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.

Potential relationship between high wall shear stress and plaque rupture causing acute coronary syndrome.

The relationship between high wall shear stress (WSS) and plaque rupture (PR) in longitudinal and circumferential locations remains uncertain. Overall, 100 acute coronary syndrome patients whose culprit lesions had PR, documented by optical coherence tomography (OCT), were enrolled. Lesion-specific three-dimensional coronary artery models were created using OCT data. WSS was computed with computational fluid dynamics analysis. PR was classified into upstream-PR, minimum lumen area-PR, and downstream-PR according to the PR's longitudinal location, and into central-PR and lateral-PR according to the disrupted fibrous cap circumferential location. In the longitudinal 3-mm segmental analysis, multivariate analysis demonstrated that higher WSS in the upstream segment was independently associated with upstream-PR, and thinner fibrous cap was independently associated with downstream-PR. In the PR cross-sections, the PR region had a significantly higher average WSS than non-PR region. In the cross-sectional analysis, the in-lesion peak WSS was frequently observed in the lateral (66.7%) and central regions (70%) in lateral-PR and central-PR, respectively. Multivariate analysis demonstrated that the presence of in-lesion peak WSS at the lateral region, thinner broken fibrous cap, and larger lumen area were independently associated with lateral-PR, while the presence of in-lesion peak WSS at the central region and thicker broken fibrous cap were independently associated with central-PR. In conclusion, OCT-based WSS simulation revealed that high WSS might be related to the longitudinal and circumferential locations of PR.

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.

The association between wedging of the aorta and cardiac structural anatomy as revealed using multidetector-row computed tomography.

The aortic root is wedged within the cardiac base. The precise extent of aortic wedging, however, and its influence on the surrounding cardiac structures, has not been systematically investigated. We analysed 100 consecutive patients, who underwent coronary arterial computed tomographic angiography. We assessed the extent of aortic wedging by measuring the vertical distance between the non-adjacent aortic sinus and the inferior epicardium. A shorter distance indicates deeper aortic wedging. We assessed the tilt angle and diameter of the ascending aorta, the relative heights of the left atrial roof and the oval fossa, the shape of the proximal right coronary artery, the angle of the aorta relative to the left ventricular axis, and the lung volume. The mean extent of wedging was 42.7 ± 9.8 mm. Multivariate analysis revealed that ageing, male gender, increased body mass index, patients without cardiomyopathy, the extent of tilting and dilation of the ascending aorta, and lung volume were all independent predictors for deeper aortic wedging (R2  = 0.7400, P < 0.0001). The extent of wedging was additionally correlated with a relatively high left atrial roof (R2  = 0.1394, P < 0.0001) and oval fossa (R2  = 0.1713, P < 0.0001), the shepherd's crook shape of the proximal right coronary artery (R2  = 0.2376, P < 0.0001), and the narrowness of the angulation of the root relative to the left ventricular axis (R2  = 0.2544, P < 0.0001). In conclusion, ageing, male gender, obesity, background cardiac disease, aortic tilting and dilation, and lung volume are all correlated with the extent of wedging of the aortic root within the cardiac base.

Effects of daily glucose fluctuations on the healing response to everolimus-eluting stent implantation as assessed using continuous glucose monitoring and optical coherence tomography.

