There are several surgical approaches for explanting a left ventricular assist device (LVAD) after recovery of cardiac function. Thus, remaining ventricular assist device components may bear significant risks of infection or thrombosis. We hereby report our technique and two-center experience with explantation of LVADs using a new double-patch technique.From March 2019 to April 2021, five patients underwent LVAD explantation after myocardial recovery . The mean patient age was 50.3 years ; the mean time on the LVAD was 23.1 ± 20.8 months. The aetiology of the primary heart failure was dilated cardiomyopathy (n = 4) and myocarditis (n = 1).LVAD explantation was performed using a median sternotomy and cardiopulmonary bypass. The LVAD was stopped, and the outflow graft was clamped. The outflow graft was ligated and sutured close to the aortic anastomosis. The driveline was clipped and removed. Under induced fibrillation, the attachment of the LVAD was released from the apical cuff and the LVAD was removed. A round pericardial patch was fixed from the inner of the ventricle. This step sealed the apex of the heart. An additional Gore-Tex patch was continuously sutured epicardially over the suture ring.The 5 cases showed technically uncomplicated explantation of the LVADs. During the follow-up of a mean of 16.4 ± 16.9 months, we observed 100% survival. There were no bleeding complications or thromboembolic events during the follow-up period.LVAD explantation with the double-patch technique is feasible and safe. This technique allows discontinuation of anticoagulation. The 30-day survival was 100%. Further studies are needed to provide better evidence for LVAD explantation and long-term follow-up. The clinical indication for a left ventricular assist device (LVAD) implant is progressive heart failure (HF) with severe left ventricular (LV) dysfunction in the setting of exhausted medical therapy [1]. The clinical indication for a left ventricular assist device (LVAD) implant is progressive heart failure (HF) with severe left ventricular (LV) dysfunction in the setting of exhausted medical therapy . MechaniSo far, different techniques have been described. Thus, decommissioning with closure of the outflow graft and capping of the driveline is described. In these cases, the LVAD was left in place. With this method, a high infection rate of 41% and high mortality have been described .A retrospective multicentre study analysed the use of a titanium plug to close the apical fixation ring after LVAD explantation and showed a low incidence of plug-related complications . The useDue to the retrospective study design and anonymous data collection, written patient informed consent was waived as considered and approved by our local ethical committee.n = 2; HeartMate 3, n = 3) at the University Heart & Vascular Center, Hamburg, Germany (n = 4), and Heinrich Heine University, Duesseldorf, Germany (n = 1). The mean patient age was 50.2 years ; the mean time on the LVAD was 23.1 ± 20.8 months. Primary HF aetiology was dilated cardiomyopathy (n = 4) and myocarditis (n = 1).From March 2019 to April 2021, five patients underwent an LVAD explant after myocardial recovery . The mean patient age was 50.2 years; 100% were male; and the mean time on the LVAD was 23.1 ± 20.8 months. The primary HF aetiologies were dilated cardiomyopathy (n = 4) and myocarditis (n = 1). Baseline characteristics are shown in Table From March 2019 to April 2021, five patients had LVADs explanted after myocardial recovery  min, and the median cardiopulmonary bypass time was 219 (IQR 18) min. As a combined procedure, 2 cases of mitral valve repair and 1 case of tricuspid valve repair were performed. A temporary right ventricular assist device implant was not necessary in any case. Results are presented in Table Our data suggest that the double-patch technique provides a feasible and safe technique for LVAD explantation after myocardial recovery. The double-patch technique also facilitates LVAD reimplantation if a patient develops a recurrence of HF after explantation. Moreover, due to the use of bovine pericardial patches, oral anticoagulation can be discontinued. In our study with 5 cases, there were no serious complications or deaths during the mean observation period of 16.4 ± 16.9 months; neither were there any infections or thromboembolic events.Especially in cases of myocarditis and dilated cardiomyopathies, different LVAD explant techniques have been described. In these cases, it has already been shown that retention of the LVAD, the outflow graft and the driveline represents a significantly increased risk for infectious events . The expAlternative explant techniques have already been described in the literature. For example, one technique involves complete removal of the LVAD and the suture ring with patch repair of the apex. This highly invasive method may pose a higher risk of LV bleeding and injury in comparison to the other methods. In addition, reinsertion of an LVAD is no longer as feasible in the case of recurrence of HF . InterveLike all observational studies, retrospective studies can suggest but not definitively prove possible causal relationships. In addition, because we were using a new technique, only a small number of patients without a control group were included. Therefore, only descriptive analyses could be performed. Further prospective randomized studies with a control group would be appreciated.LVAD explantation with the double-patch technique is feasible and safe. Using a bovine pericardial patch, this technique allows discontinuation of anticoagulation. We had no bleeding or thromboembolic events. Overall, we had 100% survival during a mean follow-up period of 16.4 ± 16.9 months.


Multiple PA/US scans were performed to cover a large field-of-view (FOV), and the acquired PA/US volumes were mosaic-stitched after manually correcting the positions and rotations in a total of 6 degrees of freedom. PA and US maximum amplitude projection images were visualized online, while spectral unmixed data was quantified offline. The performance of the system was tested via tissue-mimicking phantom experiments. The system’s potential was confirmed in vivo by panoramically imaging vascular networks in human arms and necks, with FOVs of 331 × 38 and 129 × 120 mm2, respectively. Further, we quantified hemoglobin oxygen saturation levels in the radial artery, brachial artery, carotid artery, and jugular vein. We hope that this system can be applied for various clinical fields such as cardiovascular imaging, dermatology, vascular surgery, internal medicine, and oncology.Photoacoustic (PA) imaging has gained much attention, providing structural and functional information in combination with clinical ultrasound (US) imaging systems. 2D PA and US imaging is easily implemented, but its heavy dependence on operator skills makes 3D imaging preferable. In this study, we propose a panoramic volumetric clinical PA and US imaging system equipping a handheld imaging scanner weighing 600 g and measuring 70 × 62 × 110 mm When optical absorbers in tissues are excited with pulse lasers, the resulting PA waves can be received by ultrasound (US) transducers and processed into PA images PA imaging is readily paired with clinical US imaging platforms to form a bi-modal PA/US imaging modality that provides rich functional and structural information 3D PA imaging systems have been developed with a custom-made 2D spherical array, or alternatively with 1D circular and arc array US transducers with motorized stages 2, and dimensions of 100 × 80 × 100 mm3, allowing for handheld operation. However, the scanner’s size and weight were not sufficiently small to image weight-sensitive and small areas, such as the human neck, but minimizing the size would unwantedly reduce the FOV. The acoustic coupling was provided using a water tank sealed with polyvinyl chloride (PVC) membrane, which formed multiple layers of acoustic impedance mismatch that could hamper the signal-to-noise ratios (SNRs) for deep tissue imaging. Further, previewing of the 3D images ) was only available in post-processing, and thus we could not confirm the scanning results during the imaging experiments To overcome the limitation, we previously developed a custom three-dimensional clinical handheld PA/US imaging scanner using the scotch yoke mechanism that enables the use of a small and light weight motor instead of a linear stage 3 that provides both a FOV of 38.4 × 25 mm2 and a three-dimensional PA/US imaging. The scanner uses a transparent solid US gel pad that effectively acoustic impedance-matching, enabling improved SNRs. To overcome the limitation of the reduced FOV of the updated 3D imaging scanner, we demonstrated panoramic imaging where multiple volume images are mosaic-stitched after correcting the volume position and rotation in a total of 6 degrees of freedom (DOFs). In addition, we implemented online PA MAP display to preview the panoramic scan results on-site. We performed tissue-mimicking phantom experiments to confirm that the SNRs improved on average by 10.8 dB compared to the previous system while maintaining image resolutions. Further, we conducted super-wide-FOV panoramic in vivo imaging experiments on a human arm and neck, where the FOVs of the arm and neck images were 331 × 38 mm2 and 129 × 120 mm2, respectively. The maximum PA penetration depth in the volunteer human subject was at least 28.6 mm, an increase of 13.9 mm compared to the previous system. In addition, PA sO2 values were measured in the radial artery  and y-axes, respectively. scanner a. PA ima scanner . The upd scanner b, a linedoi:10.1016/j.pacs.2023.100512.Supplementary material related to this article can be found online at The following is the Supplementary material related to this article 2.22. The scan time for one 3D scanning, , and θf c:(1)dy=Rositions c. Becaus2.32 and PA Hb values using multi-wavelength PA volumes acquired at 756 nm (Hb-dominant), 797 nm (isosbestic point), and 866 nm (HbO2-dominant). Spectral-unmixed PA HbO2 and PA Hb values less than zero (due to overfitting) were truncated to zero to eliminate false calculations of PA sO2. While it is desirable to use more wavelengths for accurate spectral unmixing, we minimized the number of wavelengths to make the scanning time tolerable for clinical situations [27,2 concentration in the axial direction were used to project PA sO2 values to create PA sO2 MAP images. For quantification, ROI was manually drawn in each US frame to form a volumetric ROI, and the mean and standard deviation of all PA sO2 values in the ROI were calculated. All offline processing was performed using MATLAB R2021b, MathWorks, USA.[38,33.12), in a weight ratio of 1000:100:1.5, respectively 2, respectively. The previous scanner had an R of 20 mm, and thus different values of 2, respectively. To evaluate the repeatability of the systems, each scan was repeated three times at the same location. During each scanning, we have applied sufficient pressures on the scanner to minimize shaking and resulting artifacts. The PA imaging results from the phantom using the two scanners were shown in [46,The system performances of the newly updated and the previous imaging systems were compared in a phantom study . The phaThe full width at half maximums (FWHMs) of the PA amplitudes of the threads in the axial, lateral, and elevation directions in each image frame were measured to quantify the average profiles of the threads in each direction in the whole volume data set. The newly updated handheld imaging system provided axial, lateral, and elevation profiles of 195 3.222.The clinical feasibility of the 3D PA/US imaging system was verified through various 3D PA/US imaging experiments on the human arm and neck, following the protocols of the Institutional Review Boards of Yeungnam University Hospital  and Pohang University of Science and Technology . All human subjects and examiners wore goggles for laser safety, and the maximum pulsed laser energy used was 10.7 mJ/cm2 and TScan was 66.8 s excluding 10 s of countdown before the laser emission. Supplementary Video S1).To demonstrate online panoramic image display, a single-wavelength of 866 nm was used and four consecutive scans were performed on a volunteer’s forearm. The FOV was 38.4 × 100 mm2 along the elevation and lateral directions, respectively. In each 3D PA/US imaging, the scanner position was manually advanced along the elevation direction, and scanning was performed according in the scan direction  implemented with real-time laser power calibration. Further, we plan to reduce scan time by using a laser system that provide a faster PRF while maintaining the laser power, using more US receiving channels, and by optimizing scan step size.In this study, we demonstrated a super-wide field human vasculature imaging by using the panoramic 3D handheld PA/US imaging. We updated 3D PHOVIS to provide mosaic stitching in 6 degrees-of-freedom, which made it applicable for coregistering multiple volume images of curved structures . To test the feasibility of the developed imaging system, we tested 3D panoramic imaging on the human arm and neck. Maximum FOV for the arm and neck were 331 × 38 and 129 × 120 mmC. Lee, S. Cho, D. Lee, J. Lee, J. I. Park, H. J. Kim, S. H. Park, W. Choi, and U. Kim declare no competing interests. C. Kim has financial interests in OPTICHO, which, however, did not support this work.


