Non invasive cardiac vein mapping: Role of multislice CT coronary angiography

Purpose

Coronary venous anatomy is of primary importance when implanting a cardiac resynchronization therapy device, besides, the coronary sinus can be differently enlarged depending on chronic heart failure. The aim of this study is to evaluate the usefulness of Coronary CTA in describing the coronary venous tree and in particular the coronary sinus and detecting main venous system variants.

Materials and methods

301 consecutive patients (196 ♂, mean age 63.74 years) studied for coronary artery disease with 64 slice Coronary CTA were retrospectively examined. The acquisition protocol was the standard acquisition one used for coronary artery evaluation but the cardiac venous system were visualized. The cardiac venous system was depicted using 3D, MPR, cMPR and MIP post-processing reconstructions on an off-line workstation. For each patient image quality, presence and caliber of the coronary sinus (CS), great cardiac vein (GCV), middle vein (MV), anterior interventricular vein (AIV), lateral cardiac vein (LCV), posterior cardiac vein (PCV), small cardiac vein (SCV) and presence of variant of the normal anatomy were examined and recorded.

Results

CS, GCV, MV and AIV were visualized in 100% of the cases. The LCV was visualized in 255/301 (84%) patients, the PCV in 248/301 (83%) patients and the SCV in 69/301 (23%) patients. Mean diameter of the CS was 8.7 mm in 276/301 (91.7%) patients without chronic heart failure and 9.93 mm in 25/301 (8.3%) patients with chronic heart failure.

Conclusions

Coronary CTA allows non invasive mapping of the cardiac venous system and may represent a useful presurgical tool for biventricular pacemaker devices implantation.     

多层螺旋CT和三维屏气MR冠状动脉成像的对比研究

目的比较16层螺旋CT（16 multi-detector CT,16-MDCT）冠状动脉血管造影（CTA）和三维屏气冠状动脉MR血管造影（MRA）的图像质量以及诊断冠状动脉显著性狭窄（＞50%）的准确性.方法40例疑有冠心病患者在3 d内均行冠状动脉CTA和MRA检查,其中31例患者在2周内行冠状动脉造影检查.将冠状动脉分成9个节段（右冠状动脉近、中、远段,左冠状动脉主干,前降支近、中、远段和旋支近、远段）,由2名影像科医生共同对各个节段的图像质量按0～4级评分,比较CTA和MRA上各个节段的图像质量.以冠状动脉造影为标准,计算并比较CTA和MRA诊断31例冠状动脉显著性狭窄（＞50%）各项准确性指标.结果CTA在右冠状动脉中段的图像质量低于MRA,右冠状动脉近段二者无区别,其他节段均优于MRA.冠状动脉造影显示31例患者共有43个节段狭窄＞50%,CTA和MRA分别正确诊断出36和27个,其敏感性、特异性、阳性预测值和阴性预测值分别为83%、84%、49%、97%和63%、90%、55%、93%.结论除右冠状动脉中段,CTA大部分节段的图像质量优于MRA.CTA诊断冠状动脉显著性狭窄的敏感性高于MRA,但特异性低于MRA.冠状动脉CTA和MRA均表现了较高的阴性预测值,对排除冠状动脉狭窄具有临床价值.     

128层螺旋CT冠状动脉成像筛查冠状动脉病变的临床价值

目的以选择性冠状动脉造影（SCA）为标准,评价128层螺旋cT冠状动脉血管成像（CTA）诊断冠状动脉疾病（CAD）的临床价值。方法回顾我院52例做过冠状动脉CTA与SCA的冠心病患者,进行对照分析。结果128层螺旋cT冠状动脉CTA可获得较好的图像质量,52例患者中,CTA成像检出心肌桥16例,血管内斑块形成98处;17例一侧明显型优势冠状动脉,冠状动脉狭窄86支,包括轻度狭窄22支、中度狭窄24支、重度狭窄40支,SCA诊断心肌桥6例,冠状动脉狭窄84支,包括轻度狭窄22支、中度狭窄21支、重度狭窄41支。结论冠状动脉CTA与SCA相比,不仅能对冠状动脉粥样硬化的狭窄程度作出判断,还可以对粥样斑块的病理性质、斑块的稳定性以及心肌桥提出明确诊断,可以用于CAD的筛查,几乎能代替诊断性的冠状动脉造影。     

