Background: It is unclear to what degree of tricuspid annulus (TA) reduction is necessary to achieve good postoperative results in surgical bicuspidization. The study aimed to evaluate TA and right heart chamber’s dimensions before and after heart surgery; and to compare TA parameters assessed by different modalities. Methods: Forty patients underwent mitral valve surgery with or without concomitant tricuspid valve (TV) bicuspidization. Preoperative and postoperative measurements of TA dimensions were performed prospectively using two-dimensional (2D) and three-dimensional (3D) transthoracic echocardiography (TTE). Additionally, preoperative transesophageal echocardiography (TOE) was performed in the operating room prior to surgery. Results: All patients had no or mild TR immediately after surgery. There was a significant reduction in 2D and 3D parameters of the TV and right chambers in the TV bicuspidization group. However, TV leaflets’ tethering parameters did not change significantly. Preoperative 3D TTE measurements were smaller than those obtained through 3D TOE in the operation room, before surgery under general anesthesia. The 2D systolic apical 4Ch diameter and the parasternal short axis diameter mainly represent the 3D minor axis of the TA and are smaller than its 3D major axis. Conclusions: Although bicuspidization results in a one-third reduction of the TV area, tethering of the TV leaflets remains unchanged. Moreover, 3D TOE parameters of the TV under general anesthesia are larger than preoperative 3D TTE measurements. Conventional 2D measurements are insufficient for evaluating the maximum diameter of the TA.  The prevalence of functional tricuspid regurgitation (TR) is high and increases with age ,2. CliniSurgical bicuspidization is one of the repair techniques which is replicated in transcatheter TV procedures. However, due to the absence of data on how baseline TV size impacts postoperative outcomes, the results of surgical bicuspidization are controversial. TV suture repair techniques are preferred among surgeons in patients with smaller TV annulus. However, the rigid ring repair technique is the treatment modality of choice in cases with severe annulus dilation.Currently, no data are available on the precise reduction in tricuspid annulus (TA) size resulting from surgical procedures in humans. Surgical suture bicuspidization obliterates the posterior leaflet, resulting in bicuspidly functioning TV . HoweverAccurate TV sizing and extensive analysis are other challenges. Two-dimensional (2D) echocardiography is commonly used in daily practice. Unfortunately, a comprehensive TV evaluation cannot be achieved by it. Three-dimensional (3D) echocardiography offers a clearer understanding of TV assessment and provides detailed TA sizing. In addition, it enables the assessment of the spatial TV anatomy and evaluation of the grade and mechanics of TR . HoweverThe present study aimed to: (1) evaluate and compare TA and right heart chamber’s dimensions before and in the early stage after the heart surgery using 2D and 3D TTE, (2) compare TA measurements performed by 3D TTE and 3D TOE, and (3) compare TA measurements obtained using 2D and 3D echocardiography.2 in 2D TTE four chambers apical view [Vilnius Regional Biomedical Research Ethics Committee have granted approval for this study (protocol number 2019/6-1131-630). We prospectively carried out 3D echocardiography in 40 patients who were referred for mitral valve surgery at Vilnius University Hospital Santaros Klinikos between November 2018 and May 2022. All patients provided written consent to participate in the study. Concomitant tricuspid valve suture annuloplasty using the bicuspidization method was performed in 21 patients. The remaining 19 patients did not undergo any intervention on TV. The TV repair was performed within current guidelines . Indicatcal view .TTE was performed before and within seven days after the operation. Two-dimensional and three-dimensional TTE images were obtained using the Vivid E95 ultrasound machine  equipped with the 4Vc transducer. The study participants underwent conventional 2D TTE, including a parasternal long-axis RV inflow and parasternal short-axis at an aortic plane, the standard apical four-chamber (4Ch) view, and the apical 4Ch view optimized for the RV. Three consecutive cardiac cycles were recorded during a breath-hold with stable electrocardiographic tracing to minimize respiratory movements and obtain high-quality images suitable for TV analysis. All patients were examined in the left lateral decubitus position using grayscale second-harmonic 2D echocardiography. The image contrast, frequency depth, and sector size were adjusted to achieve an adequate frame rate for optimal visualization of the TV.The 3D echocardiography images of the TV were acquired from the RV-focused apical view, with the gain, sector width and depth settings being adjusted prior to acquisition. The R-wave-gated acquisition was performed over four beats during a single breath-hold. Single-beat narrow volume with minimal depth was used in patients with atrial fibrillation. In patients with TR, 3D echocardiography with color Doppler was performed. All 2D and 3D echocardiography data were digitally stored and transferred to EchoPAC for further offline analysis.TOE was performed before surgery when the patient was under general anaesthesia in the operating room. The Vivid E95 ultrasound machine  with the 6VT-D probe was used to perform the TOE. The TV was imaged at the mid-oesophageal level using a 60° to 80° imaging plane, capturing a large pyramidal dataset to encompass the entire TV. Multi-beat 3D echocardiography datasets were obtained using electrocardiographic gating, with and without color Doppler. The temporal resolution was maximized by optimizing sector width and minimizing depth to achieve an optimal volume rate. The severity of TR was defined according to the guidelines of the American Society of Echocardiography and the position paper on multi-modality imaging assessment of native valvular regurgitation of the European Association of Cardiovascular Imaging (EACVI) and European Society of Cardiology (ESC) ,15. GradLeft ventricular ejection fraction (LVEF) and pulmonary artery systolic pressure (PASP) were measured as recommended in guidelines . The sysThree-dimensional TA measurements from TTE and TOE images were gathered using a 4D Auto TVQ Tricuspid Valve Quantification software package . TR mechanics are related to the anatomy of TV in mid-systole at the maximal TR velocity. Therefore, all parameters of TV were measured in mid-systole. The software provides a multiplanar reconstruction (MPR) of the TV in 4-chamber (4Ch), 2-chamber (2Ch), and short axis views. Landmarks were placed to identify the septum, free wall, anterior, posterior annulus and leaflets’ coaptation points. The cardiac cycle timing (end-diastole and end-systole) was selected and manually adjusted if necessary. The end-diastole was set as the first frame before TV closure, while the end-systole was set as the last frame before TV opening. The middle frame was selected between end-diastole and end-systole and was considered mid-systole. The segmentation process started automatically, and the TA landmarks were adjusted if needed.The software provided various measurements of the 3D TV geometry, including TV area (the area of the non-planar surface delineated by the TA 3D contour); TV perimeter (the length of the 3D contour representing the TA circumference); 4Ch diameter ; 2Ch diameter (the distance between anterior and posterior TA hinge points on 2Ch long axis view); major axis (the longest diameter of the TA); minor axis (the shortest diameter of the TA); tenting volume (the volume between the leaflets and the TA surface); max tenting height ; coaptation height (the height of the user-placed coaptation point to the 4Ch diameter of the TV annulus), and sphericity index (ratio between the minor and major axis of the TA) .Reconstructed 3D echocardiography images with Color Doppler were used to measure the 3D vena contracta area .Interobserver and intraobserver variability were checked in a subset of 20 patients for the TV area and perimeter. A single observer measured these parameters from two sequentially collected images to determine intraobserver repeatability. Furthermore, the same image was analyzed by two independent observers to determine interobserver variability.All TV repairs were performed as a concomitant procedure during mitral valve surgery, using the suture bicuspidalization technique. All operations were performed in a conventional cardiac surgery fashion, under cardiopulmonary bypass, with the heart arrested. This annuloplasty technique targets the dilation of the TA that occurs in the septal to lateral and posteroseptal to anterolateral directions . The proA mattress suture was placed from the anteroposterior to the posteroseptal commissure along the posterior annulus. The suture was tied to obliterate the posterior leaflet resulting in bicuspidization of the TV .Early mortality was defined according to the guidelines for reporting mortality and morbidity after cardiac valve interventions as any death occurring within 30 days after surgery or during the same hospital admission. Data regarding the duration of cardiopulmonary bypass (CPB), length of stay in the intensive care unit (ICU) and hospital, and postoperative complications were collected retrospectively for all patients. Postoperative complications included new-onset atrial fibrillation, use of intra-aortic balloon pump (IABP) or extracorporeal membrane oxygenator (ECMO), resternotomy for bleeding, acute kidney injury (AKI) requiring dialysis, stroke, respiratory complications, atrioventricular block, permanent pacemaker insertion, mediastinitis, and tracheostomy.All statistical analysis was performed using R (v. 4.0.4) program package. The Shapiro–Wilk test was used to assess the normality of the quantitative variables. Normally distributed continuous variables are presented as the mean and standard deviation (SD), while other continuous variables are expressed as the median, first and third quartiles. Categorical variables are presented using frequencies and percentage.t-test or nonparametric Mann–Whitney U test was used to compare quantitative variables between two independent groups, as appropriate. For comparison between two dependent quantitative dependent variables, either the paired t-test or Wilcoxon signed-rank test was used, as appropriate. Categorical variables were compared between the groups by the chi-square test or Fisher’s exact test if expected values were <5. Pearson or Spearman correlation was used to identify relations between two quantitative