In recent years, randomized trials have provided evidence to sustain the noninferiority of TAVI as compared with surgery, even in intermediate-risk and low-risk patients5 with new generation devices being associated with a very low rate of complications.7Aortic stenosis is the most common and prognostically relevant valvular heart disease because of the high prevalence in an increasingly older population and its negative consequences on morbidity and mortality.8 The significant three-fold increase in prevalence over the last 50 years poses important challenges in better preventing atrial fibrillation and its complications.9 Atrial fibrillation is present in 15% of patients with severe aortic stenosis and in up to 50% of those undergoing TAVI.10 But most importantly, in connection with the mechanisms causing and maintaining atrial fibrillation, the underlying atrial cardiomyopathy is worth mentioning as the common risk factors are also contributing to aortic stenosis progression.11Atrial fibrillation is the most common cardiac arrhythmia and a major cause of heart failure hospitalization.12 Another common cause of atrial cardiomyopathy is chronic heart failure13 with a particular and complex phenotype of atrial fibrosis that appears to occur early in the course of heart failure.14 As aortic stenosis predominantly manifests as heart failure with preserved ejection fraction, it could be assumed that both valvular heart disease and heart failure contribute to the development of atrial cardiomyopathy. In this context, prevention of atrial fibrillation may also prevent heart failure.15Notably, there are data supporting atrial remodeling as a consequence of the abnormal hemodynamics produced by aortic stenosis independently of the presence of atrial fibrillation. Left atrium volumes are higher in aortic stenosis patients compared with controls and decrease after valvular correction.et al.16 conducted a multicentered, observational, retrospective study, which enrolled 759 patients undergoing TAVI between 2012 and 2022 with the aim of evaluating the association between atrial fibrillation and both short-term and long-term outcomes. The median follow-up was 3.2 years. Patients were stratified according to their history of atrial fibrillation: no previous atrial fibrillation (68.2%) and preexisting atrial fibrillation (31.8%). They were equally distributed by gender and comorbidities, and had a mean age of 82.8 years. As for the in-hospital events, at the adjusted logistic regression analysis, patients with history of atrial fibrillation showed significantly higher rates of acute kidney injury (AKI)  and major bleedings . At discharge, the percentage of patients with atrial fibrillation had increased to 36.6% because of new-onset atrial fibrillation. The occurrence of the composite outcomes  was higher in patients with atrial fibrillation versus those without (35.6 vs. 38.2%). Also, the unadjusted Cox regression analysis showed that atrial fibrillation at discharge was associated with a higher risk of the primary outcome  and the secondary outcome of all-cause death/all-cause hospitalization  and hospitalization alone . No significant association was observed between atrial fibrillation at discharge and cardiovascular events.Arrotti et al.17 found that only preexisting atrial fibrillation was associated with increased mortality, whereas Gargiulo et al.18 showed that new-onset atrial fibrillation led to an increase in late mortality. Both atrial fibrillation types have been linked to an excess in early mortality.20 In a recent sub-analysis from the PARTNER 3 trial, preexistent atrial fibrillation in low-risk patients undergoing TAVI was found to be associated with higher rates of death, stroke or rehospitalization, but not all-cause death .21 Atrial fibrillation may also impact on quality of life. Almost 40% of patients over 65 years old had impaired quality of life related to atrial fibrillation and the geriatric factors associated were falls, frailty, depression, COPD, rhythm control and anticoagulant therapy.22 In this regard, atrial fibrillation may be considered a potential factor preventing quality of life improvement in old patients undergoing TAVI. On the other hand, Laenens et al.23 reported data from 2849 patients with severe aortic stenosis (mean age 72 years), 24% of them had a history of atrial fibrillation. Median follow-up was 60 months. Even if patients with both aortic stenosis and atrial fibrillation have reduced survival compared with those in sinus rythm, when correcting for indexed left atrial volume, E/e′ or both, atrial fibrillation was no longer associated with all-cause mortality. These results highlight that the negative outcomes may not be associated with atrial fibrillation per se, which especially in younger patients could be a by-stander, but with the underlying structural abnormalities found in aortic stenosis and atrial cardiomyopathy. With the rapidly expanding use of TAVI in young patients, further studies are urgently required to better understand the role of atrial fibrillation in these populations in terms of both hard endpoints and patient-reported outcomes (Fig. The authors need to be congratulated for shedding light on the interplay between atrial fibrillation and aortic stenosis treatment. Indeed, data available so far regarding the impact of atrial fibrillation on mortality after TAVI have reported conflicting results. In a meta-analysis, Sannino There are no conflicts of interest.


Even though advanced radiotherapy techniques provide a better protective effect on surrounding normal tissues, the late sequelae from radiation exposure to the heart are still considerable in breast cancer patients. The present population-based study explored the role of cox-regression-based hazard risk grouping and intended to stratify patients with post-irradiation long-term heart diseases.The present study investigated the Taiwan National Health Insurance (TNHI) database. From 2000 to 2017, we identified 158,798 breast cancer patients. Using a propensity score match of 1:1, we included 21,123 patients in each left and right breast irradiation cohort. Heart diseases, including heart failure (HF), ischemic heart disease (IHD), and other heart diseases (OHD), and anticancer agents, including epirubicin, doxorubicin, and trastuzumab, were included for analysis.p < 0.01) and OHD , but not HF , when compared with patients received right breast irradiation. In patients who received left breast irradiation dose of >6,040 cGy, subsequent epirubicin might have a trend to increase the risk of heart failure , while doxorubicin  and trastuzumab  did not. Older age was the highest independent risk factor for post-irradiation long-term heart diseases.Patients received left breast irradiation demonstrated increased risks on IHD (aHR, 1.16; 95% CI, 1.06–1.26; Generally, systemic anticancer agents are safe in conjunction with radiotherapy for managing post-operative breast cancer patients. Hazard-based risk grouping may help stratify breast cancer patients associated with post-irradiation long-term heart diseases. Notably, radiotherapy should be performed cautiously for elderly left breast cancer patients who received epirubicin. Limited irradiation dose to the heart should be critically considered. Regular monitoring of potential signs of heart failure may be conducted. Cardiovascular diseases (CVDs), including heart disease, cerebrovascular disease, atherosclerosis, and aortic aneurysm/dissection, are recognized as potential long-term sequelae in cancer survivors , 2. AmonThe risk of treatment-associated heart diseases in breast cancer patients is a particular issue in current clinical medicine. Anthracycline chemotherapy, targeted therapy, and radiation therapy are treatment modalities at risk for heart diseases , 4, and In the present study, we extensively explored the events of long-term heart sequelae, including heart failure, ischemic heart disease, and other heart diseases, such as acute pericarditis, cardiomyopathy, and arrhythmia. Anticancer agents, including epirubicin, doxorubicin, and trastuzumab, were selected to examine the synergic effect of radiotherapy on cardiac toxicities in patients who received left breast irradiation. Notably, hazard-based risk grouping was applied to stratify patients.The present population-based cohort study utilized the national database of the Taiwan National Health Insurance (TNHI). The TNHI database contained comprehensive information, including the records of diagnosis and treatment of approximately 99% of people in Taiwan . The Ins1.Individual propensity score (PS) was calculated from a multivariate Logistic regression model with response variable laterality coded as 0 for the right and 1 for the left while predictors including all the confounding factors listed in the baseline characteristic summary table see . The PS 2.For each individual with a value of PS, for example, ps1 in cohort of laterality 1, an individual from cohort of laterality 0 with PS value closest to the ps1 was selected as a match. Random selection was made when tied. The distance of the two PS values must be ≤0.0001; otherwise, no match was made.This is a 17-year long-term follow-up cohort study. After a 1:1 propensity score match for two groups, there were 21,123 patients were included in the left and right breast irradiation group, respectively.Three systemic anticancer agents, including epirubicin, doxorubicin, and trastuzumab, were selected to investigate each drug's independent effect under different radiation dose levels. Other agents, such as docetaxel, paclitaxel, carboplatin, cyclophosphamide, fluorouracil, and methotrexate, were included as covariates for analysis to examine their potential association with the risk of heart diseases. Radiation doses were defined into three levels, ranging from 3,000 to 5,040 cGy, from 5,040 to 6,040 cGy, and >6,040 cGy. According to the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM codes), heart diseases are categorized as a diagnosis of heart failure (HF), ischemic heart disease (IHD), and other heart diseases (OHD). The code of ICD-9-CM for heart failure was 428. The code for ischemic heart disease was 410–414, including acute and subacute myocardial infarction. We defined the codes for other heart diseases, including pericarditis (420), endocarditis (421), other diseases of pericarditis and endocarditis (423–424), myocarditis (422), cardiomyopathy (425), conduction disorders (426), cardiac dysrhythmias (427), and ill-defined descriptions and complications of heart disease (429).Other factors, including age, diabetes mellitus (including type I and type II), hypertension, surgery type, clinical and pathological staging, chemotherapy, and hormone therapy, were also applied as covariates for data analysis. In addition, socioeconomic variables, including geographic region, urbanization level, and monthly income-based insurance premiums, were included in the analysis to reduce bias from lifestyle.Cox proportional hazard regression was performed to estimate the adjusted hazard ratio (aHR) with a 95% confidence interval (CI) to examine the independent effect of left breast irradiation, when compared with right breast irradiation, on the risk of heart diseases.In addition, Cox regression was also utilized to estimate the individual hazard based on all covariates for risk grouping and explore the synergic effect of anticancer agents and irradiation dose on heart disease risk. We estimated individual hazard by using the COX regression method with the following formula: y = exp (aX + bY + cZ….); a, b, c = log (aHR); X, Y, Z = covariate variable. All included patients were allocated equally in number into 2, 3, 4, or 5 sub-groups, according to the order of each individual hazard