64排螺旋CT冠脉成像在冠心病诊断中的应用

目的 评价64排螺旋CT冠状动脉(冠脉)成像(CTA)在冠心病诊断中的应用价值.方法 以选择性冠脉造影(SCA)结果为金标准,采用64排螺旋CT对68例疑诊冠心病患者的冠脉主干及主要分支272节段进行重建和分析,评价其诊断冠心病的灵敏度和特异度.结果 CTA能够清晰显示冠脉主干及其分支狭窄、钙化、开口起源异常及桥血管病变,CTA发现钙化病变52节段,SCA仅发现钙化病变35节段.CTA诊断冠脉病变的灵敏度96.33%,特异度98.16%,阳性预测值97.22%,阴性预测值97.56%.其中对左主干、左前降支病变及＞75%的病变灵敏度最高,分别达到100%和94.4%.结论 CTA对冠脉狭窄病变、桥血管、开口畸形、支架管腔均显影良好,对冠心病诊断有较高的准确性,对钙化病变诊断率优于冠脉造影,可以作为冠心病高危人群无创性筛选检查及冠脉支架术后随访手段.     

Coronary 64-slice CT angiography predicts outcome in patients with known or suspected coronary artery disease

The aim of this study was to assess the prognostic value of 64-slice CT angiography (CTA) in patients with known or suspected coronary artery disease (CAD). Sixty-four-slice coronary CTA was performed in 220 patients [mean age 63 ± 11 years, 77 (35%) female] with known or suspected CAD. CTA images were analyzed with regard to the presence and number of coronary lesions. Patients were followed-up for the occurrence of the following clinical endpoints: death, nonfatal myocardial infarction, unstable angina, and coronary revascularization. During a mean follow-up of 14 ± 4 months, 59 patients (27%) reached at least one of the predefined clinical endpoints. Patients with abnormal coronary arteries on CTA (i.e., presence of coronary plaques) had a 1st-year event rate of 34%, whereas in patients with normal coronary arteries no events occurred (event rate, 0%, p < 0.001). Similarly, obstructive lesions (≥50% luminal narrowing) on CTA were associated with a high first-year event rate (59%) compared to patients without stenoses (3%, p < 0.001). The presence of obstructive lesions was a significant independent predictor of an adverse cardiac outcome. Sixty-four-slice CTA predicts cardiac events in patients with known or suspected CAD. Conversely, patients with normal coronary arteries on CTA have an excellent mid-term prognosis.     

Accuracy of 64-slice CT angiography for the detection of functionally relevant coronary stenoses as assessed with myocardial perfusion SPECT

Purpose CT angiography (CTA) offers a valuable alternative for the diagnosis of CAD but its value in the detection of functionally relevant coronary stenoses remains uncertain. We prospectively compared the accuracy of 64-slice CTA with that of myocardial perfusion imaging (MPI) using ^99mTc-tetrofosmin-SPECT as the gold standard for the detection of functionally relevant coronary artery disease (CAD). Methods MPI and 64-slice CT were performed in 100 consecutive patients. CTA lesions were analysed quantitatively and area stenoses ≥50% and ≥75% were compared with the MPI findings. Results In 23 patients, MPI perfusion defects were found (12 reversible, 13 fixed). A total of 399 coronary arteries and 1,386 segments was analysed. Eighty-four segments (6.1%) in 23 coronary arteries (5.8%) of nine patients (9.0%) were excluded owing to insufficient image quality. In the remaining 1,302 segments, quantitative CTA revealed stenoses ≥50% in 57 of 376 coronary arteries (15.2%) and stenoses ≥75% in 32 (8.5%) coronary arteries. Using a cut-off at ≥75% area stenosis, CTA yielded the following sensitivity, specificity, negative (NPV) and positive predictive value (PPV), and accuracy for the detection of any (fixed and reversible) MPI defect: by patient, 75%, 90%, 93%, 68% and 87%, respectively; by artery, 76%, 95%, 99%, 50% and 94%, respectively. Conclusion Sixty-four-slice CTA is a reliable tool to rule out functionally relevant CAD in a non-selected population with an intermediate pretest likelihood of disease. However, an abnormal CTA is a poor predictor of ischaemia.     