variables, as appropriateThe Independent Student’s To estimate inter- and intra-rater reliability, a two-way random Intraclass Correlation Coefficient (ICC) was used.p-value of less than 0.05 was considered significant.A n = 9; 23%) or III . The mean LVEF was 54.2 ± 6.6%, and the mean PASP was 44.0 ± 16.3 mmHg.A total of forty patients were referred for mitral valve surgery. Baseline characteristics are listed in n = 23; 58%) had atrial fibrillation. One-third of the patients  had concomitant coronary artery disease. Thirty-five patients presented with organic MR, including 18 (45%) with ruptured chordae, 10 (25%) with rheumatic MV disease, six (15%) with MV prolapse, one (3%) with MV infective endocarditis, and five (45%) patients with functional MR. Half of the patients  and mitral valve repair in 14 cases (35%). In addition, five patients had concomitant coronary artery bypass grafting, and six patients had a simultaneous aortic valve replacement.n = 21); without TV bicuspidization (n = 19). The demographics and preoperative characteristics of the patients are summarized in Table 1. No significant differences were found between these two groups in terms of age, gender, body surface area (BSA), laboratory finding (hemoglobin), preoperative LVEF, PASP, NYHA functional class, the incidence of atrial fibrillation, coronary artery disease, chronic obstructive pulmonary disease, grade of preoperative TR and MR.Of the 40 patients who underwent mitral valve surgery, 21 had indications for concomitant TV bicuspidization; therefore, the patients were divided into two groups: with TV bicuspidization , 2D TA end-diastolic diameter, right ventricle (RV) basal and mid diameters, and right atrium (RA) area . HoweverEarly outcomes are summarized in There was a significant reduction in TA area (39%), perimeter (24%), major axis (24%), minor axis (26%), 4Ch diameter (23%), 2Ch diameter (20%), TA end-diastolic diameter (21%), RV basal diameter (10%) and RA area (28%) in patients who have undergone bicuspidization . HoweverIn patients without bicuspidization, there were no significant changes in the TA geometry parameters. Additionally, this group showed a significant increase in the TA end-diastolic diameter and RV basal diameter, while the RA area significantly decreased .p = 0.863) in bicuspidized patients and from 42.6 ± 13.4% to 45.8 ± 11.3% (p = 0.116) in patients without bicuspidization. However, these changes were not statistically significant.The fractional area change (FAC) increased in both groups: from 36.2 ± 11.2% to 37.0 ± 9.2% (p < 0.05).There was a significant difference between the dimensions of the TA obtained through 3D TTE before the surgery and those obtained through 3D TOE in the operation room before the surgery under general anesthesia . The TA p < 0.001), with no significant difference between the two measurements . Similarly, 2D parasternal short axis diameter had a high correlation with 3D TA minor axis , and there was no significant difference between these two measurements .The 2D and 3D echocardiographic TA measurements were performed in all patients. There was a strong correlation between 2D systolic apical 4Ch diameter and 3D minor TA axis . Other correlations are presented in The 3D TA major axis, which represents the largest diameter of an ellipse that fits the TA shape, was significantly larger than 2D systolic apical 4Ch diameter  and 0.98 (p < 0.001), respectively. The ICC values for the TA perimeter were 0.97 (p < 0.001) and 0.96 (p < 0.001) for interobserver and intraobserver variability, respectively. The ICC values indicated near-perfect consistency for both TA area and perimeter measurements. However, the measurement of the TA area showed slightly higher consistency than that of the TA perimeter.The interobserver and intraobserver variability of 3D echocardiographic measurements was assessed and found to have high levels of consistency. The intraclass correlation coefficients (ICC) for the TA area were 0.98  surgical bicuspidization significantly decreased TA dimensions, with a one-third reduction in TA area and a one-quarter reduction in perimeter; however, TV leaflets tethering remained unchanged; (2) 3D TOE TA measurements performed in the operating room before surgery under general anesthesia were significantly larger than preoperative 3D TTE TA parameters; (3) the 2D systolic apical 4Ch diameter and parasternal short axis diameter primarily corresponded to the 3D minor axis and were significantly smaller than the 3D major axis of the TA.According to current guidelines, the indications for TV intervention include severe TR and mild or moderate TR with a dilated TA . In our In our study, the selected patients underwent left-heart surgery and concomitant TV repair using the suture annuloplasty by the bicuspidization method. In their study, Ravi K. Ghanta et al., revealed that both bicuspidization and ring annuloplasty were equally effective and durable in reducing TR up to 3 years postoperatively . HoweverOur study showed a reduction in all TV annulus parameters, including TA area, perimeter, major and minor axis, 4Ch diameter, 2Ch diameter, TA end-diastolic diameter, RV basal diameter, and RA area after the bicuspidization. Specifically, surgical bicuspidization achieved a one-third reduction in TA area and a one-quarter reduction in perimeter, major and minor axis. These findings align with the data from a recently published larger cohort study by A. Piperata, which showed a 30% reduction in TV annulus diameter after bicuspidization postoperatively. Moreover, this reduction was maintained during the latest follow-up .TM device  in humans, percutaneous bicuspidization in the porcine model showed a more significant reduction in the TV annular area than the human results [So far, little information is available regarding the effect of bicuspidisation on the precise reduction of TA size. There is a scarcity of data on how bicuspidisation affects animal hearts ex vivo. F. Sulejmani el al., studied the mechanics of the percutaneous TV bicuspidization in six porcine hearts using a novel device. The investigators found that after bicuspidization, the TA became more circular. Compared to the percutaneous bicuspidization procedure using the Trialign results .M. Mathur et al., investigated the effect of TV annular downsizing using DeVega suture annuloplasty in ten anesthetized sheep. DeVega suture annuloplasty resulted in TA shape and metrics changes, including a reduction in the area, perimeter, global height, and eccentricity. The reduction in TV annular area was primarily driven by the compression of the anterior annulus .TM  is an annuloplasty technique, which mimics Kay’s procedure by cinching the posterior portion of the tricuspid annulus. The SCOUT trial reported a reduction of the TA area from 11.6  cm2 to 10.0  cm2 using the TrialignTM device [TM  tricuspid system reduced the annulus from 14.3 ± 2.7 cm2 to 10.0 ± 2.4 cm2 [TM device (14%) or CardiobandTM system (30%). Therefore, understanding the exact degree of TA size reduction required for successful bicuspidization can be applied to percutaneous annuloplasty procedures.Currently, there is limited data available regarding the precise reduction in TA size resulting from surgical bicuspidization in humans. With the increasing number of transcatheter procedures, improving our knowledge of TA changes during surgical suture annuloplasty is important. TrialignM device . Similar 2.4 cm2 . HoweverHowever, our study found that bicuspidization did not significantly change the TV leaflets tethering parameters in the early period after the surgery. Severe TV leaflets tethering might be another reason why annuloplasty might be insufficient to correct TR. Fukuda S. et al., identified that the tethering of TV is an independent predictor of residual TR early after TV annuloplasty . AlthougRegarding early postoperative outcomes, our results revealed that bicuspidization did not increase mortality, CPB time, length of stay in the ICU, hospital stay, or the risk of postoperative complications. The study by A. Piperata et al., supports our findings. Although they reported a longer CPB time in the bicuspidised patient group, this technique did not increase perioperative mortality and complications .After cardiac surgery, the RV FAC remained unchanged in our patient cohort. Although there was a slight increase in FAC in both groups, these changes were not statistically significant. Our findings are consistent with several other studies that have examined the impact of cardiothoracic surgery on the right ventricle (RV). After cardiac surgery, there are fundamental changes in the contractile pattern of the RV. Measures of longitudinal RV shortening, such as TAPSE or the systolic tricuspid annular velocity, typically decrease postoperatively. In contrast, RV ejection fraction and RV FAC appear to remain stable or even increase after cardiac surgery ,37,38,39The TV could be visualized on either transthoracic or transoesophageal echocardiography. However, the measurements achieved by both modalities vary. We found that the dimensions of the TA obtained by 3D TTE were smaller than those obtained by 3D TOE. We hypothesize that the discrepancy in measurements may be attributed to the timing of the study. The 3D TTE was performed before surgery, while the 3D TTE was performed in the operating room just before the surgery with the patient under general anaesthesia. There is limited data available on the impact of general anesthesia on the dimensions, dynamics, and geometry of the TV. T. Jaswiec at el. showed in their animal studies using sonomicrometry  that genSince the TA is a spatial structure, only 3D echocardiography provides a better understanding of the TV geometry, and helps to assess TV dimensions more accurately. In addition, 2D echocardiography should be used only in combination with 3D echocardiography for comprehensive TV evaluation. It confirms the need and importance of establishing normal 3D TA values for future guidelines.There were several limitations in this study. Firstly, it was a single-center study with a small sample size. Secondly, the analysis did not involve the relationships between TV dimensions and both RA and RV volumes. Thirdly, the analysis was limited to short-term outcomes and further long-term follow-up results is necessary.Bicuspidization significantly reduces TA area and dimensions but minimally impacts the leaflets tethering.In patients under general anesthesia, 3D TEE parameters of the TV are larger than in conscience patients’ 3D TTE measurements.The 2D systolic measurements of the apical 4Ch diameter and the parasternal short axis diameter are insufficient for assessing the maximum dimensions of the TA.