ratios, which were based on parameters including all covariates and socioeconomic variables to assess the risks of IHD, OHD, and HF. The 1/2, 1/3, 1/4, and 1/5 risk subgroups denote the lowest risk subgroup, while the 2/2, 3/3, 4/4, and 5/5 subgroups denote the highest risk subgroup.p-value of <0.05 was considered statistically significant. The SAS software  was used for all statistical analyses.A two-sided n = 21,123) and right  breast irradiation were included for final analysis. The mean ages of the two cohorts who received left and right breast irradiation were 51.20 and 51.17 years old, respectively. After PSM, the two cohorts' pre-analysis clinical and demographic variables are comparable  and other heart diseases , but not heart failure . Regarding the risk of all heart diseases, the adjusted hazard ratio showed an increasing curve with age. Patients aged >62 years tended to have elevated risks of HF , IHD , and OHD , respectively.p < 0.05), but not doxorubicin and trastuzumab. No significant relationship was presented regarding other systemic anticancer agents such as docetaxel, paclitaxel, carboplatin, cyclophosphamide, fluorouracil and methotrexate for the risks of heart failure, ischemic heart disease and other heart diseases.Surprisingly, radiation dosage did not statistically significantly influence the risk of heart diseases . On the Regarding the influence of comorbidities, both hypertension and diabetes mellitus were markedly associated with high risks of heart diseases .p < 0.05) than those who lived in the city. However, there was no apparent influence from different urbanization levels on ischemic and other heart diseases.For socioeconomic variables, including family income, urbanization level, and geographic region, only rural areas were statistically significantly associated with an increased risk of heart diseases. Breast cancer patients who lived in rural areas had a higher risk of heart failure  and OHD , while doxorubicin  and trastuzumab  did not. Besides, there was no similar finding for the risk of ischemic and other heart diseases. This observation indicated a particular association between epirubicin and left breast irradiation on the risk of heart failure.p < 0.0001).We observed that hazard-based risk grouping effectively stratified irradiated breast cancer patients in the endpoints of IHD , OHD Fi, and HF The present population-based cohort study utilized Cox regression to estimate hazards for risk grouping and stratify breast cancer patients in post-irradiation long-term heart diseases. The risk of treatment-associated heart disease from the synergic effect of anticancer drugs and left-sided breast irradiation was also examined. Our study confirmed the previous observation that breast cancer patients had an elevated risk of treatment-associated heart disease , 10, espp < 0.001) per gray in the mean radiation dose, and they found the significant radiation-related increase in the risk of ischemic heart disease   . In addi = 0.01) , which i = 0.01) . Diabeti = 0.01) . It sugg = 0.01) .We comprehensively investigated the risk of heart diseases, including ischemic heart disease, heart failure, and other heart diseases, among patients who received left-sided breast irradiation. The strength of the present study is that this is a nationwide cohort study with a 17-year long-term follow-up in Taiwan. In addition, by examining the risk of heart diseases by each anticancer drug under different levels of left-sided breast irradiation dose, our observation provides further information concerning the synergic effect of chemotherapy- and radiotherapy-associated cardiotoxicity among breast cancer survivors. Finally, we used a propensity score to match all the covariates, including clinical information, comorbidities, and socioeconomic variables, to reduce potential bias before statistical analysis.Regarding this study's limitation, some information is unavailable in our database. For example, the mean heart dose and other heart dose parameters, such as the mean dose to the left anterior descending artery, are unavailable from our database, which may influence assessing the extent of radiotherapy-associated cardiac injury. In addition, we lack some information in our data analysis, such as a history of tobacco use, body mass index, familial history of myocardial infarction, or other cardiovascular diseases, which are reported as preexisting risk factors related to the incidence of CVDs , 46–48.Hazard-based risk grouping may help stratify breast cancer patients at risk of post-irradiation long-term heart diseases. Generally, systemic anticancer agents, including chemotherapy and targeted therapy, are safe in conjunction with radiotherapy for managing post-operative breast cancer patients. However, radiotherapy should be performed cautiously for elderly left breast cancer patients who received epirubicin. Decreasing the irradiation dose to the heart should be critically considered, and regular monitoring of potential signs of heart failure may be conducted.


Screening for critical congenital heart defects should be performed as early as possible and is essential for saving the lives of children and reducing the incidence of undetected adult congenital heart diseases. Heart malformations remain unrecognized at birth in more than 50% of neonates at maternity hospitals. Accurate screening for congenital heart malformations is possible using a certified and internationally patented digital intelligent phonocardiography machine. This study aimed to assess the actual incidence of heart defects in neonates. A pre-evaluation of the incidence of unrecognized severe and critical congenital heart defects at birth in our well-baby nursery was also performed.We conducted the Neonates Cardiac Monitoring Research Project  at the Shahid Akbarabadi Maternity Hospital. This study was a retrospective analysis of congenital heart malformations observed after screening 840 neonates. Using a double-blind format, 840 neonates from the well-baby nursery were randomly chosen to undergo routine clinical examinations at birth and digital intelligent phonocardiogram examinations. A pediatric cardiologist performed echocardiography for each neonate classified as having abnormal heart sounds using an intelligent machine or during routine medical examinations. If the pediatric cardiologist requested a follow-up examination, then the neonate was considered to have a congenital heart malformation, and the cumulative incidence was calculated accordingly.The incidence of heart malformations in our well-baby nursery was 5%. Furthermore, 45% of heart malformations were unrecognized in neonates at birth, including one critical congenital heart defect. The intelligent machine interpreted innocent murmurs as healthy heart sound.We accurately and cost-effectively screened for congenital heart malformations in all neonates in our hospital using a digital intelligent phonocardiogram. Using an intelligent machine, we successfully identified neonates with CCHD and congenital heart defects that could not be detected using standard medical examinations. The Pouya Heart machine can record and analyze sounds with a spectral power level lower than the minimum level of the human hearing threshold. Furthermore, by redesigning the study, the identification of previously unrecognized heart malformations could increase to 58%. CHD and CCHD are the leading causes of birth defect-associated illnesses and deaths of infants , 2 and aBecause of the limitations of the human auditory system  and the presence of clicks and non-pathological heart sounds, some heart abnormalities may not produce an audible murmur , 15; theScreening for CHD in neonates and performing echocardiography examination for positive cases is essential to saving lives and reducing the incidence of undetected pediatric and adult congenital heart diseases. Most heart sounds in neonates are inherent additional sounds that are not indications of any disease; instead, they are merely sounds rooted in the physiology of newborn hearts called innocent murmurs . High puBased on our internationally patented technology , we developed the first accurate intelligent digital phonocardiogram for screening CHD in children in 2008 . The firThe actual incidence of heart malformations (CHD and CCHD) in neonates is subject to social and economic factors . The Doppler ultrasound examination allows accurate screening and diagnosis of CHD in newborns; however, considering the timing of the examinations and that the echo must be done by a pediatric cardiologist, performing this examination for all neonates is impractical, especially in less privileged areas. However, a precise screening for congenital heart malformations in neonates and referring the positive cases to the subspecialist is now possible using a neonatal version of the certified and internationally patented digital intelligent phonocardiography machine known as Pouya Heart.This study aimed to assess the actual incidence of newborn heart malformations in our well-baby nursery. In addition, our well-baby nursery also performed a pre-evaluation of the incidence of unrecognized severe and critical CHD at birth. This is the first study to evaluate the incidence of heart malformations in neonates using intelligent phonocardiography.2.2.1.The obstetrics and gynecology departments of our hospital are accredited for the 4-year residency period and are considered the largest specialized centers in the field in Iran. Our hospital is a tertiary referral center for patients requiring gynecological and neonatal services. Furthermore, it has the country's largest and most advanced neonatal intensive care unit, with 60 active beds. Approximately 12 neonates are born daily at our hospital. Each neonate undergoes a routine medical examination, including heart auscultation, which is performed by a neonatologist within the first 24 h of birth and again before discharge. The neonatologist used a Littman Classic II stethoscope . Newborns with possible CCHD or other types of disease requiring special care are transferred to the neonatal intensive care unit, whereas healthy neonates are transferred to the well-baby nursery. Those with possible CHD are also transferred to the well-baby nursery for an echocardiography examination. Echocardiography is also performed for neonates with gestational ages <34 weeks, those with weight <1,500 g, and those whose mothers had gestational diabetes or any other illness associated with the risk of causing heart malformations in their children.2.2.This was a retrospective analysis of 840 neonates. Neonates were randomly selected from the well-baby nursery to undergo intelligent phonocardiogram screening in a double-blinded manner. Informed consent was obtained from their legal guardians according to the study protocol. The local ethics committee of the Shahid Akbarabadi Clinical Research and Development Unit approved the study , which was conducted according to the guidelines of the World Medical Association and Declaration of Helsinki.A pediatric cardiologist performed echocardiography to obtain a diagnosis for each neonate classified as having abnormal heart sounds by the intelligent machine. The dataset included the following: pulse rate and strength; neonatologist auscultation results; results of pulse oximetry testing of four limbs; family medical history; intelligent phonocardiography examination results; echocardiography diagnosis results.2.3.The intelligent phonocardiogram comprises an electronic stethoscope, a medical computer cart, and a medical monitor . It is c2.4.Patent Cooperation Treaty number: EP2009/051410). The operating principle of the Pouya Heart machine is based on the spectral analysis of the heart sounds of neonates on an acoustical, mathematical