Technical challenges of coronary CT angiography: Today and tomorrow

Rapid advancements in multidetector row computed tomography (MDCT) are beginning to revolutionise cardiac imaging applications. As a consequence, coronary CT angiography (CTA) is fast emerging as a highly effective, noninvasive imaging technique for the assessment of coronary artery disease (CAD). Technology is improving at a robust pace, which brings with it the benefits of superior spatial and temporal resolution as well as fast volume coverage, achieved through the development of systems with an increased number of detectors and shorter gantry rotation time, as well as the advent of systems equipped with dual-source X-ray tubes. The main power of CTA was thought to lie in its high negative predictive value in excluding coronary disease with a high degree of accuracy in patients with low probability for CAD. However, this rapid progress has meant that we are also adding to the growing list of additional potential applications of CTA that are possible with the technology. The aim of this review is to present an overview of the technical capabilities of cardiac MDCT relating to coronary CTA and other applications, the limitations of current technologies, as well as discuss political perspectives and how to address these in medical practice.     

双源CT冠状动脉成像评价冠状动脉搭桥术后桥血管通畅情况

目的探讨双源 CT 冠状动脉成像对冠状动脉搭桥术后桥血管通畅状况的诊断价值.资料与方法38例患者于冠状动脉搭桥术后行双源 CT 冠状动脉成像与冠状动脉造影检查,以冠状动脉造影作为“金标准”,对双源 CT 冠状动脉成像结果进行分析.结果38例患者共检出桥血管92支,其中内乳动脉桥31支,大隐静脉桥61支;31支内乳动脉桥中,26支(83.9%)桥血管通畅,5支(16.1%)管腔狭窄、闭塞;61支大隐静脉桥血管中35支(57.4%)桥血管通畅;26支(42.6%)管腔狭窄、闭塞.大隐静脉桥血管狭窄、闭塞的发生率明显高于内乳动脉桥血管(P<0.05).双源 CT 冠状动脉成像评价桥血管狭窄、闭塞的敏感性为93.9%,特异性为100.0%.结论双源 CT 冠状动脉成像对冠状动脉搭桥术后桥血管通畅状况的评价有较高的诊断价值,是一种快速、无创、准确、安全的检查方法.     

应用受试者工作特征曲线分析256层CTA诊断冠状动脉狭窄的价值

目的:结合受试者工作特征(receiver operating characteristic,ROC)曲线探讨256层CTA在冠状动脉成像及冠状动脉狭窄诊断中的价值。方法:与DSA对照,回顾性分析100例拟诊冠心病患者CTA检查结果。根据心率,将患者随机分为3组:低心率组40例,心率75次/min;中等心率组35例,75次/min≤心率90次/min;高心率组25例,心率≥90次/min。统计学分析采用多个独立样本非参数检验、ROC分析和One-Way ANOVA方法。结果:100例心率范围(39~107)次/min,平均(76.44±13.36)次/min。全部1 500冠脉节段中,CTA显示1 447个节段(96.47%);可以满足诊断者1 403个节段(占96.96%),其中低心率组97.76%、中等心率组96.86%、高心率组95.80%,不同心率组间图像质量评分比较P0.05,差异无统计学意义。ROC曲线分析,低、中、高心率组CTA诊断冠状动脉狭窄的特异性分别为98.40%、96.00%、97.60%,敏感性95.00%、93.70%、92.20%,曲线下面积值0.971、0.955、0.955,3组比较P0.05,差异无统计学意义。结论:256层CTA可在一定程度上不受心率的限制行冠状动脉成像,并且能够清晰地显示冠状动脉的主要节段,较为准确地诊断冠状动脉狭窄。     

Coronary plaque imaging by coronary computed tomography angiography

Coronary computed tomography angiography (CTA) has become the useful noninvasive imaging modality alternative to the invasive coronary angiography for detecting coronary artery stenoses in patients with suspected coronary artery disease (CAD). With the development of technical aspects of coronary CTA, clinical practice and research are increasingly shifting toward defining the clinical implication of plaque morphology and patients outcomes by coronary CTA. In this review we discuss the coronary plaque morphology estimated by CTA beyond coronary angiography including the comparison to the currently available other imaging modalities used to examine morphological characteristics of the atherosclerotic plaque. Furthermore, this review underlies the value of a combined assessment of coronary anatomy and myocardial perfusion in patients with CAD, and adds to an increasing body of evidence suggesting an added diagnostic value when combining both modalities. We hope that an integrated, multi-modality imaging approach will become the gold standard for noninvasive evaluation of coronary plaque morphology and outcome data in clinical practice.     