Therefore, they can constitute relevant targets for selective control of heart rate and cardioprotection during AMI.Acute myocardial infarction (AMI) is the major cause of cardiovascular mortality worldwide. Most ischemic episodes are triggered by an increase in heart rate, which induces an imbalance between myocardial oxygen delivery and consumption. Developing drugs that selectively reduce heart rate by inhibiting ion channels involved in heart rate control could provide more clinical benefits. The Cav1.3 (v1.3−/−Ca) L-type calcium channel and of the cardiac G protein gated potassium channel (−/−Girk4) in association with the funny (f)-channel inhibitor ivabradine.We aimed to investigate the relationship between heart rate and infarct size using mouse strains knockout for Cav1.3+/−Ca, v1.3−/−Ca and −/−Girk4 mice were used as models of respectively normal heart rate, moderate heart rate reduction, bradycardia, and mild tachycardia, respectively. Mice underwent a surgical protocol of myocardial IR (40 min ischemia and 60 min reperfusion). Heart rate was recorded by one-lead surface ECG recording, and infarct size measured by triphenyl tetrazolium chloride staining. In addition, v1.3−/−Ca and WT hearts perfused on a Langendorff system were subjected to the same ischemia-reperfusion protocol ex vivo, without or with atrial pacing, and the coronary flow was recorded.Wild-type (WT), v1.3−/−Ca mice presented reduced infarct size (−29%), while −/−Girk4 displayed increased infarct size (+30%) compared to WT mice. Consistently, heart rate reduction in v1.3+/−Ca or by the f-channel blocker ivabradine was associated with significant decrease in infarct size  in comparison to WT mice.in vivo and reveal a close relationship between basal heart rate and IR injury. In addition, this study suggests that targeting Cav1.3 channels could constitute a relevant target for reducing infarct size, since maximal heart rate dependent cardioprotective effect is already observed in v1.3+/−Ca mice.Our results show that decreasing heart rate allows to protect the myocardium against IR injury  Among them, Acute Myocardial Infarction (AMI) is the number one killer and is responsible for a substantial fraction of fatalities of cardiovascular origin . Reperfu2+ release (fI)  constitute an important mechanism to slow heart rate upon parasympathetic activity (−/−Girk4) display slight basal tachycardia and blunt cholinergic regulation of SAN pacemaking  by ion channels of the plasma membrane and ryanodine receptor-mediated intracellular Ca release . Among iase (If) , 20, L-tf) . All mice were maintained under environmentally controlled conditions  in the animal facility of the Institute. The surgical protocols were approved by the “Comité d’Ethique pour l’Expérimentation Animale Languedoc-Roussillon” (CEEA-LR) with the authorization number CE-LR-0814. For ex vivo experiments, the protocol “Study of physiological parameters and cardioprotection ex vivo” was approved by the SBEA  committee from the Institute according to the European directive 2010/63/EU and the French ministerial regulation of February 01, 2013. The “n” number of mice included in the study for each experiment is the “n” authorized by the ethics committee as being the minimal “n” number allowing a valid statistical analysis while respecting the 3R rule  established in Europe.Wild-type  and transgenic mice harboring 2.2.v1.3−/−Ca, v1.3+/−Ca and −/−Girk4, as well as in WT controls as previously described , and all perfusate delivered to hearts was filtered via an in-line 0.45 µm filter for removing microparticulates.Adult male mice were anesthetized with an intraperitoneal dose of ketamine (100 mg/kg) and xylazine (10 mg/kg), followed by sodium pentobarbital . An IP injection of heparin  was administered to avoid thrombus formation. A thoracotomy was performed and beating hearts were quickly removed and excised into ice-cold perfusion fluid. The aorta was cannulated under magnification and hearts were quickly mounted and perfused by the Langendorff method  on an isDuring the stabilization phase, a 7.0 prolene ligature  was placed around the left coronary artery 1–2 mm distal from where it emerges beneath the left atrium. The ends of the ligature were passed through an occluder tube, initially without tension. ECG was continuously recorded by Ag/AgCl electrodes placed on the right atrium and near the apex. Heart temperature was continuously assessed by a probe positioned on the base of the heart and recorded by using a TH-5 monitoring thermometer . Perfused hearts were then immersed in a water-jacketed bath and continuously maintained at 37°C. After a stabilization phase of 15 min (baseline), regional normothermic ischemia was then induced by tightening the suture with the occluder tube for 40 min. After ischemia, reperfusion was allowed by loosening the ligature and perfusing the heart for 60 min. For atrial pacing, a bipolar stimulating electrode was placed on the right atrium and pacing was started during the stabilization phase.At the end of reperfusion, the artery was reoccluded, the hearts were removed from the perfusion system and phthalocyanine blue was injected through the aortic cannula to perfuse the non-ischemic portions of the myocardium, allowing the area at risk to be delineated.2.4.ex vivo IR protocol, the coronary flow from the isolated heart system apparatus was continuously digitized at 0.1 Hz and recorded using an IOX data acquisition system . Excel software  was used to perform offline analysis of the data recorded. For each mouse, a mean value of maximal coronary flow (MaxF) was calculated every 10 min. Values during ischemia and reperfusion were normalized with respect to the pre-ischemia phase (baseline) and were expressed in percentages.During the whole 2.5.in vivo and ex vivo models, signals were digitized continuously at 1 kHz and recorded using an IOX data acquisition system . EcgAuto software  was used to perform offline analysis of the data recorded. For each mouse the mean heart rate (HR) value during baseline, ischemia and reperfusion was calculated.For both 2.6.in vivo and ex vivo experiments were dissected and the LVs were sliced transversally into 1 mm-thick sections and incubated in a 1% (w/v) solution of 2.3.5-triphenyltetrazolium chloride  for 15 min at 37°C. After fixation in a 4% paraformaldehyde-phosphate-buffered solution, the slices were weighted, and each side was photographed with an Olympus camera. The ischemic risk area (unstained in blue) and the infarcted area (unstained by TTC) were outlined on each photograph and measured by planimetry using Image J . The area of each region was averaged from the photographs of each side for each slice, and multiplied by the weight of that tissue section. Infarct size was expressed as a percentage of the ischemic risk area (AR). Mice with an AR of less than 40 (in % of LV mass) and those greater than 60 were excluded from the study to ensure that infarct size values were compared in a pool of animals with the same infarct severity.Infarct sizes were measured using the technique developed by Fishbein et al. . Hearts 2.7.post hoc test or ANOVA  or by the three-way ANOVA when considering three different variables . Values of p < 0.05 were accepted as statistically significant. The p values, indicated in the text, were noted in the figures as: ns for p > 0.05, * for p < 0.05, ** for p < 0.001, *** p < 0.01 and **** p < 0.0001. All data were analyzed with GraphPad Prism . A linear relationship between HR and IS was fitted by linear regression model using the least squares method (GraphPad Prism software) based on the minimization of the sum of squares of the vertical distances of the points from the line.All values are expressed as mean ± SD. For comparisons between two groups, the Mann–Whitney non-parametric test was used. Multiple comparisons between groups were assessed by the Kruskal–Wallis nonparametric test followed by the Dunn's 3.3.1.fI) plays an important role in the generation of heart rate. Therefore, we first investigated the effects of the selective fI inhibitor ivabradine on IR injury , ivabradine treated mice  showed a significant decrease in both basal heart rate   that was associated with a 26.7%-decrease in infarct size . In homozygous v1.3−/−Ca mice (n = 7), characterized by a marked reduction (54%) of the basal heart rate in comparison to WT counterparts (n = 6) , a 28.8%-decrease in infarct size vs. WT was observed . By contrast, mean heart rates from −/−Girk4 and −/−Girk4 Iva were higher compared to WT [360 ± 54 bpm, n = 5; p**** < 0.0001 for −/−Girk4 and 271 ± 32 bpm, n = 5; pns = 0.356 for −/−Girk4 Iva vs. WT . −/−Girk4 mutant mice exhibit the largest  and v1.3−/−Ca the lowest  infarct sizes. A moderate heart rate reduction in Girk4−/− mice induced by a bolus injection of ivabradine  yielded infarct sizes that were in between those recorded in WT and −/−Girk4  mice.In order to elucidate the correlation between heart rate and infarct size, we used genetically modified mice harboring different basal heart rates. We thus measured infarct size in protocol  in contrg groups . Mean her2 values of the linear regression were obtained for heart rate values recorded at baseline and during ischemia   .3.4.in vivo, we investigated whether increase in heart rate prevented cardioprotection. To this aim, atrial pacing ex vivo was performed to increase heart rate in the absence of the vagus nerve influence (in vivo through the implementation of a reversible ligation on the left coronary during 40 min ischemia followed by 60 min reperfusion (v1.3−/−Ca hearts ex vivo exhibit complex atrioventricular conduction block (v1.3+/−Ca associated with strong cardioprotection. v1.3+/−Ca hearts with a mean heart rate of 341 ± 20 bpm (n = 6) were paced at 475 bpm (n = 5), representing a 39%-increase. Infarct size in paced hearts was 44%-increased  and upon atrial pacing (20% increment in heart rate), infarct size was increased by 32% in those hearts .Since heart rate reduction prolongs the ventricular diastole allowing to augment the coronary perfusion, we recorded the coronary flow during eriments ; Table 1ex vivo and suggest that the cardioprotective effect associated to a decreased heart rate might be related to a better coronary circulation during reperfusion.Taken together, these results demonstrate positive correlation between heart rate and infarct size 4.in vivo. We found that infarct size is closely correlated with heart rate recorded during the pre-ischemic and ischemic phases in WT and mutant mice tested. Genetic ablation of one allele of L-type Cav1.3 channels led to moderate heart rate reduction and a reduced infarct size in vivo when compared to WT counterparts. Increased heart rate via atrial pacing ex vivo abolished both the cardioprotective effect of heart rate reduction induced by genetic ablation of Cav1.3 and improvement of the post-ischemic coronary flow observed at a lower heart rate. Taken together, our data show, for the first time, that heart rate per se is a major predictor of IR injury: the lower is heart rate, the greater being cardioprotection. In conclusion, our results indicate positive correlation between heart rate and infarct size both in vivo and ex vivo in the absence of vagal stimulation. Furthermore, our data suggest that targeting of Cav1.3 channels can constitute a new potential therapeutic strategy to reduce IR injury and infarct size.In this study we have investigated the relationship between heart rate and infarct size using a protocol