model of the heart sound spectrum of neonates in conjunction with advanced artificial intelligence and machine-learning techniques  is practically inaudible; however, the incidence of a small PFO is relatively high for newborns , 33. A P3.Screening using Pouya Heart was performed for 840 neonates with a median age of 30.85 h and a median weight of 3.12 kg to detect congenital heart malformations. This resulted in detecting abnormal heart sounds in 43 neonates, including one CCHD, one severe CHD, and one false-positive error. The screening and diagnosis results of the 42 neonates with congenital heart malformations identified by echocardiography are shown in Based on the routine medical examination results, 45% of the abnormalities observed in 42 neonates, including one CCHD, were unrecognized at birth . The incThe sensitivity, which indicated the precision of the false-negative results, was 100%, 97.1%, and 94.8% for the intelligent phonocardiogram examination, routine medical examination, and auscultation, respectively . The int4.The intelligent phonocardiogram detected heart malformations in 43 neonates. Among these, 42 neonates had heart defects confirmed by echocardiography. The pediatric cardiologist requested follow-up examinations for all 42 neonates. However, the pediatric cardiologist performed echocardiography 48 h after auscultation using Pouya Heart. Consequently, it is possible that Pouya Heart detected trivial heart defects that self-recovered after 48 h, self-recovery of trivial CHD after 48 h is possible. The complete screening process using Pouya Heart required approximately 6 min; a trained technician operated the machine. The main cost of this study was attributable to the screening of 840 neonates with Pouya Heart and echocardiography to diagnose malformations in 43 neonates. The only alternative method of obtaining such results is the performance of 840 echocardiography examinations by a pediatric cardiologist; however, this is not practical.This study had some limitations. First, screening for CHD and CCHD in newborns using Pouya Heart is novel; consequently, some families did not allow their newborns to undergo the recommended echocardiography examinations. Second, because of the study design, we had to replace neonates who did not undergo the echocardiography examination with randomly chosen neonates from the well-baby nursery. Eleven neonates with abnormal heart sound detected by the Pouya Heart did not undergo echocardiography; consequently, they were replaced with other neonates from the well-baby nursery. Therefore, the number of neonates with congenital heart malformations who were not detected by the routine medical examination could have increased to 58% if those 11 neonates had undergone echocardiography or if other newborns from the well-baby nursery were unavailable as replacements or if we replaced those 11 neonates with those with abnormal heart sounds recognized by the Pouya Heart . Third, some neonates for whom an echocardiography follow-up was recommended were referred to other subspecialist centers; some might not follow those recommendations.Consequently, it was impossible to include the follow-up results evaluation in this study, although it would be very informative to investigate the echocardiography follow-up evaluations. Forth, screening using Pouya Heart is based on an analysis of heart sounds , 26. TheIn summary, we introduced a novel, practical, and cost-effective screening method for CHD and CCHD in newborns that can be performed immediately after birth. As a result, Pouya Heart detected heart malformations, including CCHD and CHD, that were unrecognized at birth by routine medical examinations at our hospital. Moreover, Pouya Heart interpreted innocent murmurs as healthy heart sounds.Timely screening of the cardiac health of newborns is vital. Screening for CCHD should be performed as early as possible. Furthermore, screening for CHD in neonates is essential to saving lives and reducing the incidence of undetected pediatric and adult congenital heart diseases. The Pouya Heart machine can detect more congenital heart abnormalities in neonates than routine clinical examinations because of the high pressure on the right side of the heart. With many defects and anomalies, a clear murmur is sometimes not heard because of the high pressure. This critical issue emphasizes the need to use the Pouya Heart machine for screening CHD in neonates. Screening for heart malformations in newborns using Pouya Heart will significantly improve pediatric heart healthcare and eliminate unrecognized adult CHD. This intelligent machine should be tested at various hospitals in different countries to validate its accuracy across populations.Echocardiography examination, which must be performed by a pediatric cardiologist, is essential for simultaneous screening, diagnosis, and patient's management. The Pouya Heart machine is a screening tool for congenital heart malformations. Therefore, we can conclude that the cost of conducting 43 echocardiography examinations and 840 intelligent phonocardiogram examinations to that of conducting 840 echocardiography examinations was highly cost-effective.


Patients with bilateral primary aldosteronism (PA) generally are treated with antihypertensive drugs, but optimal treatment for patients with complications due to refractory hypertension has not been established. In this report, we present a case with bilateral PA who presented with persistent hypertension, despite treatment with 6 drugs, and left-dominant heart failure, which was improved after unilateral adrenalectomy.A 61-year-old man was admitted to our hospital because of severe left-dominant heart failure. His heart rhythm was atrial fibrillation and the left ventricle was diffusely hypertrophic and hypokinetic. Coronary arteries were normal on coronary arteriogram. Primary aldosteronism was suspected based on severe hypokalemia (2.5 mEq/L) and plasma aldosterone concentration . Although computed tomography (CT) showed a single left cortical nodule, adrenal vein sampling (AVS) indicated bilateral PA. Early in the case, heart failure and hyperkalemia in this patient were improved by treatment with a combination of 6 antihypertensive drugs ; however, heart failure relapsed after four months of treatment. We hypothesized that hypertension caused by excess aldosterone was inducing the patient’s heart failure. In order to reduce aldosterone secretory tissue, a laparoscopic adrenalectomy was performed for the left adrenal gland, given the higher level of aldosterone from the left gland compared to the right. Following surgery, the patient’s heart failure was successfully controlled despite the persistence of high PAC. Treatment with anti-hypertensive medications was reduced to two drugs (eplerenone 100 mg/day and bisoprolol fumarate 10 mg/day). In order to elucidate the mechanism of drug resistance, immunohistochemistry (IHC) and real time-polymerase chain reaction (RT-PCR) assays were performed to assess the expression of steroidogenic factor 1 (SF-1), a regulator of steroid synthesis in adrenal tissue. IHC and RT-PCR demonstrated that the expression of SF-1 in this patient (at both the protein and mRNA levels) was higher than that observed in unilateral PA cases that showed good responsivity to drug treatment.Unilateral adrenalectomy to reduce aldosterone secretory tissue may be useful for patients with drug-refractory, bilateral PA. Elevated expression of SF-1 may be involved in drug resistance in PA. Primary aldosteronism (PA) is one of the most pervasive causes of secondary hypertension . AldosteAlthough aldosterone initially induces sodium and water retention, these effects are followed within a few days by a spontaneous diuresis  that returns excretion to the level of intake and partially restores the extracellular fluid volume to normal levels –6. ThereBilateral PA patients are rare; such individuals sometimes show refractory hypertension, even when treated with MR antagonists and more than three antihypertensive drugs , and optDetermination mRNA expression level and western blotting analysis were repeated at least three times independently, and the results were expressed as the mean ± SE. Analysis was performed with SPSS Statistics 21 software (IBM Japan). Data were statistically evaluated using the unpaired two-tailed Student’s t test and values were considered statistically significant when P < 0.05.A 61-year-old man was admitted to our hospital because of severe left-dominant heart failure. Chest radiography showed an enlarged cardiac silhouette, a congested pulmonary hilum, and bilateral pleural effusion Fig. ; therefoImmediately after surgery, the patient’s heart failure was successfully controlled, despite the fact that the PAC remained elevated  and immunohistochemistry (IHC) assays were performed on the resected tissue to detect the mRNA and protein expression (respectively) of steroidogenic factor 1 (SF-1), a regulator of steroid synthesis in adrenal tissue Fig. . Tissue Primary aldosteronism is a disease that causes hypertension and hypokalemia; generally, PA can be controlled with anti-aldosterone drugs such as MR antagonists . HoweverBilateral surgical removal generally is not recommended for bilateral PA . This caIn the case described here, 6 antihypertensive drugs were needed to control refractory hypertension before surgery. There are individual differences in the efficacy of antihypertensive drugs such as anti-aldosterone drugs in PA, and the actual mechanism of action of these medications remains poorly understood. SF-1 is a regulator of steroid synthesis, and overexpression of SF-1 in adrenal tissue has been shown to promote steroid hormone biosynthesis –12. Seve


Echocardiography is the gold standard clinical tool for the evaluation of left ventricular diastolic dysfunction (LVDD) and is used to validate other cardiac imaging modalities in measuring diastolic dysfunction. We examined Cardiac Magnetic Resonance Imaging (CMR) in detecting diastolic dysfunction using the time-volume curve-derived parameters compared to echocardiographic diastolic parameters. We evaluated patients who underwent both CMR and transthoracic echocardiography (TTE) within 2 ± 1 weeks of each other. On echo, Doppler/Tissue Doppler Imaging (TDI) measurements were obtained. On CMR, peak filling rate (PFR), time to PFR (TPFR), 1/3 filling fraction (1/3FF), and 1/3 filling rate (1/3FR) were calculated from the time-volume curve. Using the commonly employed E/A ratio, 44.4% of patients were found to have LVDD. Using septal E/E′ and lateral E/E′, 29.6% and 48.1% of patients had LVDD, respectively. Correlation was found between left atrial (LA) size and E/A ratio (R = −0.36). Using LVDD criteria for CMR, 63% of patients had diastolic dysfunction. CMR predicted LVDD in 66.7% of the cases. CMR-derived diastolic filling parameters provided a relatively easy and promising method for the assessment of LVDD and can predict the presence of LVDD as assessed by traditional Doppler and TDI methods. Left ventricular diastolic dysfunction (LVDD) is the abnormality of diastolic distensibility, filling, or relaxation of the left ventricle regardless of whether the ejection fraction is normal or abnormal or whether the patient is symptomatic or asymptomatic . DiastolDiastolic dysfunction is present in a wide range of cardiac disorders. The mechanisms that lead to diastolic dysfunction are (1) primary myocardial disease such as restrictive, dilated, and hypertrophic cardiomyopathy; 2) coronary artery disease such as ischemia and infarction; (3) secondary left ventricular hypertrophy caused by hypertension, aortic stenosis, and congenital heart disease; and 4) extrinsic constraint such as pericardial tamponade and pericardial constriction [ extrinsi coronaryAs the left ventricle decreases in distensibility and relaxation, diastolic filling pressures increase . The incCurrently, transthoracic echocardiography (TTE) is almost exclusively used to assess diastolic dysfunction and is widely accepted and employed because of its non-invasive nature as opposed to cardiac catheterization . TTE offThe limitations of TTE are in contrast with CMR, in which all values are more objectively calculated, giving less room for error . CMR is This retrospective study, conducted at a single tertiary hospital center, includes 27 consecutive subjects. Data collection was obtained via retrospective search of medical records in the clinical database. Patients who underwent both CMR and TTE within 2 ± 1 weeks of each other over a 3-year period from January 2005 to December 2008 were included. Patients were candidates for CMR based on clinical indications during their standard of care practice. The investigators abstracted one case at a time and in one place. No patient identifiers were collected, and once the data had been abstracted and confirmed, all identifying information was removed. Basic demographic data such as age and gender were recorded. Study subjects were randomly assigned a patient study number on the data collection sheet, which was not derived from any patient identifiers. This study was approved by our Institutional Review Board (IRB# 08-314) as an exempt protocol, and all human subjects protection regulations were adhered to and followed.