Rationale and design of the PREDICT (Plaque Registration and Evaluation Detected In Computed Tomography) registry

BackgroundAt least two-thirds of cases of acute coronary syndrome are caused by disruption of an atherosclerotic plaque. The natural history of individual plaques is unknown and needs to be established.ObjectivesThe Plaque Registration and Evaluation Detected In Computed Tomography (PREDICT) registry is a prospective, multicenter, longitudinal, observational registry. This registry was designed to examine the relationships among coronary CT angiography (CTA) findings and clinical findings, mortality, and morbidity. The relationships among progression of coronary atherosclerosis, including changes in plaque characteristics on coronary CTA, and serum lipid levels and modification of coronary risk factors will also be evaluated.MethodsFrom October 2009 to December 2012, 3015 patients who underwent coronary CTA in 29 centers in Japan were enrolled. These patients were followed for 2 years. The primary end points were considered as all-cause mortality and major cardiac events, including cardiac death, nonfatal myocardial infarction, and unstable angina that required hospitalization. The secondary end points were heart failure that required administration of diuretics, target vessel revascularization, cerebral infarction, peripheral arterial disease, and invasive coronary angiography. Blood pressure, serum lipid, and C-reactive protein levels and all cardiovascular events were recorded at 1 and 2 years. If the initial coronary CTA showed any stenosis or plaques, follow-up coronary CTA was scheduled at 2 years to determine changes in coronary lesions, including changes in plaque characteristics.ConclusionAnalysis of the PREDICT registry data will clarify the relationships between coronary CTA findings and cardiovascular mortality and morbidity in a collaborative multicenter fashion. This trial is registered at www.clinicaltrials.gov as NCT 00991835.     

Non-invasive evaluation of coronary artery stent patency with retrospectively ECG-gated 64-slice CT angiography

The aim of our study has been to evaluate the ability of 64-slice computed tomographic angiography (CTA) to assess coronary artery stent patency, relative to selective coronary angiography (SCA). Fifty-five consecutive patients (age range 45–80 years) with 97 previously implanted coronary artery stents underwent 64-slice CTA. The 55 patients comprised 40 subjects (group A) who were referred for follow-up SCA at a mean interval of 9.6 months after stent positioning, and 15 subjects (group B) in whom SCA was clinically indicated. Stent evaluation was performed independently by two blinded readers in terms of image quality and presence of in-stent restenosis (ISR; lumen obstruction of ≥50%). SCA was performed in 41/55 patients; 14 patients refused to undergo SCA after the 64-slice CTA exam. A total of 88 stents in 74 segments were analyzed. Twenty-one of the 74 stented segments were of poor image quality and were not considered for further analysis. Sixty-four-slice CTA detected 12/16 ISR (sensitivity: 75%) and ruled out ISR in 32/37 cases (specificity: 86%). Sixty-four-slice CTA is a valuable modality for follow-up of coronary artery stent patency only in selected patients. Appropriate candidates for follow-up 64-slice CTA should be established based on stent diameter, stent material and type as well as HR and heart rhythm. However, given the number of non-assessable segments, further work would appear necessary before 64-slice CTA can be considered a suitable procedure for broad clinical application in the evaluation of coronary artery stent patency.     

电子束CT血管造影对冠状动脉疾病的诊断与随访

目的评价电子束CT血管造影(EBA)及其三维血管成像技术对冠状动脉疾病的诊断与随访价值. 资料与方法 87例经EBA检查的患者,其中支架置入术后随访16例,搭桥术后随访9例.除9例搭桥患者外,其余78例均有冠状动脉造影(CAG)结果证实. 结果 EBA可评价的冠状动脉中,对左主干和前降支的诊断敏感性、特异性最高,尤其是近段,其次为右冠,对回旋支的诊断敏感性和特异性则较低;16例支架置入术后患者共放置支架47枚,EBA准确定位45枚(95.7%),对支架内开通诊断的符合率为74.5%;9例冠状动脉搭桥术后的患者,共搭建冠状动脉桥血管27支,EBA对桥血管开通与否诊断的符合率为81.5%. 结论 EBA对冠状动脉狭窄的诊断具有较高的术前筛选价值,对术后的随访也有较大的潜力,是一项很有优势的无创性冠心病检查方法.     