of IR injury v1.2-driven calcium currents, a physiological mechanism involved in the Bowditch “staircase” allowing an adaptation to exercise and stress upon β-adrenergic regulation (Heart rate is a vital parameter assessed at admission in all patients with acute myocardial infarction. Several prognostic studies have shown that resting heart rate is predictive of poor outcome in patients and heart rate at discharge is predictive of long-term outcome in patients with coronary artery disease . In thisgulation . In addigulation . These fgulation , 16. Phagulation , 40. As gulation . Howevergulation , 43. Thev1.3 channels underlying Cav1.3I current constitute with fI the predominant mechanisms in the generation of diastolic depolarization (KAChI constitute both tonic and phasic brakes of diastolic depolarization and heart rate (v1.3 knockout and ivabradine reduced heart rate by similar percentages in freely-moving mice (v1.3 knockout lead to comparable infarct sizes, supporting our hypothesis that cardioprotection mediated by Cav1.3 targeting is primarily due to heart rate reduction, at least under our experimental conditions. Furthermore, Cav1.3 channels are not expressed in the adult ventricle (v1.3 channels thus constitute an important candidate, in addition to fI, to obtain slowing of heart rate without concomitant negative inotropism. Consequently, we have compared cardioprotection conferred by pharmacological inhibition of fI to that obtained upon genetic ablation of Cav1.3 and GIRK4 channels.Carization , 32, 44,art rate , 45. In ing mice . This isentricle  and are entricle . Cav1.3 in vivo mouse model of IR for studying the effects of genetic ablation of ion channels involved in pacemaking. Our results show that genetic ablation of Cav1.3, or GIRK4 channels regulates the infarct size in close correlation with heart rate recorded in three phases considered: baseline, ischemia and reperfusion. Importantly, genetic targeting of Cav1.3 channels and pharmacologic inhibition of fI reduced infarct size, similarly, suggesting comparable efficacy in controlling IR injury (v1.3 compares to ivabradine, suggesting that selective pharmacological targeting of Cav1.3 could induce at least as much cardioprotection as ivabradine. Consistently with heart rate being an important factor in determining cardioprotection against IR injury, similar heart rates obtained by ivabradine infusion, or genetic ablation of Cav1.3 channels yielded comparable infarct sizes. We noticed that despite v1.3−/−Ca mice presented with lower heart rates than v1.3+/−Ca mice, deletion of the two Cav1.3 alleles did not significantly reduce the infarct size in comparison to heterozygous v1.3+/−Ca mice (v1.3+/−Ca heterozygous and −/−Cav1.3 homozygous hearts have increased degree of remodeling secondary to sporadic atrioventricular block found in this genotype (v1.3−/−Ca mice exceeds bradycardia observed in vivo in freely moving −/−Cav1.3 mice. This could be related to the cardiodepressant effect of xylazine-ketamine-based anesthesia, which would tend to exacerbate the effects on heart rate of total genetic ablation of Cav1.3 in cardiac pacemaker activity, an effect that would not translate into overt cardioprotection compared to v1.3+/−Ca hearts. Bradycardia during the acute phase of myocardial infarction is correlated to early cardiovascular mortality. In their study, Salwa et al. demonstrated a J-curve for the mortality as a function of heart rates suggesting that bradycardia was associated to worsen injury within the myocardial tissue (v1.3 blockade may help explain these discrepancies.Pharmacological heart rate reduction by ivabradine effectively reduced the heart rate and the infarct size in control WT mice , thus vaR injury . Consequ+/− mice , possiblgenotype , 45. Sucgenotype , 27. In l tissue . Future v1.3+/−Ca hearts was abolished when atrial pacing was applied to compensate the lowering effect of Cav1.3 inactivation expressed in the pacemaker of v1.3+/−Ca mice, clearly showing that cardioprotection was related to heart rate reduction, since Cav1.3 channels are not expressed in the adult ventricle (v1.3 channels. Our data indicate that, similar to that reported for ivabradine (v1.3+/−Ca hearts. In this context, previous work showed that part of the cardioprotective effect of ivabradine is not dependent on its heart rate reduction effect (v1.3 mutant hearts, atrial pacing ex vivo negated the cardioprotective effect of the genetic ablation of one allele of the Cav1.3 gene. These results obtained in isolated perfused hearts suggest that cardioprotection observed in v1.3+/−Ca was dependent on its heart rate reduction effect.The cardioprotective effect observed in entricle . These oabradine , 26, impabradine . In linen effect . For Cav


Introduction: The perisylvian region is the cortical core of language and speech. Several accessory sulci have been described in this area, whose presence could modify the results of the automatic quantification of gray matter by popularly used software. This study aimed to assess the expression of accessory sulci in the frontoparietal operculum (FPO) and to evaluate their influence on the gray matter volume estimated by an automatic parcellation of cortical gyri and sulci.Methods: Brain MRI scans of 100 healthy adult volunteers were visually analyzed. The existence of the triangular and diagonal sulci, and the number of accessory sulci in the frontoparietal operculum, were assessed on T1 images. Also, the gray matter volume of gyri and sulci was quantified by an automatized parcellation method. Interhemispheric differences in accessory sulci were evaluated with Chi-square and Wilcoxon paired tests. The effects of the hemisphere, sex, age, total intracranial volume, and accessory sulci on morphometric variables were assessed by linear models.Results: These sulci were found in more than half of the subjects, mostly in the left hemisphere, and showed a significant effect on the gray matter content of the FPO. In particular, the volume of the inferior frontal sulcus, pars opercularis of the inferior frontal gyrus, horizontal ramus of the lateral sulcus, angular gyrus, and postcentral gyrus showed a significant influence on the presence of accessory sulci.Discussion: The prevalence of tertiary sulci in the FPO is high, although their meaning is not yet known. Therefore, they should be considered to reduce the risk of misclassifications of normal variation. The frontoparietal operculum (FPO) comprises regions of the frontal and parietal cortex, dorsal to the lateral sulcus (Sylvian fissure), including the inferior frontal gyrus and the ventral parts of the precentral and postcentral gyri, subcentral gyrus, supramarginal and angular gyri , we study a large sample of MRIs from healthy volunteers. We particularly assessed the presence and the number of accessory sulci by a visual survey and estimated the volume of cortical gyri and sulci using an automatic segmentation pipeline implemented in Freesurfer . All volunteers had at least 12 years of education, 48.96% were undergraduate students, and 36.46% had completed a university qualification. Participants gave their informed consent to participate in the study, approved by the Ethical Committees of the Hospital El Cruce and Hospital Angel Roffo, in agreement with the Declaration of Helsinki ethical standards. All the acquired images were visually inspected by an expert neuroradiologist (JP) to exclude subjects with incidental findings.We recruited 100 healthy volunteers  living in the Buenos Aires Metropolitan Area (Argentina) that met the requirements for inclusion in the sample. These criteria comprised no known neurological or psychiatric disease or systemic disease which could impact neurological function and not taking any medication which could have effects on neurological function. Subjects with implanted metal clips or wires are not allowed to undergo MRI scanning and so were excluded. The mean age was 31.4 years (range: 18–57). Subjects were right-handed, as revealed by the Edinburgh Handedness Inventory  located in the Hospital El Cruce in Florencio Varela (second urban belt of the metropolitan area of Buenos Aires) and a 3T Siemens Trio (n = 45) located in the Hospital Angel Roffo from Buenos Aires. Volumetric T1 images were obtained using a 3D FFE sequence  in the 3T Philips Achieva, and MP-RAGE sequence  in the 3T Siemens Trio. The images were converted from DICOM to NIFTI format using Dcm2NiiSubjects were scanned in two scanners, a 3T Philips Achieva , who visually identified the accessory sulci  in each n = 6).Two observers  tested the frequency of the presence of each accessory sulcus on a subset of the sample. The identification of these sulci was carried out until significant differences between observers disappeared. Then, one observer (MV-A) assessed the accessory sulci in the entire sample, and the results were checked by an experienced neuroanatomist (MB). The sulci were visualized in parasagittal MRI sections and verified in orthogonal slices , navigatWe used Chi-squared tests to evaluate whether the presence of the triangular and diagonal sulci depended on the hemisphere and whether this differed according to sex. The presence of significant interhemispheric differences in the number of sulci in the frontal and parietal operculum  was assessed by a Wilcoxon paired test. To evaluate any potential allometric effect between brain size and the presence of accessory sulci, we correlated total intracranial volume (as a measure of brain size) with the number of accessory sulci found in each brain, i.e., diagonal and triangular sulci, and parietal notches, using Spearman’s rank correlation. Finally, to test whether brains with accessory sulci in the frontal operculum have more folds in the parietal operculum, we applied Pearson’s Chi-squared Test. All tests were performed in Rstudio (v 3.6.3)MR images were processed using Freesurfer (v 6.0.0.0)p-values were adjusted through a False Discovery Rate test (FDR), to minimize type 1 error rate To assess the effect of accessory sulci on the gray matter content of gyri and sulci of the FPO, we applied linear models, where the accessory sulci were introduced as independent variables and the volume of cortical regions as the dependent variables. The scanner site of each sample was also included as a covariate to account for any effects related to the acquisition of the MRI sequences , we found accessory sulci in the precentral, postcentral, and supramarginal gyri. These sulci extend from the lateral sulcus in variable numbers ranging from 1 to 7 (p < 0.01). The presence of accessory sulci was not statistically different between sexes .The triangular sulcus was found in 51% of the individuals in our sample . Though m 1 to 7 , and witR = 0.0048; p > 0.05), indicating that larger brains do not necessarily have more folds (or more accessory sulci). In addition, brains with accessory sulci in the frontal operculum do not necessarily have more folds in the parietal operculum (triangular sulcus: χ2N = 200).Regarding the relationship between brain size and the folding in the FPO, the correlation was very low and non-significant  compared to those without accessory sulci . The joint presence of the diagonal and triangular sulci showed a significant effect on the volume of the parcel of the horizontal ramus of the lateral sulcus , and drafted the manuscript. PG conceived and designed the study, and drafted the manuscript. All authors contributed to the article and approved the submitted version.