® statistical package, and all the variables were summarized as mean ± standard deviation. Pearson’s chi-square and independent sample t-tests were used to determine differences for normally distributed proportions and means, respectively. A p-value of <0.05 was considered significant.Data from all CMR and TTE for each subject were recorded. The data collected includes (1) left ventricular ejection fraction, time activity curves, peak filling rate (PFR), and time to peak filling rate (TPFR) from CMR, and (2) left ventricular ejection fraction and other determinants of diastolic dysfunction using TTE. After the measurements were taken, the 1/3 filling fraction (1/3FF) and 1/3 filling rate (1/3FR) were calculated from the time-volume curve. The E/A ratio, septal E/E′, and lateral E/E′ were calculated from the echocardiogram. For the purpose of this study and to make our findings and process as widespread and easily performed by all medical personnel and not just physicians specialized in echocardiography, we kept our diastolic dysfunction criteria to the basic easily obtained variables of E/A, septal E/e′, and lateral E/e′ with the intention of being as efficient and concise as possible for wide applicability. The agreement between CMR and TTE was assessed. All statistical analyses were performed using the SPSSp = 0.15) difference between the mean of patients with presence and absence of diastolic dysfunction in the 1/3FF group as sub-categorized using the septal E/E′ cut-off value. Using the E/A ratio, 12 (44.4%) patients were found to have LVDD (p = 0.03). Additionally, correlation was found between 1/3FF and lateral E/E′ (R = 0.46), but there was no significant difference between the mean of patients with presence and absence of diastolic dysfunction in the 1/3FF group as defined by the lateral E/E′ cut-off value. We did find moderate correlation between TPFR and 1/3FF (R = −0.3).A total of 27 subjects  were analyzed . There wave LVDD . Using sOur results show that CMR detected left ventricular diastolic dysfunction in more patients than echocardiography did. The E/A  and E/E′  ratios are among the most effective CMR parameters for measuring and determining LVDD ,15. The CMR is not only comparable to TTE but also offers additional features that can guide clinical assessment. Cine imaging, phase contrast imaging, and myocardial tagging are features that allow for analysis of global function, flow, and regional function, respectively. These features on CMR allow for both a broad and narrow scope of assessing diastolic function. Phase contrast imaging allows for blood flow analysis, as can be measured by echocardiography, but with the added benefit of less margin of error . CMR hasCMR can also be used in diagnosing patients who have diastolic heart failure but may have been missed by conventional echocardiography or TDI. By measuring the peak filling rate, time to peak filling rate, and filling fraction, CMR can allow for the calculation of left ventricular function and detect diastolic dysfunction using the appropriate criteria. That CMR can detect LVDD in cases missed on more traditional imaging is significant. CMR may be used as an effective screening tool to detect sub-clinical diastolic dysfunction in patients before they progress to overt diastolic heart failure. Diastolic heart failure has a poor prognosis after the first hospitalization, with a 5-year mortality rate of 24% and 54% for patients above 60 and 80 years old, respectively . By screLifestyle modifications and/or treatment with antihypertensive medications can help reduce the risk of progression from diastolic dysfunction to diastolic heart failure in a cost-effective manner. In the long run, this can reduce progression to diastolic heart failure, life-time medication treatment, and invasive procedures if complications develop. CMR can help shift the diastolic dysfunction treatment approach to preventative care rather than management of disease. This is especially significant when medical cost and patient quality of life are considered. Preventative medicine and early treatment can not only reduce the number of patients admitted to the hospital for acute care, but also give patients more control over their own health. Preventative care allows the patient to be an active member of their treatment team, allowing for more time for education about risk factors, lifestyle changes, and preventing progression from diastolic dysfunction to heart failure.It is worth noting that CMR is less applicable for certain patient populations, such as claustrophobic patients and certain patients with older models of pacemakers and defibrillators. The convenience of CMR in a clinical setting is also limited by its inability to be portable as TTE can. Despite these limitations, CMR is still a beneficial modality for assessing diastolic dysfunction and offers functions that surpass those of TTE. Various CMR techniques allow for a more thorough evaluation of diastolic cardiac function with a diverse clinical application. CMR is a remarkable tool for assessing myocardial contractility using features such as strain-encoding (SENC) and displacement encoding with stimulated echoes (DENSE) . With th


In the neurorehabilitation field, robot-aided motion analysis (R-AMA) could be helpful for two main reasons: (1) it allows the registration and monitoring of patients’ motion parameters in a more accurate way than clinical scales , and (2) the multitude of data produced using R-AMA can be used to build machine learning algorithms, detecting prognostic and predictive factors for better motor outcomes (research purpose). Despite their potential in clinical settings, robotic assessment tools have not gained widespread clinical acceptance. Some barriers remain to their clinical adoption, such as their reliability and validity compared to the existing standardized scales. In this narrative review, we sought to investigate the usefulness of R-AMA systems in patients affected by neurological disorders. We found that the most used R-AMA tools are the Lokomat  and the Armeo . The motion analysis provided by these robotic devices was used to tailor rehabilitation sessions based on the objective quantification of patients’ functional abilities. Spinal cord injury and stroke patients were the most investigated individuals with these common exoskeletons. Research on the use of robotics as an assessment tool should be fostered, taking into account the biomechanical parameters able to predict the accuracy of movements. In the field of neurorehabilitation, innovative technologies, such as robotic devices, have been widely used to treat and evaluate patients affected by motor impairment due to different neurological disorders , and spinal cord injury (SCI)) . CompareIn this narrative review, we aimed to investigate the usefulness of R-AMA systems in patients affected by neurological disorders.Given the narrative nature of the paper, we only described the most relevant papers on the issue by searching for them on PubMed, IEEE Xplore, and Scopus, considering the period from 2010 to 2023. We chose this period because this past decade has witnessed the implementation of robotic devices in the neurorehabilitation field. To select evidence, we used the following keywords: “robotic device” OR “exoskeleton” AND “motor assessment” OR “biomechanical assessment” OR “biomechanical parameters” OR “lower limb assessment” OR “upper limb assessment” OR “motion analysis.” Since this is a narrative review, we included the most relevant pilot studies, observational studies, randomized controlled trials, case–control studies, and systematic reviews, considering also the references of the selected articles, including only English papers. Each article was evaluated through the title, abstract, text, and scientific validity [Motion analysis involves registering the three-dimensional movements of human body segments and then calculating biomechanical parameters that describe human movement . The modWithin a rehabilitation setting, quantitative analysis of human body kinematics is a powerful tool that has been used to understand the different biomechanical patterns of both healthy and pathological individuals . RecentlKinematic  and kinetic  data are acquired from sensors affixed to robotic and passive mechanical devices to measure biomechanical aspects of upper extremities ,26,27,28®Spring was the most used for this issue, followed by the Armeo®Power, InMotion 2.0, and Gloreha Sinfonia, as reported in These kinds of measures are commonly registered in post-stroke patients, who may present unilateral hemiplegic involvement. However, the percentage of studies dealing with R-AMA for upper limbs is still poor. It seems that the Armeo®Power, an exoskeleton for upper limb training. Its efficacy in improving functional outcomes is already demonstrated in the literature [For example, one of the most used robotic devices in post-stroke neurorehabilitation is the Armeoterature ,35; howe®Power evaluates the range of joint movement, which is expressed in degrees, and the force of muscles, which is expressed in Newton meters (Nm). According to Galeoto et al. [®Power can be considered an objective robotic tool compared to the Fugl–Meyer for upper limb (FM-UL) clinical scale items. The FM-UL clinical scale is the most used and reliable scale to assess motor functions, joint range of motion, joint pain, dysmetria, and tremor in post-stroke patients [®Power. This suggests that the Armeo®Power is more accurate than the FM-UL clinical scale in evaluating upper limb movements [Specifically, this robotic device can evaluate specific kinematic parameters , as repoo et al. , the Armpatients . The autovements .®Spring to conduct these measurements. To obtain objective data on upper limb functions, the Armeo®Spring calculates a set of numerical indices based on the 3D endpoint trajectory during the “vertical capture” task. The patient receives visual feedback of their hand position through a display, which is used to facilitate rehabilitation exercises. Indeed, the derived indices  are easy to share with clinicians because they describe the motor impairment of the upper limb [Other researchers have also evaluated the motor function of stroke patients using robotic devices and measuring upper limb biomechanical features, such as movement velocity, accuracy, and smoothness in active training ,31. Merlper limb .