Baffle leaks are a frequently encountered and often overlooked complication after the atrial switch procedure for transposition of the great arteries. Baffle leaks are present in up to 50% of non-selected patients, and while they initially may not cause clear symptoms, they can complicate the hemodynamic course and influence the prognosis in this complex patient group. A shunt from the pulmonary venous atrium (PVA) to the systemic venous atrium (SVA) can lead to pulmonary overflow and subpulmonary left ventricular (LV) volume overload, while a shunt from the SVA to the PVA can result in (exercise-associated) cyanosis and paradoxical embolism. We report three cases of baffle leaks in patients with systemic right ventricular (sRV) failure late after the atrial switch procedure. Two symptomatic patients who presented with exercise-associated cyanosis due to SVA to PVA shunting over the baffle leak underwent successful percutaneous baffle leak closure with a septal occluder device. One patient with overt sRV failure and signs of subpulmonary LV volume overload due to PVA to SVA shunting was managed conservatively, as baffle leak closure was expected to lead to an increase in sRV end-diastolic pressure and aggravation of sRV dysfunction. These three cases illustrate the considerations made, challenges faced, and necessity of a patient-tailored approach when addressing baffle leaks. Transposition of the great arteries (TGA) is the second most common cyanotic congenital heart defect after Tetralogy of Fallot and affects 2 to 3 out of every 10,000 live births [The morphological and functional characteristics of the sRV, which are not equipped to chronically sustain the pressure of the systemic circulation, lead to a range of long-term complications. Over 50% of patients with TGA who underwent the atrial switch procedure develop symptomatic heart failure by the age of 45 years, and their 40-year survival rate varies from 82 to 90% . AlthougThe diagnosis of baffle leaks can be challenging due to the low sensitivity of transthoracic echocardiography, and might necessitate contrast echocardiography, cardiac magnetic resonance imaging (MRI), computed tomography (CT), and/or exercise testing ,8. The 2This case series presents three cases of adult TGA patients with reduced systolic sRV function and baffle leaks late after the atrial switch procedure, illustrating the patient-tailored approach to the management of baffle leaks in the modern era. A 53-year-old woman born with TGA who underwent atrial correction according to Mustard at the age of 3 years was reviewed in the outpatient clinic due to sRV failure. She had a rate adaptive atrial (AAI-R) pacemaker implanted at the age of 29 due to sick sinus syndrome, which was upgraded to a primary prevention dual chamber implantable cardioverter-defibrillator (DDD-ICD) at the age of 45. She had a history of an ambulant, uncomplicated COVID-19 infection two years ago and has since been checking her peripheral oxygen saturations (SpO2) at home. The patient now reports that SpO2 drops to 87% at ambient air during daily activities. She was in New York Heart Association (NYHA) functional class III despite pharmacological treatment with a beta-blocker, an angiotensin receptor-neprilysin inhibitor (ARNI), and a sodium-glucose cotransporter 2 inhibitor (SGLT2i). Bicycle exercise ergometry revealed an exercise capacity of 100 watts (95% of what was predicted) with a VO2 max of 19.5 mL/min/kg (66% of what was predicted) with progressive decline in SpO2 to 77% at maximal effort. Her SpO2 in ambient air was 97% at rest, and she was euvolemic. Transthoracic echocardiography (TTE) showed a poor systolic function of the dilated sRV and trivial tricuspid regurgitation. The function of the subpulmonary LV was normal A,B. SubsThe patient underwent a successful baffle leak closure with a 10 mm Amplatzer Septal Occluder . The procedure was performed using left femoral access under local anesthesia with fluoroscopic and intracardiac echocardiography (ICE) guidance D–I. No rA 47-year-old woman with TGA late after the atrial switch procedure according to Senning, was analyzed in the outpatient clinic due to progressive dyspnea and decreased exercise tolerance over the past year. She had a history of concomitant pulmonary valve commissurotomy, resection of an infundibular pulmonary stenosis, and ventricular septal defect (VSD) closure at the age of two years. She had two uncomplicated pregnancies at the ages of 23 and 24, respectively. A third pregnancy at the age of 26 years was terminated during the first semester due to a decline in clinical condition and persistent hypertension. In the following decades, as the sRV progressively deteriorated to a moderately reduced systolic function, she underwent a total of five atrial tachycardia ablation procedures, and a dual