PVS showed no difference between the groups . T2 showed a clear dose–response relationship with PVS, with increasing T2 values along the PVS tertiles. In spite of this, T2 was found to be an independent marker of myocardial inflammation in logistic regression , even after adjusting for PVS . Despite a dose–response relationship between T2 and the volume status, T2 was found to be an independent indicator of myocardial inflammation.Myocardial inflammation and edema are major pathological features in myocarditis. Myocardial tissue water content and myocardial edema can be quantified via T2 mapping. Thus, cardiac magnetic resonance (CMR) is the noninvasive gold standard for diagnosing myocarditis. Several studies showed an impact of short-term volume changes on T2 relaxation time. Plasma volume status (PVS) is a good surrogate parameter to quantify a patient’s volume status, and it is simple to use. The aim of this study was to determine the effect of PVS on the diagnostic value of T2 relaxation time in myocardial inflammation. Between April 2017 and December 2022, patients who were indicated for cardiac CMR were included in our prospective clinical registry. Patients with myocardial inflammation and those with unremarkable findings were analyzed in the present study. A blood sample was drawn, and PVS was calculated. Patients were separated into PVS tertiles to explore a possible nonlinear dose–response relationship. Logistic regression analysis was used to determine whether T2 is an independent predictor of myocardial inflammation. A total of 700 patients  were eligible for analysis. Of these, 551 patients were healthy (78.7%), while 149 (21.3%) showed signs of myocardial inflammation. The T2 relaxation time was elevated in patients with myocardial inflammation (40 ms [IQR 37–42 ms] vs. 38.0 ms [IQR 36–39 ms],  Myocarditis is an important differential diagnosis of chest pain, heart rhythm disorders, and, above all, heart failure ,2. The iCardiac magnetic resonance imaging (CMR) has become the gold standard in the noninvasive diagnosis of myocarditis because of its unique characterization of tissue and its high reproducibility ,9. The uOn the other hand, volume fluctuations due to heart failure decompensations are hallmarks of the disease in both acute and chronic heart failure. Recent reports suggest that volume fluctuations may also influence myocardial T1 and T2 . LuetkenThus, while the value of T2 as an inflammatory marker is well known, it remains unclear if it might be hampered by volume fluctuations. The given volume state of the patient might not be clearly visible as in the more experimental settings of hydration/dehydration or after volume filtration. We therefore sought for an easy-to-use approach reflecting volume changes that are not assessable via visible estimation.The plasma volume status (PVS) according to Hakim’s formula, which is based on the hematocrit, is a simple and noninvasive way of estimating a patient’s volume status . It was Therefore, the purpose of this study was to examine in a large cohort whether PVS influences myocardial T2 and its corresponding effect on diagnostic accuracy regarding myocardial inflammation.Our study population was drawn from a prospective CMR/biobank (BioCVI) all-comers registry of patients who underwent clinically indicated CMR at a single center  between April 2017 and December 2022. All patients enrolled in the registry who had a hematocrit that was measured immediately before the CMR examination were included, as this was required for PVS calculation. Clinical indications for CMR included the assessment of myocardial function, ischemia testing, viability testing, myocarditis, and differentiation of cardiomyopathy.For this analysis, we extracted patients with confirmed myocarditis and patients with normal findings as the control group. Myocarditis was defined according to the criteria proposed by Caforio et al. in the 2013 position paper of the European Society of Cardiology (ESC) Working Group on Myocardial and Pericardial Diseases :typical clinical presentation with recent onset of chest pain, symptoms of heart failure, or arrhythmia;myocarditis-typical tissue characterization via CMR: subepicardial or intramural LGE and elevated native T1 and T2 values;at least one of the following features:recent-onset arrhythmias in 12-lead ECG;elevation of troponin above the 99th percentile.Patients with normal findings were defined as having left ventricular ejection fraction ≥50%, left ventricular end-diastolic volume index ≤105 mL, absence of LGE and perfusion defects, and normal native T1 values.The registry includes a standardized questionnaire about symptoms, clinical and family history, medication, a single blood sample for the BioCVI biobank, a standard CMR examination with post-processing, and a clinical routine follow-up via questionnaire or telephone interview after one year.All patients gave their written informed consent. The registry was approved by the ethics committee of the University of Giessen.Standard CMR was performed on a 3 Tesla scanner  in the head-first supine position with an 18-array coil in agreement with the recommendations of the Society of Cardiovascular Magnetic Resonance (SCMR) . Categorical variables are provided as number and percentage. Differences between two groups were tested via the Wilcoxon signed-rank test. Nonlinear trends along tertiles of PVS were tested by using the Jonckheere–Terpstra test. Diagnostic prediction of the presence of inflammation was tested via univariable and multivariable logistic regression analysis presenting odds ratios. A n = 149) or normal findings (n = 551) were used. The mean age was 56.31 years (41.46–67.87 years), and 332 were female (47.43%). Heart failure, diabetes mellitus, and reduced renal function were more prevalent in the group of patients with myocardial inflammation, whereas there was no difference in age and arterial hypertension between the groups  than in healthy patients. Accordingly, cardiac biomarkers hs-cTnT and NT-proBNP, as well as inflammatory marker CRP, were also elevated in patients with myocardial inflammation (hs-troponin T 6.0 (3.4–10.2) ng/L vs. 14.6 (5.2–30.1) ng/L p < 0.001; NT-proBNP 95.1 (40.4–233.9) pg/mL vs. 387 (90.3–1635.5) pg/mL, p < 0.001; CRP 0.1 (0.1–0.4) mg/dL vs. 0.2 (0.1–0.55) mg/dL, p < 0.05). Ejection fraction was lower in patients with inflammatory disease (61% (56–65%) vs. 53% (37–58%), p < 0.001). Additional CMR data are provided in T2 relaxation time was higher in patients with myocardial inflammation (40 ms (37–42 ms) vs. 38 ms (36–39 ms), p < 0.001) (p < 0.01). To test for the presence of a dose–response relationship between NT-pro-BNP and PVS, PVS was divided into tertiles (p < 0.001).PVS distribution for the whole cohort showed a normal distribution . There w< 0.001) . PVS wastertiles : the firp < 0.01). There was a positive dose–response relationship between PVS and T2, with T2 increasing along PVS tertiles (37 (35–39) ms vs. 39 (36–40) ms vs. 39 (37–41) ms, p < 0.001) (p < 0.001). This result was still significant when only patients with myocardial inflammation were considered (37 (36–39) ms vs. 40 (38–42) ms vs. 42 (40–44) ms, Jonckheere–Terpstra p < 0.001).PVS was associated with T2 relaxation time  with a b< 0.001) , Jonckhep < 0.001). This result was independent of PVS in multivariable logistic regression analysis (OR 1.31 [95% CI 1.22–1.41]) despite detecting a significant interaction of PVS and T2, with a higher OR of T2 in the upper PVS tertiles   .p < 0.001).Furthermore, we found a significant nonlinear relationship of T2 and troponin T, with the highest values of troponin T in the third tertile of T2 values  [One interesting approach is to calculate the PVS via the Hakim’s formula. PVS can easily be calculated by using body weight, sex, and hematocrit. In the Val-HeFT cohort, PVS correlated with biomarkers of intravascular filling and with plasma volume measured via the gold-standard method by using 25I-HSA) . Moreove25I-HSA) ,27. A cu25I-HSA) .p < 0.01). NT-proBNP also showed elevated values in patients with PVS above −4%, and NT-proBNP increased over PVS tertiles  is an important marker of myocardial injury . The finA limitation of our study is that it is derived from a single center. However, it uses the all-comers approach in a clinical routine, which renders a generalization of our findings more plausible. Another potential limitation is that all patients who were labeled as “healthy” initially presented with cardiac symptoms, although the CMR scan revealed no pathology with respect to function, LGE, volume, and T1. It should be noted that PVS is only a surrogate parameter for volume status and not the invasive gold standard, but its easy use made it possible to apply this parameter to a very large cohort with an adequate control group.Our data confirm the findings that T2 relaxation time correlates with patients’ volume status in a larger cohort. Furthermore, the diagnostic value of elevated T2 times was found to be independent of the volume status in multivariable regression analysis, which renders T2 a very robust parameter for the diagnosis of myocardial inflammation.


Evidence suggests that patients suffering from angina with no obstructive coronary artery disease (ANOCA) experience coronary microvascular dysfunction (CMD). We aimed to understand the diagnosis value of noninvasive myocardial work indices (MWIs) with left ventricular pressure-strain loop (LV PSL) by echocardiography in ANOCA patients with CMD.97 patients with ANOCA were recruited. All subjects underwent standard echocardiography with traditional ultrasound parameters, two-dimensional speckle-tracking echocardiography with global longitudinal strain (GLS), LV PSL with MWIs include global work index (GWI), global constructive work (GCW), global waste work (GWW) and global work efficiency (GWE). In addition, all enrolled cases underwent high-dose adenosine stress echocardiography (SE) with coronary flow velocity reserve (CFVR). CMD was defined as CFVR <2.0.P < 0.001 for both). GWI and GCW were moderately correlated with CFVR . In the multiple logistic regression analyses, GCW was identified as the only independent echocardiography parameter associated with CMD after adjusting for age and baseline APV . Moreover, the best predictor of CMD in patients with ANOCA using receiver operating characteristic (ROC) curve was GWI and GCW, with an area under the curve (AUC) of 0.800 and 0.832, sensitivity of 67.3% and 78.8%, specificity of 80.0% and 75.6%, respectively.Of the 97 patients with ANOCA, 52 were placed in the CMD group and 45 in the control group. GWI and GCW were decreased significantly in the CMD group compared with the control group (MWIs with LV PSL is a new method to detect LV systolic function noninvasively in ANOCA patients with CMD. CoronarCMD-triggered ischemia is comparable with obstructive epicardial coronary artery disease (CAD)-mediated ischemia. Several research revealed that, in patients suffering from CMD, there is a strong association with an enhanced risk of severe cardiovascular events such as nonfatal myocardial infarction (MI), hospitalization due to heart failure, and cardiac-related mortality , 4. TherCoronary microvascular function cannot be assessed directly at present. However, targeting the distal of left anterior descending artery (LAD) by transthoracic doppler echocardiography makes it possible to infer coronary microvascular function indirectly. In patients not suffering from epicardial disease, a decrease of coronary flow velocity reserve (CFVR) during drug-induced stress can reflect the function of coronary microvascular .Global longitudinal strain (GLS) plays an important part in the evaluation of LV systolic function. Two-dimensional speckle-tracking echocardiography (2D-STE) provides extensive quantitative information on myocardial activity in patients with CMD , 7. HoweThe LV pressure-strain loop (LV PSL) with myocardial work indices (MWIs) is an accurate and noninvasive new parameter. It provides potential value for the assessment of myocardial function by accounting for the strain associated with dynamic noninvasive LV pressure. Multiple clinical works have demonstrated that MWIs have superior performance compared with GLS . One stuThe present study was conducted to achieve two goals. The first goal was to assess LV systolic function via LV PSL with MWIs in patients with ANOCA who also suffering from CMD. The second goal was to provide a new method for the diagnosis of LV systolic dysfunction in ANOCA patients with CMD.2.2.1.n = 45), who had CFVR ≥2.0; CMD (n = 52), who had CFVR <2.0. Written informed consent was acquired from all patients before study commencement.This was a retrospective, single-center study that, between October 2019 and December 2021, evaluated 97 patients with ANOCA. Based on invasive angiography, patients with angina pectoris did not display obstruction in a coronary artery (≤50% stenosis) within the last 3 months. CFVR was obtained using high-dose adenosine stress echocardiography (SE) in all included patients. Based on CFVR values , patientThe inclusion criteria were: (1) age of 18–80 years; (2) symptomology of angina pectoris, with an absence of obstructive CAD (<50% diameter stenosis) within the last 3 months according to coronary angiography ; (3) norA detailed description of the exclusion criteria (as well as the precautions for adenosine SE) has been provided previously –17. In a2.2.Echocardiography was undertaken by experienced sonographer working more than five years, using an ultrasound system  via a standard two-dimensional (2D) cardiac probe (M5S) and an Echo PAC204 post-processing workstation. Three cardiac cycles of standard 2D images were collected in DICOM format using QRS as the recording standard for offline analyses. All variables were assessed based on the recommendations of the American Society of Echocardiography (ASE) .All 2D and doppler-parameter readings were conducted based on ASE guidelines in standard views. Measurements of the left atrium volume (LAV), LV end-diastolic volume (LVEDV), LV end-systolic volumes (LVESV), and LVEF were based on four- and two-chamber apical views. The LV end-diastolic dimension (LVEDD) was obtained perpendicular to the long axis of the left ventricle. Chamber recordings were standardized to the body surface area (BSA) before computing the LAV, LVEDV, LVESV, and LVEDD indices, and these parameters were finally marked as LAVI, LVEDVI, LVESVI, and LVEDDI, respectively. The mitral peak E and A velocities were obtained from the four-chamber view via pulsed wave doppler prior to E/A calculation. The mean mitral annulus and lateral wall in early diastole (e′ peak) velocities, as well as the mean mitral annulus and lateral wall in systolic (S′ peak) velocities, were acquired from the apical four-chamber view via tissue doppler prior to E/e′ calculation.2.3.Grayscale images were captured in apical two-, three-, and four-chamber views, with frame rates >50 frames/s. LV outflow pulsed doppler was utilized to record the duration of end systole. Subsequently, the operator identified three points, in particular, two on either side of the mitral valve, and a third at the LV apex. Using the 17-segment LV model, the peak GLS value from the systolic period was then recorded automatically .Through the LV PSL, MWIs were obtained automatically as described using data from LV strain, valvular event times, and systolic BP . Subsequ2.4.