®Spring to distinguish between stroke patients and healthy subjects. Second, they assessed the validity of the indices used to measure movement. Lastly, they investigated the concurrent validity of these indices by comparing them with the Wolf Motor Function test, a clinically validated scale for assessing UL motor function. The authors’ results confirmed the construct validity of the three indices, which is consistent with the findings of Merlo et al. [®Spring can be a promising tool for objectively assessing UL motor skills. In addition, Goffredo et al. [For example, the loss of movement accuracy can be related to a reduction in sensibility, whereas the decrease in velocity refers to paresis/paralysis, and the loss of smoothness refers to an abnormal muscle tone (spasticity) . Howevero et al. . This suo et al.  performe®Power and the Armeo®Spring cannot perform hand motion analysis due to their biomechanical architecture. To this aim, Cordella et al. [The kinematic parameters were calculated from the trajectories recorded by the robot, starting from the central target and extending to the peripheral targets in various directions. The kinematic parameters described by the authors  refer toa et al.  conductea et al. . Once caa et al.  demonstrAnother concern that should be considered in clinical practice is the objective evaluation of spasticity. The Modified Ashworth Scale (MAS) is, in fact, the most commonly used clinical tool for assessing spasticity. However, it does have several limitations . Indeed,They registered kinematic, kinetic, and electromyographic (EMG) signals during the tracking movement in order to develop biomechanical indices for evaluating muscle synergies. In fact, their results revealed that abnormal synergies can be assessed through two tracking directions: D2  and D4 (left–right) . Lastly,Walking recovery in neurological patients is one of the most important goals planned by therapists . In ordeThe Lokomat, which is a tethered exoskeleton, is one of most used robotic devices for gait training and for motion analysis in neurological disorders. In fact, 57% of the selected papers reported the use of the Lokomat in performing R-AMA, followed by Ekso and the WelWalk, as reported in According to a systematic review , the LokAnother point to consider is the evaluation of proprioception provided by robotic devices. Three studies ,51,52 in®Spring, R-AMA may provide clinicians and researchers with reliable and more objective data regarding motion analysis of the lower and upper limbs, respectively [In this narrative review, we found that robotic devices may be used to assess motor behavior in patients with neurological disorders. Indeed, according to the few available studies, two main exoskeletons, namely the Lokomat and the Armeoectively ,52,53,54ectively ,33,36,37ectively . Indeed,ectively . Similarectively ,51,52, wCompared with conventional assessment methods, such as clinical scales or tests administered by physiotherapists and/or physicians, R-AMA offers several advantages. It can provide tri-axial measurements, analyze the patient’s limb trajectory, accurately register spatial-temporal parameters of movement, and collect a large amount of data. Altogether, these elements allow for personalization of the rehabilitation path according to patients’ needs. This personalized approach can be used to create a tailored patient profile, which includes a precise physiotherapy program. This program considers both traditional and cutting-edge devices for treatment. In recent years, the concept of personalized treatment has gained significant traction in various medical fields , includiIn this vein, the so-called “rehabilomics” sheds some light on the role of biomarkers in the clinical and rehabilitation setting . This apLegend: R-AMA could be useful to personalize neurorehabilitation programs, thanks to both biomarkers provided by EMG biosignals (on the left) and biomechanical parameters (on the right), including kinematic and kinetics. In the end, the great quantity of data obtained through R-AMA could be further used for MLA for individuating motor biomarkers involved in recovery prediction.To date, research on robotic devices has primarily focused on neuromotor training and recovery in patients with neurological disorders, without considering the potential role of these devices in objectively evaluating movement. However, physicians frequently criticize these technical solutions, claiming that the outcome measures offered by robotic devices are too abstract, do not translate into practical function, and lack ecological validity. An important point that should be addressed is that robotic devices may require a lengthy setup time and the support of technical staff to operate. In the clinical setting, the physiotherapist has 30–60 min of rehabilitation treatment for each patient, and this could further discourage the use of robotic devices in clinical practice. Additionally, robotic devices, especially exoskeletons, must be perfectly aligned with the user to avoid undesired interaction forces . These fHowever, recent technological developments in the field of wearable devices, such as accelerometers and inertial sensors, have the advantage of providing objective motion analysis as low-cost and easy-to-use tools, as opposed to robotic devices ,45. In tThe selection of motion biomarkers predicting recovery remains an open and under-debate question. According to Amrani El Yaakoubi et al. , EMG andIn conclusion, the utility of R-AMA for both clinical and research purposes is still a subject of debate, although some promising findings have been reported regarding the effectiveness of the Lokomat and the Armeo. The motion analysis provided by these robotic devices is used to customize rehabilitation sessions, relying on the objective quantification of patients’ functional abilities. It should be considered that clinical scales and tests used to monitor motor recovery in neurological patients are less accurate than motion analysis conducted by robotic devices. Next, research on the use of robotics and assessment tools should be encouraged. Future studies should be oriented toward two different frontiers: (1) understanding the most useful biomechanical parameters that can predict the accuracy of movements and (2) validating robotic device assessments for clinical purposes.


Cardiogenic shock is a critical condition of low cardiac output resulting in insufficient systemic perfusion and end-organ dysfunction. Though significant advances have been achieved in reperfusion therapy and mechanical circulatory support, cardiogenic shock continues to be a life-threatening condition associated with a high rate of complications and excessively high patient mortality, reported to be between 35% and 50%. Extracorporeal membrane oxygenation can provide full cardiopulmonary support, has been increasingly used in the last two decades, and can be used to restore systemic end-organ hypoperfusion. However, a paucity of randomized controlled trials in combination with high complication and mortality rates suggest the need for more research to better define its efficacy, safety, and optimal patient selection. In this review, we provide an updated review on VA-ECMO, with an emphasis on its application in cardiogenic shock, including indications and contraindications, expected hemodynamic and echocardiographic findings, recommendations for weaning, complications, and outcomes. Furthermore, specific emphasis will be devoted to the two published randomized controlled trials recently presented in this setting. Hemod≥15 mmHg . End-org≥15 mmHg . The lea≥15 mmHg . Other c≥15 mmHg . CS acco≥15 mmHg ,8.Extracorporeal membrane oxygenation has been increasingly used in the last two decades and has been shown to be an effective tool in the management of CS ,9,10. VeVA-ECMO, also commonly referred to as extracorporeal life support (ECLS), is a form of cardiopulmonary bypass that uses a centrifugal flow pump, membrane oxygenator, as well as venous inflow and arterial outflow cannulas ,11. AddiCannulation may occur centrally or peripherally ,16. ApprIt is important to note that VA-ECMO can also be accomplished via a novel ambulatory approach. In ambulatory ECMO, cannulation in the groin is avoided and sufficient oxygen is provided to allow patients to stand, walk, and participate in active physiotherapy and thus help prevent deconditioning ,22. AlthOnce ECMO is initiated, frequent monitoring of hemodynamics and assessment of arterial and venous blood gases, as well as gas samples from the VA-ECMO circuit, are essential to ensure that the cardiac output and oxygenation can promote myocardial recovery and help restore renal, hepatic, and pulmonary function, acid–base balance, coronary perfusion, and neurological status ,10,27. IPatient selection is an important, though clinically challenging component of VA-ECMO use that aims to identify patients with the highest chance of recovery or candidacy for destination therapy ,11,34. EIndications for VA-ECMO include CS refractory to conventional medical and device-based therapy, most commonly in the setting of acute coronary syndrome, acute on chronic decompensated heart failure, fulminant myocarditis, and unsuccessful cardiopulmonary bypass weaning following cardiotomy ,11,31. LOverall, ECMO should not be used as therapy in patients with cardiac disease that is unlikely to recover, as well as in patients with a poor life expectancy, typically less than one year, and in patients with preexisting conditions that have a very high mortality rate and that are incompatible with ECMO weaning and recovery, most notably severe neurological injury, disseminated malignancy, and irreversible multiorgan failure ,17. Addi2, and a profound fall in blood pressure lead to low systemic and coronary perfusion, triggering reflex-mediated increases in heart rate and systemic vascular resistance (SVR) [Cardiogenic shock is the most severe form of LV failure, in which systolic or diastolic dysfunction leads to diminished cardiac output (CO), most often due to a decrease in contractility and a subsequent severe reduction in LVEF ,46,47,48ce (SVR) ,49. In tce (SVR) . Volume ce (SVR) . Ultimatce (SVR) .The hemodynamic effects of a mixed shock state also need to be considered, as approximately 20% of patients admitted to the cardiac intensive care unit have this form of shock . TypicalThe specific hemodynamic effects of VA-ECMO on the heart and cardiovascular system in CS are still being analyzed. It is known that VA-ECMO reduces central venous pressure while increasing MAP and the arteriovenous pressure gradient, thereby increasing systemic perfusion . One theThe major disadvantage with peripheral VA-ECMO is that it lacks complete LV “unloading” capabilities—it does not lessen the work of the LV—therefore, optimization of preload, afterload, and contractility may be needed to maintain forward flow through the LV and prevent pulmonary edema and decreased LV function ,17,18. WAccording to the ELSO, of the 12,734 adult patients who received VA-ECMO between 2010 and 2019, 3399 patients required mechanical unloading, 82.9% with the intra-aortic balloon pump (IABP) and 17.1% with transvalvular percutaneous ventricular assist device (pVAD), such as the Impella . The IABLess commonly utilized means of unloading the LV include atrial septostomy, left atrial or pulmonary artery VA-ECMO, and an LV direct surgical vent ,18,62. SAlthough multiple studies have reported lower mortality and higher rates of weaning in adult patients with CS treated with VA-ECMO in combination with LV mechanical unloading, there are currently no randomized trials comparing