TDS (both SES and SLS) and QRS duration, with SLS showing an excellent correlation (SES: r = 0.554, P < 0.001; SLS: r = 0.779, P < 0.0001). CONCLUSIONS: These findings suggest that in DCM patients with LBBB, hypoperfusion and myocardial damage in the septum might occur in accordance with an increase in the QRS duration.