−1·min−1) using a syringe pump. The BP and heart rate were documented at 1-min intervals during intravenous pumping until all of the drug had been administered. The hyperemic peak APV of the LAD was recorded during the entire infusion. CFVR was described as the ratio of the hyperemic peak: baseline APV.The distal LAD was acquired via modification of the two-chamber view in color doppler mode before introduction of a sample volume (width = 1.5 mm) on the color signal. Displaying the anterior interventricular sulcus in the apical region, under the guidance of color doppler blood flow, the LAD branch shows small diastolic blood flow. The probe angle needs to be carefully adjusted to minimize the angle between blood flow sound beams and record the LAD branch blood flow spectrum. The stable frequency spectrum of the LAD was obtained while recording the baseline average peak velocity (APV). Under monitoring by electrocardiography and BP, adenosine was administered for 6 min  were measured by two experienced observers who were not provided with the clinical data or study data. The same individuals were also assessed at different time points to ascertain intra-observer variability.2.6.t-test. Analyses of data with a non-normal distribution were carried out using the Mann-Whitney test. Analyses of categorical data were based on the chi-square test. Spearman's correlation coefficient was used to test correlations of MWIs (including GWI and GCW) with CFVR.SPSS 25.0  was employed for all data analyses. Categorical statistics are provided as numbers and percentages. Results with a normal distribution were confirmed via the Shapiro-Wilk test. Based on the data distribution, normal data are provided as mean ± standard deviation, and non-normal data as the median . Analyses of data with a normal distribution were undertaken using the independent P < 0.05 at univariable logistic analysis were considered for multivariate logistic regression analysis to determine the independent factor that affects CMD. Analyses of receiver operating characteristic (ROC) curves were done to evaluate the suitable threshold along with sensitivity and specificity values for MWIs and GLS in the detecting of CMD. P < 0.05 (two-sided) was considered significant.We used univariate logistic regression analysis to identify the factors that affect CMD. In order to rule out multicollinearity issues, the independent variables included are age, baseline APV, GWI, GCW. All variables with 3.3.1.One hundred and two patients met our strict criteria for inclusion and were evaluated. Five patients were eliminated from the analyses: three patients had data with poor image quality for analyses of GLS and MWIs; two patients had an incomplete adenosine stress test owing to chest pain and physical discomfort. Ultimately, we recruited 97 patients with ANOCA for evaluation and separated them into a CMD group and control group.We observed no discernible differences in the height, weight, body mass index, BSA, tobacco-smoking history, or disease history  between patients in the CMD group and control group . The CMD3.2.P < 0.001 for both]  (CI) 1.009 (1.005–1.013); P < 0.001] (We have summarized the data for echocardiography parameters for the two groups in or both] . GWI andctively) . In the < 0.001] . We empl< 0.001] . Based o3.3.GLS and all MWIs revealed excellent intra- and inter-observer relationships, with a minimum intraclass correlation coefficients (ICCs) value of 0.900 .4.We revealed, for the first study time, the impairment of LV systolic function in ANOCA patients with CMD by MWIs. We demonstrated that: (1) GWI and GCW were strongly diminished among ANOCA patients suffering from CMD; (2) GWI and GCW were associated with CFVR; (3) GCW was the only independent predictor of CMD; (4) the best parameters from ROC curve to predict LV systolic function in ANOCA patients with CMD were GWI and GCW.The primary characteristics of CMD are myocardial ischemia and hypoxia . CMD hasStudies have reported that, among all MWIs, GWI and GCW are the most robust indicators of ischemia in patients with CAD . In accoWe found that CFVR was positively correlated with GWI and GCW in patients with ANOCA. GCW was identified as the only independent echocardiography parameter associated with CMD after adjusting for age and baseline APV. In patients with CAD, CFVR can be used to predict cardiopulmonary fitness independent of resting systolic and diastolic function . In a prOur further analyses of GLS and MW parameters in patients with CMD revealed that the AUCs of GWI and GCW were significantly higher than those of GLS, GWW, and GWE. These data are similar to those from a study on patients with CAD by Guo and colleagues . They foIn our study, the ROC results have found that GWI and GCW are moderate in predicting of CMD, but with low sensitivity and specificity. This may be related to the characteristics of our selected patients. We choose cases with coronary stenosis less than 30% and normal wall motion, which has little effect on the cardiac mechanical indices. This may lead to some overlap in MWIs between the CMD group and control group, so it will cause the decrease of sensitivity and specificity in the ROC curve We also found a moderate correlation between WMIs and CFVR, this may be related to the different measurement units of the two variables.Several reports have suggested use of GLS for the diagnosis of myocardial ischemia, which may also be applicable as an adjunct diagnostic tool in the clinic , 36. AmoGiven the evidence stated above, MWIs by LV PSL appears to be important for the diagnosis and prediction in patients with ANOCA and CMD. This new method for the quantitative evaluation of LV systolic function in patients with ANOCA and CMD is non-invasive and accurate.5.In ANOCA patients with CMD, reduced LV systolic function may be associated with functional alterations within the coronary microcirculation. Our noninvasive LV PSL demonstrated incremental value for the identification of CMD in people suffering from ANOCA.6.The present study had four main limitations. First, the study cohort was recruited from a single center. Second, the study was retrospective. Hence, in future investigations, we recommend a multicenter prospective investigation involving a large sample population to validate our findings. Second, CMR and positron emission tomography provide extensive information on the tissue profile and myocardial metabolism among patients with CMD. However, these data were not available for use during our study. Third, we assessed alterations in LV systolic function among patients with CMD only at rest: future research should involve examination of LV systolic function under stress.


Level of Difficulty: Advanced.)Varying degrees of atrioventricular block can be associated with old age or a manifestation of an ischemic, metabolic, or infective pathology. In patients with no clear explanation, it is important to investigate secondary causes. Our case describes the first case of an adult with Rosai-Dorfman histiocytosis presenting with complete heart block. (  An electrocardiogram was conducted that showed third-degree heart block, prompting further investigation .LearningShe had a background of Rosai-Dorfman disease (RDD) with bony involvement, type 2 diabetes mellitus, and first-degree atrioventricular (AV) block. Her only medication history was metformin 500 mg twice a day. Previously, she had a histiocytic lesion in the right hip that resulted in a fragility fracture requiring a right total hip replacement. Furthermore, there was a lesion in the left hip that was being monitored and a lesion in the left sacrum that required radiotherapy.Differential diagnosis included all causes of pathologic blockade of AV conduction, including infective, metabolic, pharmacologic, and structural disturbances.Initial blood results demonstrated a normal blood count, electrolytes, and thyroid function, and chest x-ray appeared normal with no signs of infection. Due to a high index of suspicion for structural cardiac disease, it was decided to carry out cardiac magnetic resonance imaging (MRI) in the first instance.Cardiac MRI was performed using a 1.5-T Siemens Aera scanner; steady-state free precession cine imaging, T1-weighted imaging pre- and post-gadolinium-based contrast, T2-weighted imaging, pre-contrast T1 and T2 mapping, and early- and late-gadolinium enhancement images were acquired.The interatrial septum (IAS) was thickened by an irregular mass (37 × 23 mm) encroaching onto the basal interventricular septum and extending from the level of the coronary sinus up to the aortic valve annulus  and 2B. Biventricular indexed end-diastolic volume and systolic function were normal . Outside of the mass, there was no evidence of myocardial edema on T2w imaging, no intracardiac thrombus on long TI early gadolinium enhanced imaging, and no myocardial infarction or fibrosis on late gadolinium imaging . BiatriaThe impression was that the intracardiac mass represented an extranodal manifestation of the known non-Langerhans histiocytosis and had imaging characteristics that would be consistent with this. Its location was also consistent with the presentation of complete heart block.Following detailed tissue characteristics from the MRI, a transesophageal echocardiogram was carried out to detail the structure of the intracardiac mass. The transesophageal echocardiogram corroborated the findings from the MRI of an infiltrative IAS mass . The masTo further investigate the IAS mass, an endomyocardial biopsy was carried out. The myocardial biopsy specimens of the IAS mass showed diffuse infiltration by large numbers of histiocytes with an abundance of foamy eosinophilic cytoplasm on hematoxylin and eosin staining .Figure 5Also noted were many small mature lymphocytes, few plasma cells, and occasional eosinophils and neutrophils. No granulomas were seen, and no obvious emperipolesis was identified. No micro-organisms were seen with special stains . Immunostaining phosphoglucomutase 1 highlighted abundant histiocytes  and 5C. Although the classically seen emperipolesis was not present on this biopsy, our patient did have a previous left iliac biopsy showing emperipolesis . As suchGiven the location of the IAS mass, it was agreed that resection would not be feasible due to its association with surrounding structures including mitral apparatus, interventricular septum, and coronary sinus. Medical management of the RDD was discussed but, because the progression of the disease was uncertain, it was agreed that on balance the patient should be offered a dual-chamber pacemaker. Ten months later she presented with clinical heart failure and significantly impaired left ventricular systolic function most likely as a result of pacing-induced cardiomyopathy. She underwent an attempted upgrade to biventricular pacing, however, we were unable to successfully cannulate the coronary sinus and she was implanted with a left bundle area pacing lead for resynchronization.RDD is an uncommon histiocytic disorder, which classically presents with massive bilateral painless cervical lymphadenopathy associated with weight loss, fevers, and night sweats.,Extranodal disease has been reported in >40% of patients with common sites being the skin, nasal cavity, bone, orbital tissue, and central nervous system.Given the scarcity of reported cardiac involvement of RDD, the optimal approach to management remains unclear. The most recent consensus of management (2018) suggests that the disease progression is often unpredictable, and that extranodal involvement is often associated with a poor prognosis.In our case, the presence of first-degree heart block 2 years before any cardiac imaging suggests there had been intracardiac involvement of Rosai-Dorfman that was not rapidly expanding. This was in the context of no systemic treatment for the disease because the previously discovered bony lesion was managed with localized radiotherapy. This may give some indication of the natural progression of the disease, but further studies are required before this can be confirmed.After implantation of the permanent pacemaker, pacing parameters remained stable, however, she developed clinical heart failure with new depression of left ventricular systolic function hence the decision for upgrade to resynchronization. Our patient was offered systemic steroid treatment as an attempt to limit the growth of the interatrial mass, but this was declined due to the side effect profile of systemic glucocorticoids. As such, the patient will remain under follow-up and is planned for interval imaging to assess the progression of the mass.Understanding the pathophysiology remains a key component to managing patients with complete heart block and this is highlighted in the current European Society of Cardiology 2021 pacing guidelines.The authors have reported that they have no relationships relevant to the contents of this paper to disclose.