Sixty four multi-detectors CT coronary angiography: An easy and accurate method to detect graft patency post CABG

Objective

To assess the accuracy of coronary CTA in detection of coronary artery bypass graft patency, occlusion and stenosis.

Patients and methods

Twenty-four patients with past history of coronary bypass surgery were included in this study and underwent MDCT coronary angiography. Invasive coronary angiography was done within 2 weeks of MDCT coronary angiography. All grafts considered patent were then evaluated for the presence of significant stenosis. Significant stenosis was defined as reduction in diameter of more than 50%.

Results

All the MDCT scans were interpretable and a total number of 78 CABG conduits were analyzed. At MDCT angiography 4 (5.2%) grafts were classified as occluded and 74 (94.8%) grafts were patent. Significant stenosis was detected in 7 (9.4%) out of the 74 patent grafts. At invasive coronary angiography; when occlusion and significant stenosis pooled together they were 9 grafts; 4 arterial and 5 venous. All these 9 grafts were detected at MSCT (sensitivity is 100%). In 67 out of 69 grafts occlusion or significant stenosis was correctly ruled out (specificity 97.1%). The diagnostic accuracy of MDCT angiography when compared with invasive angiography was 97.4%. The negative predictive value was 100% and positive predictive value was 81.8%.

Conclusion

MDCT coronary angiography is an accurate imaging technique for the evaluation of CABG patency and in detection of graft stenosis and confirms of previous studies using 64 MDCT.     

Rationale and design of the HeartFlowNXT (HeartFlow analysis of coronary blood flow using CT angiography: NeXt sTeps) study

IntroductionCoronary CT angiography (CTA) is an established noninvasive method for visualization of coronary artery disease. However, coronary CTA lacks physiological information; thus, it does not permit differentiation of ischemia-causing lesions. Recent advances in computational fluid dynamic techniques applied to standard coronary CTA images allow for computation of fractional flow reserve (FFR), a measure of lesion-specific ischemia. The diagnostic performance of computed FFR (FFR_CT) compared with invasively measured FFR is not yet fully established.Methods/DesignHeartFlowNXT (HeartFlow analysis of coronary blood flow using coronary CT angiography: NeXt sTeps) is a prospective, international, multicenter study designed to evaluate the diagnostic performance of FFR_CT for the detection and exclusion of flow-limiting obstructive coronary stenoses, as defined by invasively measured FFR as the reference standard. FFR values ≤0.80 will be considered to be ischemia causing. All subjects (N = 270; 10 investigative sites) will undergo coronary CTA (single- or dual-source CT scanners with a minimum of 64 slices) and invasive coronary angiography with FFR. Patients with insufficient quality of coronary CTA will be excluded. Blinded core laboratory interpretation will be performed for FFR_CT, invasive coronary angiography, and FFR. Stenosis severity by coronary CTA will be evaluated by the investigative site in addition to a blinded core laboratory interpretation. The primary objective of the study is to determine the diagnostic performance of FFR_CT compared with coronary CTA alone to noninvasively determine the presence of hemodynamically significant coronary lesions. The secondary end point comprises assessment of diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of FFR_CT.     

Prognostic performance of coronary computed tomography angiography in asymptomatic individuals as compared to symptomatic patients with an appropriate indication

Introduction

Current Appropriatene Usa Criteria exclude coronary computed tomography angiography (CTA) in asymptomatic individuals. We compared the prognostic value of coronary CTA in asymptomatic individuals to symptomatic patients with “definitely appropriate” indications for coronary CTA.