the various venting strategies ,72. EarlA further hemodynamic concern is the development of “north–south syndrome,” also known as “harlequin syndrome,” which has been reported to occur in up to 8.8% of patients on VA-ECMO ,74. ThisThe hemodynamic benefits of VA-ECMO are irrespective of intrinsic LV function and have an advantage over IABP and Impella devices alone by functioning regardless of RV function due to bypassing the pulmonary circuit for oxygenation . Thus, uEchocardiography plays an important role in VA-ECMO management. Although no specific guidelines currently exist, assessment with the imaging modality provides anatomical and diagnostic information that can aid in patient selection, facilitates safe cannulation and weaning, and serves as a standardized tool to monitor patients and evaluate for complications ,77. CompOnce it is determined that VA-ECMO is indicated, cannulation can be performed under fluoroscopy, TTE, or TEE guidance to allow for direct visualization of the guidewire, ensure appropriate cannula placement, and promptly identify complications during insertion and positioning, including life-threatening pericardial effusion, aortic dissection, and stroke or other embolic event ,53. ThesVA-ECMO is a promising form of MCS in patients with CS; however, utilization, must be carefully weighed against potential complications, many of which can significantly increase the risk of morbidity and mortality ,10.Because therapeutic anticoagulation is standard practice with VA-ECMO, bleeding is the most commonly reported adverse event, reportedly occurring in 30–79% of patients with VA-ECMO use ,82,83,84Risk of hemorrhagic complications must be balanced with risk of thrombosis, as thrombotic complications are also regularly encountered, occurring in up to 22% of patients ,85,86,87Limb ischemia is also a known complication of VA-ECMO, and its associated mortality rate is reported to be as high as 60% ,11,34. PAcute kidney injury (AKI) is another frequently encountered complication. The incidence is estimated to be between 43–85% and typically occurs within 48 h of VA-ECMO cannulation ,100,101.Other common complications of VA-ECMO include infections, most commonly accessed site, bloodstream, and lower respiratory and urinary tract infections, which are reported to occur in up to 20% of patients and can be prevented by utilizing strict aseptic technique. Additionally, patients can experience neurological complications, such as acute ischemic stroke, intracerebral hemorrhage, seizure, and anoxic brain injury; These can be mitigated with an improved understanding of potential neurological complications that can be expected with VA-ECMO that can lead to morbidity and mortality, as well as with regular and multimodal monitoring, in order to arrive at an early diagnosis and initiate timely treatment ,105,106.VA-ECMO serves as a window during which the decision to proceed with durable LVAD or cardiac transplantation is performed or reversible causes of cardiac failure can be treated . Weaning2/FiO2 greater than 200 on 0.21 FiO2 is recommended, and transition to VV-ECMO should be considered in patients with PaO2/FiO2 less than 100 [Several other weaning algorithms have been proposed, though the basis of each strategy includes weaning trials, in which the performance of the ventricles and patient hemodynamic response is assessed throughout an incremental decrease in support in order to determine whether VA-ECMO can safely be terminated ,107. Thethan 100 ,54,109. than 100 . The basthan 100 . It is cOnce these criteria are met and patients are deemed ready for weaning, an algorithmic approach is recommended for incrementally decreasing the bedside VA-ECMO blood flow rate, exposing the patient to an increased RV preload and decreased LV afterload . In patiThe precise criteria to define successful weaning have not been established, though VA-ECMO device removal with no further necessity for MCS in the following 30 days for refractory CS is generally accepted . SuccessBased on retrospective and observational studies, morbidity and mortality remain exceptionally high in patients requiring VA-ECMO, and outcomes are largely dependent on the underlying indication, patient comorbidities, severity of organ dysfunction at initiation, and complications or adverse events during MCS ,109. TheTo date, there have been two randomized controlled trials (RCT) examining VA-ECMO use in patients in CS: the Extracorporeal Membrane Oxygenation in the Therapy of Cardiogenic Shock  and the Venoarterial Extracorporeal Membrane Oxygenation or Standard Care in Patients with Cardiogenic Shock Complicating Acute Myocardial Infarction .The ECMO-CS trial examined the effectiveness of VA-ECMO in patients with rapidly deteriorating or severe cardiogenic shock. Specifically, the study compared outcomes in patients randomly assigned to immediately start VA-ECMO with those who were assigned to start with conservative management (CM) with delayed VA-ECMO initiation in the case of hemodynamic worsening. Of the patients in the CM group, 39% were ultimately started on VA-ECMO, an average of 1.9 days following randomization. The incidence of adverse events , as well as all-cause mortality at 30 days , was similar between the two groups, suggesting that immediate initiation of VA-ECMO in rapidly progressing or severe cardiogenic shock did not improve outcomes .The EUROSHOCK trial was a prospective, multicenter RCT that examined outcomes of VA-ECMO vs. standard therapy in 35 patients with CS 30 min following percutaneous coronary intervention, of which 17 were randomized to the VA-ECMO group and 18 to standard therapy. The all-cause mortality at 30 days was 43.8% in the VA-ECMO group compared with 61.1% in the control, and at one year 51.8% and 81.5%, respectively. The rate of adverse events was found to be significantly higher in the VA-ECMO group: 21.4% of patients experienced vascular complications and 35.7% had bleeding complications, compared with 0% and 5.6% in the standard therapy group. Although the survival outcomes suggest a benefit in using VA-ECMO, given the limited sample size and risk of complications, definitive recommendations cannot be made based on this trial .It is also important to note that the addition of VA-ECMO to CPR for cardiac arrest is reported to significantly improve patient outcomes ,123. AltIn sum, despite the significant risk of mortality and potentially fatal complications, VA-ECMO offers a substantial chance of survival for patients in cardiogenic shock with an otherwise particularly poor prognosis . Many quVA-ECMO provides rapid, complete biventricular circulatory support in addition to simultaneous gas exchange to allow time for diagnostic and therapeutic interventions and potential organ recovery, often serving as a bridge to recovery, bridge to further decision-making, or bridge to cardiac transplantation, and offers a chance of survival for patients in cardiogenic shock refractory to conventional medical and device-based therapy with an otherwise poor prognosis. Despite recognized benefits of the use of VA-ECMO, utilization must be carefully weighed against potential complications and patient selection is an important component of VA-ECMO use that aids in optimizing patient outcomes, while avoiding medical futility. Outcomes following VA-ECMO are largely dependent on the underlying indication, patient comorbidities, severity of organ dysfunction at initiation, and complications or adverse events during MCS. Significant advances have been achieved in our understanding of VA-ECMO; however, rigorous investigation with prospective, randomized controlled trials are needed in order to establish standardized evidence-based guidelines for optimal management of patients with cardiogenic shock requiring VA-ECMO.


Indications for stress-cardiovascular magnetic resonance imaging (CMR) to assess myocardial ischemia and viability are growing. First pass perfusion and late gadolinium enhancement (LGE) have limited value in balanced ischemia and diffuse fibrosis. Quantitative perfusion (QP) to assess absolute pixelwise myocardial blood flow (MBF) and extracellular volume (ECV) as a measure of diffuse fibrosis can overcome these limitations. We investigated the use of post-processing techniques for quantifying both pixelwise MBF and diffuse fibrosis in patients with clinically indicated CMR stress exams. We then assessed if focal and diffuse myocardial fibrosis and other features quantified during the CMR exam explain individual MBF findings.This prospective observational study enrolled 125 patients undergoing a clinically indicated stress-CMR scan. In addition to the clinical report, MBF during regadenoson-stress was quantified using a post-processing QP method and T1 maps were used to calculate ECV. Factors that were associated with poor MBF were investigated.β = −0.191, p = 0.001) and ECV  were independent predictors of reduced MBF. In patients without clinically defined first pass perfusion deficits, the microvascular risk-factors of age and wall thickness further contributed to poor MBF (p < 0.001).Of the 109 patients included , global and regional perfusion was quantified by QP analysis in both the presence and absence of visual first pass perfusion deficits. Similarly, ECV analysis identified diffuse fibrosis in myocardium beyond segments with LGE. Multivariable analysis showed both LGE (Quantitative analysis of MBF and diffuse fibrosis detected regional tissue abnormalities not identified by traditional visual assessment. Multi-parametric quantitative analysis may refine the work-up of the etiology of myocardial ischemia in patients referred for clinical CMR stress testing in the future and provide a deeper insight into ischemic heart disease. As ischemic heart disease remains one of the most common and fastest growing causes of mortality, the number of stress examinations to investigate inducible ischemia are rapidly expanding and are being performed in imaging centers outside of university hospitals. Cardiovascular magnetic resonance imaging (CMR) is considered one of the most comprehensive diagnostic imaging modalities and the advancement of parametric tissue characterization techniques allows for a deeper investigation into diffuse myocardial dysfunction.A typical clinical CMR exam for ischemic testing relies mostly on a combination of qualitatively assessing myocardial perfusion under stress or a vasodilating stimulus and imaging of permanent myocardial injury or viability of the tissue . A comprThus, we investigated the use of post-processing techniques for quantifying pixelwise MBF in comparison to standard clinical visual analysis of visual FPP in patients undergoing clinically indicated CMR stress testing. Moreover, to shed light on potential discrepancies in regional and global hypoperfusion between the two perfusion analysis techniques we investigated if patient characteristics and quantification of other myocardial features acquired within the same multi-parametric CMR could explain MBF findings acquired by QP post-processing analysis. In particular, the primary aim was to investigate if visually assessed focal scar and quantified diffuse fibrosis have an independent impact on QP-derived MBF under regadenoson stress.The study was approved by the ethics board of the Canton of Bern, Switzerland (2021_00139) and complies with the Declaration of Helsinki. All subjects had given their written informed consent before enrolment into this study. This was a prospective observational study that enrolled 125 patients at the Hospital Centre of Biel, Switzerland who were referred for a clinically indicated stress-CMR to investigate inducible ischemia (May 2021–May 2022). Exclusion criteria were caffeine consumption in the last 12 h, <18 years of age, inability