The solid-state cadmium-zinc-telluride (CZT) gamma camera for myocardial perfusion single-photon emission computed tomography (MPS) has theoretical advantages compared to the conventional gamma camera technique. This includes more sensitive detectors and better energy resolution. We aimed to explore the diagnostic performance of gated MPS with a CZT gamma camera compared to a conventional gamma camera for detection of myocardial infarct (MI) and assessment of left ventricular (LV) volumes and ejection fraction (LVEF), using cardiac magnetic resonance (CMR) as the reference method.Seventy-three patients  with known or suspected chronic coronary syndrome were examined with gated MPS using both a CZT gamma camera and a conventional gamma camera as well as with CMR. Presence and extent of MI on MPS and late gadolinium enhancement (LGE) CMR was evaluated. For LV volumes, LVEF and LV mass, gated MPS images and cine CMR images were evaluated.P ≤ .002 for all measures). The underestimation was slightly less pronounced for the CZT compared to the conventional gamma camera . For LVEF, however, accuracy was high for both gamma cameras.MI was found in 42 patients on CMR. The overall sensitivity, specificity, positive and negative predictive values for the CZT and the conventional gamma camera were the same . For infarct size > 3% on CMR, the sensitivity was 82% for the CZT and 73% for the conventional gamma camera, respectively. LV volumes were significantly underestimated by MPS compared to CMR (Differences between a CZT and a conventional gamma camera for detection of MI and assessment of LV volumes and LVEF are small and do not appear to be clinically significant.The online version contains supplementary material available at 10.1007/s12350-022-03185-0. Previous studies have shown that MPS has limited ability to detect MI’s, especially small subendocardial infarcts, compared to the reference method late gadolinium enhancement cardiac magnetic resonance (LGE-CMR).10 However, the diagnostic performance of gated MPS with a CZT gamma camera compared to a conventional gamma camera for detection of MI and assessment of LV volumes and EF, using CMR as the reference method, has to our knowledge not yet been investigated.One of the main reasons behind the limited diagnostic performance of MPS, is the limited spatial resolution associated with the SPECT technique using the conventional Anger scintillation gamma camera with NaI crystal detectors and parallel hole collimators. In recent years, a new generation of gamma camera systems has evolved utilizing a solid-state detector technique with cadmium-zinc-telluride (CZT) and pin hole collimators, resulting in improved spatial resolution, energy resolution and count sensitivity compared to the conventional gamma cameras. Thus, this technique could potentially improve the diagnostic performance of MPS.The aim of this study was to explore the diagnostic performance of gated MPS with a dedicated cardiac CZT gamma camera compared to a dedicated cardiac conventional gamma camera for detection of MI and assessment of LV volumes and LVEF, using CMR as the reference method.11 Thus, 36 patients could be used for image analysis of both MPS and CMR. (2) In addition, a subset of the patients was recruited from another study (the MYOMER study), in which patients clinically referred for an elective coronary angiography (CA) because of known or suspected chronic coronary syndrome were included. The goals with the MYOMER study were to study myocardial perfusion imaging before and after CA, with or without percutaneous coronary intervention. From the MYOMER study, 37 patients were examined with CMR and MPS at rest with image acquisition in both gamma cameras before the CA examination, and therefore could be included in the current study. Thus, in total the study population consisted of 73 patients with two MPS image acquisitions each resulting in 146 datasets that were evaluated. Patient charts were reviewed for patient characteristics and to exclude any cardiac adverse event, coronary revascularization or changes in cardiac medication occurring between the CMR and MPS examinations.The study protocol was approved by the Regional Ethics Committee at Lund University (LU2013/550 and LU2013/4010). Patients were included in two ways. (1) Patients clinically referred for CMR imaging, where CMR images showed evidence of ischemic scar were asked to participate in the study. The patients were examined with MPS at rest and images were acquired in two gamma cameras, a CZT gamma camera and a conventional gamma camera. Out of 47 included patients, 7 were excluded because SPECT data for both gamma cameras could not be obtained due to intermittent technical problems with the scanner table on the conventional gamma camera, one was excluded because of inadequate LGE-CMR image quality, one was excluded because CMR was performed during the acute phase of the MI and two were excluded because of presence of left bundle branch block which is known to possibly affect the MPS image uptake pattern.−1 of 99mTc-tetrofosmin  (356 ± 69 MBq). Image acquisition was performed 45-60 minutes after the injection. Each patient was examined in both supine and prone position and in both a cardiac dedicated CZT gamma camera  and a cardiac dedicated conventional gamma camera . There was no systematic order in which gamma camera was used for the first and second image acquisition, since image acquisition of the study patients had to be accommodated to the clinical flow of patients.Patients were examined at rest and injected with a weight adjusted activity of 4 MBq·kgThe acquisition time on the CZT gamma camera was 480 seconds. The images were reconstructed with a Maximum Likelihood Estimation Method (MLEM) algorithm, 40 iterations; Green OSL regularization α parameter of 0.51 and a β of 0.3 and post filtered with a Butterworth filter with a cut-off frequency of 0.37 and a power of 7. For the conventional gamma camera the examination was performed with the detectors in L-mode. Sixty projections were acquired in a total angular range of 180° with a stop condition of 25 seconds per projection. The conventional gamma camera images were reconstructed with a resolution recovery OSEM algorithm  using 12 iterations and 10 subsets and post filtered with a Butterworth filter with a cut-off frequency of 0.4 and a power of 10. All reconstruction parameters used followed recommendations from the manufacturer. The reconstructed images were reformatted to the standard cardiac axis format . ECG-gated image acquisition using 8 frames per cardiac cycle was performed for all supine acquisitions. ECG-triggering failed in two acquisitions for the conventional gamma camera, due to poor ECG signal. Attenuation correction was not applied.3 Briefly, a perfusion defect in the summed images with decreased wall thickening in the gated images was reported as MI. If the observer felt uncertain after evaluating the images acquired in supine position, the summed images acquired in both supine and prone position were used. Infarcts were located to the left anterior descending artery (LAD) territory  or to the left circumflex artery/right coronary artery (LCx/RCA) territory . Additionally, regional myocardial tracer uptake in each LV segment according to the standardized 17 segments model12 was quantified using a 5-point scale ranging from 0  to 4 (absent uptake), where regional motion according to the gated images was taken into account. Thus, for a segment to be scored as reduced uptake, regional motion in that segment would have to be affected. If uptake was judged to be reduced but motion in that segment was judged to be normal, the score was set to 0. The total score of the left ventricle at rest, summed rest score (SRS) was calculated. Twenty cases were evaluated twice and by a second observer to calculate intra- and interobserver variability for infarct detection. For both the CZT and the conventional gamma camera, epi- and endocardial borders were derived from automated delineation provided by the MPS software. Therefore, intra- and interobserver variability for functional parameters by MPS were not assessed.All MPS images were analyzed using the software Segment, version 2.2  and QGS/QPS, version 2015.6 . For LV volumes, EF and mass the software were used following recommendations from the manufacturers. Briefly, both reconstructed static and gated images were analyzed by fully automated LV segmentation algorithms. LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), LV stroke volume (LVSV) and LVEF were calculated from the gated images and LV mass (LVM) was calculated from the static images. Manual correction was performed if the automatic segmentation was obviously wrong. For assessment of MI, gated and summed MPS images, acquired in supine position, were loaded into the QGS/QPS software. One experienced observer, blinded to patient data, visually evaluated the images in random order as previously described.−1, Guerbet, Gothia Medical AB, Billdal, Sweden) an inversion-recovery (IR) sequence was used to acquire late gadolinium enhanced (LGE) images in the corresponding planes as for the cine images. Typical LGE sequence parameters were: slice thickness = 8 mm, TR = 3.9 ms, TE = 1.2 ms, in-plane resolution = 1.5 × 1.5 mm and flip angle = 15º with acquisition every heartbeat. The inversion time, typically 250-350 ms, was manually adjusted to null the signal from remote myocardium.CMR imaging was performed on a Philips Intera CV  for seven patients, on a Siemens Magnetom Aera  for 63 patients and on a Siemens Magnetom Avanto  for three patients. All subjects were placed in supine position. Cine short-axis gradient-recalled echo images covering the left ventricle were acquired using a balanced turbo field echo (bTFE) sequence: slice thickness = 8 mm, field-of-view = 340 mm, TR = 3.14 ms, TE = 1.58 ms. Three cine long-axis images  were acquired using the same sequence. Approximately 15 min after intravenous administration of an extracellular gadolinium-based contrast agent .13 Assessment of MI was performed on the LGE-CMR images, where hyperenhanced regions extending from the LV endocardium in two perpendicular imaging planes according to typical coronary artery territories, were considered MI. MI’s were visually located to the LAD or the LCx/RCA territory. MI size was quantified using a semi-automatic method, the EWA algorithm, as previously described with manual corrections if needed.14 Infarct transmurality was quantified as the infarct extension measured from the endocardium to the epicardium, both per segment and for the over-all infarct .All CMR images were analyzed using the software Segment, version 2.2. The endo- and epicardium of the LV were manually delineated in the cine short-axis images in both end-diastole and end-systole by two observers in consensus. The LV end-diastole and end-systole were defined as the time frame with the largest and the smallest LV blood pool volume, respectively. Trabecular and papillary muscles not contiguous with the myocardial wall were excluded, thus included in the LV cavity volume. The endo- and epicardial borders were adjusted between end-diastole and end-systole to accomplish the same LVM in both time frames. Based on the LV delineation, LVEDV, LVESV, LVSV and LVEF were calculated. LVM was calculated as the muscle volume between the endo- and epicardial delineations, multiplied by the density of the myocardium  unless otherwise stated. All statistical calculations were performed using either Prism 7.04  or Microsoft Excel 2013 . LV volumes, EF and mass by MPS and CMR were compared