BACKGROUND: Several studies have revealed that glucose fluctuations provoke oxidative stress that leads to endothelial cell dysfunction, progression of coronary atherosclerosis, and plaque vulnerability. However, little is known regarding their effect on neointimal growth after stenting in patients with coronary artery disease (CAD). We aimed to investigate the effects of glucose fluctuations on neointimal growth after everolimus-eluting stent (EES) implantation. METHODS: This study examined 50 patients who underwent a 9-month follow-up using optical coherence tomography (OCT) after EES implantation. Glucose fluctuation was expressed as the mean amplitude of glycemic excursion (MAGE), and was determined via continuous glucose monitoring before stenting. At the OCT follow-up, we evaluated the percentage of uncovered struts and three-dimensional uniformity of neointimal distribution by calculating the mean neointimal thickness (NIT) within 360 equally-spaced radial sectors for every 1-mm cross-sectional OCT analysis, and assessed the incidence of major adverse cardiovascular events (MACE). RESULTS: We evaluated 60 lesions in 50 patients. Linear mixed effect models were used to explore the influence of different variables on variability in NIT and the percentage of uncovered struts and to adjust for covariates. Univariate analysis showed that MAGE was most strongly correlated with the previously mentioned OCT measurements (coefficient ß ± standard error = 0.267 ± 0.073 and 0.016 ± 0.003, t = 3.668 and 6.092, both P < 0.001, respectively). In multivariate analysis, MAGE had the strongest effect on variability in NIT (coefficient ß ± standard error = 0.239 ± 0.093, P = 0.014) and the percentage of uncovered struts (coefficient ß ± standard error = 0.019 ± 0.004, P < 0.001). Five lesions in four patients required target lesion revascularization (10.0 %) at a mean duration of 9 months after EES implantation. Compared to non-MACE cases, cases of MACE exhibited a significantly higher MAGE (99 vs. 68; P = 0.004), maximum NIT (580 vs. 330 µm; P = 0.002), and variability in NIT (100 vs. 65; P = 0.007), although there was no significant difference in these groups' HbA1c levels. CONCLUSIONS: Glucose fluctuation may affect vessel healing after EES implantation in patients with CAD who are receiving lipid-lowering therapy. Therefore, glucose fluctuations may be an important target for secondary prevention after coronary stenting, which is independent of dyslipidemia control.

Slit-Like Deformation of the Coronary Sinus Orifice due to Compression of the Inferior Pyramidal Space by the Severely Dilated Left Ventricle.

The coronary sinus is located within the inferior pyramidal space, which is the part of the epicardial visceral fibroadipose tissue wedging between the four cardiac chambers from the bottom of the heart. Therefore, this region is susceptible to the morphological changes of the cardiac chambers. We present a case of slit-like deformation of the coronary sinus orifice due to compression of the inferior pyramidal space by the severely dilated left ventricle, which has not been previously described.

Characteristics of Residual Atrial Posterior Wall and Roof-Dependent Atrial Tachycardias after Pulmonary Vein Isolation.

BACKGROUND: Roof-dependent atrial tachycardia (roof AT) sometimes occurs after pulmonary vein isolation (PVI) of atrial fibrillation (AF). This study aimed to investigate the relationship between the anatomy of the residual left atrial posterior wall and occurrence of roof AT. METHODS: A total of 265 patients with AF who underwent PVI were enrolled. After the PVI, induced or recurrent roof AT was confirmed by an entrainment maneuver or activation mapping using a three-dimensional (3D) mapping system. To identify the predictors of roof AT, the minimum distance between both PVI lines (d-PVI) was measured by a 3D mapping system and the anatomical parameters, including the left atrial (LA) diameter, left atrial volume index (LAVi), and shape of the left atrial roof, were analyzed by 3D computed tomography. RESULTS: Roof AT was documented in 11 (4.2%) of 265 patients. A multivariable analysis demonstrated that the d-PVI, Deep V shape of the LA roof, and LAVi were associated with roof AT occurrences (d-PVI: odds ratio: 0.72, confidence interval [CI]: 0.61-0.86, P < 0.001; Deep V shape: odds ratio: 0.19, CI: 0.04-0.82, P = 0.03; LAVi: odds ratio: 1.05, CI: 1.02-1.07, P = 0.001). A receiver-operating characteristic curve analysis yielded an optimal cut-off value of 15.5 mm and 55.7 mL/m2 for the d-PVI and LAVi, respectively. CONCLUSION: The shorter d-PVI at the LA roof, greater LAVi, and Deep V shape were associated with the occurrence of a roof AT.