Coronary CTA enhanced with CTA based FFR analysis provides higher diagnostic value than invasive coronary angiography in patients with intermediate coronary stenosis

BackgroundCTA based FFR, a software based application, enhances diagnostic value of coronary computed tomography angiography (CTA) examination. However it remains unknown whether it improves accuracy over the gold standard of invasive coronary angiography (ICA) in predicting functionally significant coronary stenosis. The aim of our study was to compare diagnostic accuracies of coronary CTA, CTA based FFR, and ICA, with invasive FFR as the reference standard in patients with intermediate stenosis on CTA.Methods96 intermediate stenoses (50–90%) from 90 subjects, with intermediate pre-test probability of CAD, who underwent coronary CTA were analyzed. Each patient had subsequent ICA with FFR. CTA based FFR (cFFR v2.1, Siemens) analysis was performed on-site. The stenoses with invasive FFR≤0.8 were considered hemodynamically significant.Results41/96 stenoses were hemodynamically significant (FFR≤0.8). While the area under ROC curves (AUC) for identification of significant stenosis evaluated on QCA (0.653), visual ICA (0.652), qCTA (0.690) and visual CTA (0.660) did not significantly differ, the AUC for CTA based FFR (0.835) was significantly higher (p = 0.004, p = 0.004, p = 0.010, p = 0.007, respectively). The accuracies of CTA based FFR, qCTA and QCA were 76%, 63% and 58% respectively.ConclusionOur results suggest that diagnostic potential of routine coronary CTA, augmented with CTA based FFR analysis, is superior to ICA in patients with intermediate stenosis.     

常规血脂指标联合冠状动脉CT血管造影检查对2型糖尿病患者合并冠状动脉病变的预测研究

目的 探讨常规血脂指标联合CT血管造影(CTA)检查对2型糖尿病(T2DM)患者合并冠状动脉病变的预测价值.方法 选取我院2019年2月至2021年2月收治的78例T2DM患者进行回顾性分析,纳入研究患者均行常规血脂、CTA检查,冠状动脉造影(CAG)为金标准判定,根据CAG检查结果,将T2DM患者分为合并与未合并冠脉...     

64层螺旋CTA对冠状动脉病变的诊断价值

目的探讨64层螺旋CT在冠状动脉病变中的临床应用价值,为临床进一步数字减影血管造影(DSA)检查或其他治疗提供依据。方法对80例临床拟诊为冠心病的患者进行64层螺旋CT动脉血管造影(SCTA)检查,对所有扫描图像采用西门子工作站提供的各种分析软件进行后重建,观察冠状动脉管腔情况并进行分析判定。结果 64层螺旋CT可对冠状动脉的起源变异、狭窄程度、桥血管通畅程度及支架术后进行评估。结论 64层SCTA是一种安全、快速、无创的诊断冠心病的方法,也可作为筛查公众中冠状动脉病变的重要手段。     

Multidetector-row cardiac CT: diagnostic value of calcium scoring and CT coronary angiography in patients with symptomatic,but atypical,chest pain

The aim of this study was to investigate the accuracy of multidetector-row cardiac CT (MDCT), calcium scoring (Ca-Sc), and MDCT coronary angiography (MD CTA) in the assessment of coronary atherosclerosis. Thirty-eight patients underwent invasive coronary angiography (CA) and MDCT (collimation 4×1 mm, pitch 1.5 mm, TI 500 ms, 120 kV, 300 mAs, and retrospective ECG-gating). Calcium scoring was calculated for the total coronary artery territory and for RCA, LCA, and LCX separately. The MD CTA served to assess the degree and the localization of stenoses. All findings were compared to invasive coronary angiography. Approximately 68.4% (390 of 570) of all coronary segments could be visualized by MDCT. Correlation coefficient for MD CTA and CA amounted to r=0.58, showing distinct differences for the individual segments. Proximal segments generally showed better correlation (range 0.81–0.77) than medial segments (range 0.91–0.20), distal segments (range 0.55–0.04), or side branches (range 0.76–0.00). Patients with hemodynamically relevant (>75%) stenoses were detected by MD CTA with 72.2% sensitivity (13 of 18) and 100% specificity (20 of 20). For Ca-Sc sensitivity ranged between 94.7% (17 of 18) and 66.7% (12 of 18), specificity between 20% (4 of 20) and 80% (16 of 20) respectively, depending on the prevailing cutoff value. Combination of both methods led to 83.3% sensitivity (15 of 18) and 100% specificity (20 of 20), reaching no level of significance as compared with Ca-Sc (p=0.73) or MD CTA (p=0.23) alone. Calcium scoring as a single method showed highest sensitivity in the detection of coronary atherosclerosis but at the expense of low specificity. In patients with no or moderate calcifications, combination with MD CTA helped to distinctly increase specificity and NPVM. Britten and C. Herzog contributed equally to this study