using Student’s −1 and during CMR imaging 65 ± 10 beats·min−1 (P = .09). For gamma camera imaging, 37 patients were scanned in the CZT gamma camera first, while 36 patients were scanned in the conventional gamma camera first.Patient characteristics are presented in Table MIs were found in 42 patients on CMR, in 28 patients on MPS with the CZT gamma camera and in 28 patients on MPS with the conventional gamma camera. On a patient level, no patients were found to have MI on MPS but not on CMR, neither for the CZT nor for the conventional gamma camera Tables . On a paFor intra-observer variability, twenty cases were evaluated twice for presence of MI or not on a per patient level, showing agreement in 19 out of 20 cases. For inter-observer variability, the same twenty cases were evaluated by a second observer for presence of MI or not on a patient level, showing agreement in 16 out of 20 cases.Infarct size on CMR expressed as volume, % of the LV and transmurality is shown in Table In 13 examinations, the observer used summed MPS images acquired in both supine and prone position. In one case with a small MI on CMR (1.4% of the LV), the MPS CZT gamma camera diagnosis was changed from MI to no MI after the use of prone images. In two cases with no MI on CMR, the MPS conventional gamma camera diagnosis was changed from MI in the inferior wall to no MI after the use of prone images. Diagnosis was unchanged for the other 10 cases.P ≤ .002 for all comparisons). LVEF did not differ between CMR and MPS with the CZT gamma camera , while a significant overestimation of LVEF was shown for MPS with the conventional gamma camera compared to CMR . Comparing MPS software, there were significant differences for LV volumes and LVM between Segment and QGS/QPS , while no significant difference was shown for LVEF . Bias of LV parameters for MPS compared to absolute values by CMR are shown in Figure P ≤ .03 for all measurements by Segment software and P ≤ .01 for all measurements by QGS/QPS software).Table The MPS bias compared to CMR for all measures are shown in the “Appendix”.This is the first study to explore the diagnostic performance of gated MPS with a CZT gamma camera compared to a conventional gamma camera for detection of MI and assessment of LV volumes and LVEF, using CMR as the reference method. Diagnostic accuracy is good for detection of MIs > 3% of the LV for MPS both with a CZT gamma camera and a conventional gamma camera. Furthermore, LV volumes are significantly underestimated with low precision by MPS compared to CMR but slightly less for the CZT compared to the conventional gamma camera, whereas the impact of MPS software on LV volume assessment is larger. The accuracy for assessment of LVEF is high.16 although the specificity in the current study was higher. Compared to two other previous studies,3 the overall sensitivity in the current study was lower while specificity was equally high. However, compared to the study by Carlsson et al3 the MI size in the current study was smaller. For infarcts > 3% of the LV the sensitivity in the current study becomes higher. The main reason of why small infarcts is missed by MPS compared to CMR is the limited spatial resolution of MPS compared to CMR. The spatial resolution for the GE Discovery 530c camera was found to be approximately 7 mm and approximately 15 mm for a conventional gamma camera,8 whereas the spatial resolution for CMR is approximately 1.5 mm. Thus, a lower detection rate of small infarcts for MPS compared to CMR would be expected. Despite that the higher spatial resolution and count sensitivity of the CZT gamma camera would give a theoretical diagnostic advantage compared to a conventional gamma camera, no difference in diagnostic accuracy for MI detection between the CZT and conventional gamma camera was shown in the current study. As shown in Figure 18The overall diagnostic accuracy for MPS with a CZT gamma camera for detection of MI was moderate. The overall sensitivity on a patient level was low/moderate but specificity was excellent. No difference was shown compared to MPS with a conventional gamma camera. The overall sensitivity was in line with two previous studies,19 The patient group with smallest infarcts, mean infarct size of 1.4% of the left ventricle, had a > 7-fold increased risk for MACE. This highlights the importance of not only focusing on presence of stress-induced ischemia but also on MI when examining patients with MPS.It has been shown that patients with no clinical history of MI showing evidence of myocardial scar on CMR has an increased risk for future major adverse cardiac events (MACE).68Ga-labeled fibroblast activation protein inhibitor (FAPI). Post myocardial infarction imaging with 68Ga-FAPI-PET have shown fibroblast activation in the early phases of fibrosis evolvement, whereas no fibroblast activation was seen in mature myocardial scar.22 Further studies are warranted to elucidate the potential of using new radiotracers for myocardial fibrosis assessment in nuclear cardiology imaging.Recently, interesting results of myocardial fibrosis assessment have been published, using positron emission tomography (PET) and new radiotracers with 23 and overestimation of LVM by MPS compared to CMR is in line with the results from a previous study.7 An important reason for this underestimation is the limited spatial resolution of MPS compared to CMR as discussed above. The thickness of a normal myocardial wall ranges approximately between 5 and 10 mm on CMR,24 which is in the same range as the limits for MPS spatial resolution. Delineation of myocardial wall contours is therefore challenging for MPS compared to CMR. Wall thickness on MPS is most often assessed larger than on CMR and the LV lumen therefore becomes smaller compared to CMR. Another reason why LV volumes are underestimated by MPS compared to CMR is differences in time resolution. In the current study, MPS was acquired with ECG-gating using 8 frames per cardiac cycle whereas the CMR images were acquired with 25 frames per cardiac cycle. It has been shown that assessment of LVEF by MPS using 8 frames per cardiac cycle gives an average reduction of LVEF by 3.7 percentage points compared to 16 frames per cardiac cycle.25LV volumes were significantly underestimated by MPS compared to CMR with both the CZT and the conventional gamma camera and both Segment and QGS/QPS MPS software, whereas LVM was significantly overestimated by MPS compared to CMR. Precision was low. Underestimation of LV volumes by MPS compared to CMR has also been shown in previous studies,23 Since LVEF is calculated as a ratio including LVEDV and LVESV, an underestimation of LVEDV and LVESV of the same magnitude yields an accurate ratio, i.e., LVEF. In a previous study by Sharir et al,26 LVEF was found to be slightly higher for the CZT gamma camera compared to the conventional gamma camera. They examined patients post-stress with the conventional gamma camera first followed by CZT for all patients which may explain a systematic difference between the CZT and the conventional gamma camera due to post-ischemic stunning. Patients in the present study were examined at rest.Assessment of LVEF by MPS showed good accuracy compared to CMR, with no bias for CZT MPS and a slight overestimation for conventional MPS compared to CMR. However, precision was low. A better accuracy for LVEF compared to LV volumes assessment by MPS has also been shown by previous studies.8 which may facilitate a correct delineation of the myocardial walls, yielding a larger LV lumen.LV volumes by MPS differed significantly between the CZT and the conventional gamma camera but the absolute values of the differences were relatively small. Mean LVEDV and LVESV were significantly larger for the CZT gamma camera compared to the conventional gamma camera, thus closer to the reference values by CMR. This is probably due to the known higher spatial resolution and count sensitivity of the CZT gamma camera compared to the conventional gamma camera,5 and Soneson et al7 the bias for QGS/QPS software is in the same range, whereas the bias for Segment software was larger in the current study.Comparing MPS software, there were significant and relatively large differences between Segment and QGS/QPS. Bias for LVEDV and LVESV on MPS compared to absolute values by CMR were approximately 10%-15% for the Segment software and 40%-45% for the QGS/QPS software. However, LVEF by MPS showed no significant difference between the software, neither for the CZT nor for the conventional gamma camera. Compared to Hedeer et alHence, we recommend that absolute values of LV volumes and mass should be handled with care in a clinical report of an individual patient, and rather be interpreted compared to specific reference values for each setting, where type of gamma camera, image reconstruction parameters and MPS software have been taken into account. Since precision was low for all measures, caution should be taken so that methodological differences are not misinterpreted as biological differences and vice versa in a patient examined repeatedly.27 In delineation of the left ventricle in the CMR images, trabecular and papillary muscles not contiguous with the myocardial wall were excluded, thus included in the LV cavity volume. This may lead to an over estimation of the LV cavity blood volumes by CMR by approximately 10%, thus partly explaining the differences in assessed LV volumes between MPS and CMR.28 The MPS images were interpreted by visual analysis only and not automatically quantified by the MPS software.The study population in the current study was relatively small. Thus, a small difference in diagnostic performance between the gamma cameras for detection of MI might be missed. However, given that there were no differences between the gamma cameras in overall sensitivity, specificity, PPV and NPV for detection of MI, the likelihood for type 2 errors is considered to be small. The diagnostic accuracy for MPS found in the current study is partly dependent on the size of the infarcts in the study population. In the current study a significant number of patients had small sized infarcts. The number of patients with MI in the current study population was high, and probably higher than the prevalence to be expected in patient populations of many MPS diagnostic centers. Of note, this does not affect the sensitivity or specificity. On the other hand, the use and availability of MPS are probably highly variable for different diagnostic centers worldwide, with a large variation in pre-test probability in the patients referred for MPS. Vessel territories were divided into two territories, LAD territory and LCx/RCA territory. The reason why LCx and RCA territories were analyzed as one territory is the difficulties to correctly determine the LCx and RCA territories.Differences in diagnostic accuracy for detection of MI and assessment of LV volumes and LVEF between MPS with a CZT gamma camera compared to a conventional gamma camera, are small and do not appear to be clinically significant.The diagnostic performance of gated MPS with a CZT gamma camera compared to a conventional gamma camera for detection of MI and assessment of LV volumes and LVEF, using CMR as the reference method, shows good diagnostic accuracy for detection of MIs > 3% of the LV with both gamma cameras. However, LV volumes are significantly underestimated by MPS compared to CMR but slightly less for the CZT compared to the conventional gamma camera, whereas the impact of MPS software is larger.Supplementary file1 (PPTX 376 kb)Below is the link to the electronic supplementary material.