to give consent, or patients deemed unfit for an extended protocol by the imaging physician.The CMR studies were performed using a clinical 1.5 T MRI . Patients underwent cine imaging with a short axis stack and three long-axis views for functional analysis. Stress was induced with intravenous administration of regadenoson (fixed dose of 400 μg), and perfusion at stress was imaged using a dual bolus protocol , 11 Fig. FPP imaImages were analyzed by three independent groups of readers. First, a clinical analysis was performed by the local imaging team of senior physicians with CMR certification and >5 years of CMR experience. The clinical report included volumetric function, septal wall thickness and a visual assessment of the presence of LGE and qualitative FPP deficits. The presence or absence of the latter two parameters were reported for each myocardial segment [American Heart Association (AHA) 16-segment model] and classified by distribution pattern. A semiquantitative segment score was calculated for both measures based on the sum of segments with either LGE enhancement or visual FPP deficits. A patient was reported to have clinically relevant inducible ischemia by the presence of two adjacent segments with visual FPP deficits and have clinically relevant LGE if any myocardial enhancement was detected.42 . For the quantitative perfusion contours were added automatically and adjusted by the reader if required. Hyperemic myocardial blood flow (MBF) per voxel was then quantified by the software and reported as numerical result per AHA segment and for a global MBF  were then forwarded into a multivariable model. For secondary analysis investigating categorical comparisons, global and segmental MBF from QP analysis were grouped based on the presence of LGE and ECV ≥ 30% and compared with a multivariate ANOVA and Tukey's post-hoc tests accounting for multiple comparisons. Similar models were used to compare the visual and quantitative techniques. Quantified MBF (ml/g/min) was compared between segments categorized by the presence and distribution of visual FPP deficits. The same analysis was performed for ECV(%) in the presence of LGE. For tests using segmental analysis, multiple measures per patient were accounted for in the statistical models. Intra- and interobserver reliability was calculated with an intra-class correlation (ICC) test for absolute agreement. Results were considered statistically significant at a two-tailed value p < 0.05. Statistical analyses were performed with GraphPad Prism version 9.0 (GraphPad Software) and R software .Patients were included in the final analysis if QP, ECV and LGE were all successfully acquired. For the primary endpoint, the relationship between other CMR findings and patient characteristics to global and segmental MBF were assessed with a univariable linear regression. Continuous variables were utilized for MRI measurements such as segment score for LGE and visual FPP, or % for ECV. Significant variables , while the remainder had transmural hypoperfusion (n = 4). MBF was higher in segments without visual FPP deficit [1.6 (1.1–2.3 ml/g/min)], than those with a classified FPP deficit . Yet as shown in All included patients presented with signs of a sufficient hemodynamic response during regadenoson, defined by an increase in heartrate of ≥10 bpm (18 ± 7 bpm) and/or a drop in systolic blood pressure of ≤−10 mmHg [−5.0 (−16-2.5)mmHg]. Of the 109 patients, 22 (20%) had a visually classified FPP deficit in at least one myocardial segment, and 10 patients (9%), were diagnosed with a clinically relevant inducible ischemia, defined by adjacent segments with FPP deficits. Regionally, the majority of segments with a visual FPP deficit were classified with endocardial hypoperfusion  patients. In these patients presenting with LGE, enhancement was observed in a median of 3 [1–5] AHA segments (/16). Of the 132 total segments with LGE, 63 were classified with a sub-endocardial distribution, 40 as transmural and 29 as intramural/diffuse. Quantitative analysis of ECV as a pixelwise measurements of diffuse fibrosis was lower in segments without LGE than with LGE . Univariable analysis investigating variables that impact MBF demonstrated that increased age, males, low ejection fraction and cardiac output, increased wall thickness, ECV(%) and number of segments with LGE all had significant associations ml/g/min. Twenty-five (23%) patients presented positive for both LGE and ECV ≥30% averaged across the whole heart (LGE+/ECV+), 22 (20%) patients had elevated ECV but no LGE (LGE-/ECV+), 16 (15%) patients had LGE with ECV <30%, and 46 (42%) patients presented with no LGE or ECV elevation . Global n = 1,695), 6% had both LGE and ECV ≥ 30% (LGE+/ECV+), 35% of the segments had ECV ≥ 30% but no LGE (LGE-/ECV+), only 2% of segments showed LGE with ECV < 30%, and 57% patients presented with no LGE or ECV elevation. Similar to global analysis, segments presenting with both LGE and ECV ≥ 30% had a MBF of 0.9[0.6–1.4]ml/g/min, which was significantly lower than the three other categories . Moreover, even in the absence of LGE, segments with ECV ≥ 30% yielded lower MBF than segments without diffuse fibrosis , whereas the few segments with LGE+/ECV- did not differ .When investigating individual segments , LGE  and ECV  all independently explained the MBF accounting for multiple measurements per subject. Taking this one step further, univariable and multivariable analysis was again performed for the subset of patients (n = 99) that did not have clinical classification of inducible ischemia (two or more adjacent segments with an FPP deficit). In these patients, presence of LGE  and elevated ECV  still independently explained a lower segmental MBF, but in this subgroup increased age  and a larger wall thickness  were also independently associated with MBF , p < 0.001] global MBF quantification. Similar reliability was yielded for segmental MBF quantification .Reader reliability  for the In a cohort of patients undergoing clinical stress CMR exams, analysis of pixel-wise MBF by post-processing quantitative perfusion (QP) software was feasible, reliable and was successfully performed in 97% of the acquired exams with pharmacological vasodilation. Hypoperfusion was identified in patients undergoing stress CMR, in both the presence and absence of visually assessed first pass perfusion (FPP) deficits. Even in patients who were not diagnosed with inducible ischemia by visual FPP analysis, both the presence of focal and diffuse fibrosis represented by the presence of LGE and ECV along with a thicker septal wall and patient age were independently associated with reduced regional MBF.In this study, both traditional qualitative and modern quantitative analysis techniques were applied to characterize the myocardial tissue features of perfusion and fibrosis. In the case of diffuse perfusion abnormalities and fibrosis patterns, abnormalities can remain undetected with the qualitative approaches because of the absence of healthy reference myocardium. This regional analysis technique can be compromised in the case of balanced impaired perfusion, arising from pathological processes including microvascular disease or 3-vessel CAD , 13. ThiOur results demonstrate the importance of segmental analysis. Averaging the entire myocardium into a single global MBF can lead to false negative results, if a regional perfusion deficit or a focal elevated ECV is compensated for or cancelled out by an otherwise healthy myocardium, resulting in a normal global value. Similarly, it was reported in hypertrophic cardiomyopathy patients that comparison of global MBF did not differ between patients with and without visual perfusion deficits, but investigation of individual segments revealed significant insights into regional decrease in perfusion . Thus, sIn this cohort, as expected, the presence of a visual perfusion deficit and LGE were both associated with a co-localized segmental reduction in MBF. Hypoperfusion and tissue-injury have a mutually antagonistic relationship with each other. While poor blood flow can lead to myocardial ischemia and development of myocardial edema and fibrosis, structural damage to the tissue itself also impedes myocardial blood flow which subsequently can lead to further tissue injury . LGE excThe fact the perfusion is attenuated in the presence of fibrosis is well established , but theWe also observed in the sub-analysis that other factors beyond replacement and diffuse forms of myocardial fibrosis impact MBF. Increased age and larger wall thickness, both considered risk-factors for microvascular dysfunction, were also independently associated with reduced MBF. Measures of fibrosis along with increased wall thickness has already been linked to poor vascular function in specific pathological settings as in hypertrophic cardiomyopathy, Anderson-Fabry disease and HFpEF –33. ConsQP has been primarily reserved to research settings, but multiple directions are currently developing techniques to translate QP to clinical routine such as through generation of in-line automated perfusion maps with respiratory motion correction, or through off-line software , 9, 34. This study uses a dual-bolus technique instead of the more validated dual-pulse single-bolus approach, where both the AIF and myocardial stress are acquired within the same acquisition. The main disadvantages of the applied dual-bolus technique is that it can be prone to T2* effects, it requires longer imaging time under stress as the sequence has to be repeated individually for the AIF and myocardial stress, and inline maps are not provided on the scanner , 35. HowThis combination of a dual-bolus protocol and post-processing software we have applied in our analysis was recently validated to fractional flow reserve measurements by Zhao et al. . NeverthThe used post-processing technique quantified a single transmural value per segment, and did not quantify regions of interests, sub-endocardial values or transmural gradients, which may provide more differentiated picture of the hypoperfusion , 41. SimWe observed in patients referred for a clinical stress-CMR exam to test for inducible ischaemia, that post-hoc quantitative analysis detected hypoperfusion and diffuse fibrosis in myocardium beyond territories categorized as abnormal by traditional visual evaluation. Incorporating quantitative analysis into clinical work may help explain the symptoms that led to a referral for ischemic stress testing in the first place. This could be especially useful to patients who present with signs of ischemia without the traditional patterns of sub-endocardial or transmural FPP deficits and LGE. This includes investigation of pathologies such as microvascular disease, myocardial infarction with non-obstructive coronary arteries, hypertrophy among others. Use of traditional stress FPP has been shown to be a cost-effective measure by helping derive a suitable treatment plan , 43, andQuantitative perfusion image acquisition is feasible in a clinical setting and post-processing techniques can quantify pixel-wise myocardial blood flow using product perfusion sequences. Applying QP techniques, it was determined that MBF during pharmacological vasodilation was reduced in some patients independent of conventional visual FPP classification. Moreover, it was shown that ECV as a quantitative measure of diffuse fibrosis is independently associated with reduced MBF beyond focal scar on LGE images, while patient age and myocardial wall thickness are also independent contributors to hypoperfusion. Multi-parametric quantitative analysis may refine the work-up of the etiology of myocardial ischemia in patients referred for clinical CMR stress testing in the future and provide a deeper insight into ischemic heart disease.