chamber (DDD) pacemaker was implanted due to sick sinus syndrome . Upon presentation, she was in NYHA functional class III. Pharmacological treatment included a beta-blocker, an ARNI, a mineralocorticoid receptor antagonist, a loop diuretic, amiodarone, and a vitamin K antagonist. Bicycle exercise ergometry revealed a reduced exercise capacity of 80 watts (61% of what was predicted) and a VO2 max of 12.5 mL/min/kg (48% of what was predicted). SpO2 decreased from 93% at ambient air at rest to 84% at maximal effort. TTE showed a stable, moderately reduced function of the sRV, trivial tricuspid regurgitation, and preserved function of the subpulmonary LV. Suspicion of a baffle leak was raised by the apical four chamber view, which revealed systolic flow from the SVA to the PVA (right-to-left) at rest A,B. SignThe patient underwent a successful baffle leak closure with a 18 mm Occlutech Figulla Flex II Atrial Septal Defect (ASD) Occluder . The procedure was performed using left femoral access under conscious sedation and local anesthesia with fluoroscopic and ICE guidance E,F. No rA 60-year-old woman with TGA with VSD, secundum ASD, mild infundibular pulmonary stenosis, partial anomalous pulmonary venous drainage, and a persistent left superior vena cava was evaluated in the outpatient clinic due to progressive sRV failure. She underwent the atrial switch procedure according to Mustard with VSD closure at 11 years of age, followed by surgical closure of a baffle leak at 30 years of age, and combined tricuspid valve restrictive annuloplasty with a second surgical baffle leak closure at 43 years of age. She had a history of paroxysmal supraventricular tachycardias, for which she had undergone two catheter ablation procedures. A DDD-pacemaker was implanted due to sick sinus syndrome. The system was later upgraded to a transvenous DDD-ICD due to symptomatic episodes of ventricular tachycardia, and she required chronic ventricular pacing due to symptomatic atrioventricular conduction block and bradycardia-induced (non-sustained) polymorphic ventricular tachycardia. At the age of 57 years , the patient was diagnosed with a cardiobacterium hominis endocarditis involving a small, hemodynamically not significant baffle leak and the pacemaker leads A,B. Her She was now in NYHA functional class II-III despite pharmacological treatment with a beta-blocker, an ARNI, a SGLT2i, a loop diuretic, and a vitamin K antagonist. Bicycle exercise ergometry revealed a reduced exercise capacity of 50 watts (51% of what was predicted) and a VO2 max of 8.7 mL/min/kg (36% of what was predicted). SpO2 remained above 95% during exercise. TTE showed a dilated sRV with moderately to severely reduced systolic function, signs of dyssynchrony, and mild tricuspid regurgitation. The subpulmonary LV had preserved systolic function but was dilated. During diastole, there was a septal shift towards the sRV, consistent with volume overload of the subpulmonary LV. TTE also demonstrated the presence of a hemodynamically significant baffle leak with a PVA to SVA (left-to-right) shunt causing volume overload of the subpulmonary LV and contributing to the LV dilatation C. The case was discussed in the heart team. The PVA to SVA flow over the baffle leak was deemed to have an unloading effect due to the elevated sRV end-diastolic pressure. A closure of the leak was therefore expected to increase the sRV pressures and potentially aggravate systolic sRV dysfunction. Combined with the lack of cyanosis, closure of the baffle leak at this point was therefore deferred, and it was decided to first attempt to optimize the systolic sRV function. Given the pacing-induced sRV dyssynchrony observed under chronic subpulmonary LV pacing, the patient was considered to be a good candidate for epicardial sRV lead placement and cardiac resynchronization therapy. In this case series, we describe the clinical considerations and contemporary management strategies for baffle leaks in adult patients with TGA late after the atrial switch procedure. The first two cases suffered from progressive sRV failure and exercise-associated cyanosis due to SVA to PVA shunting upon exertion. The baffle leaks were successfully closed through catheter intervention, eliminating the exercise-associated hypoxemia. The third patient had progressive sRV failure without significant cyanosis, yet with a PVA to SVA shunt that resulted in a volume overload of the subpulmonary LV, while “unloading” the failing sRV. The baffle leak closure was deferred, and the initial management strategy focused on optimizing the sRV function. These three cases illustrate the considerations made and challenges faced when choosing the optimal management strategy for an individual patient with a baffle leak. Baffle leaks are a common complication late after the atrial switch procedure, and they are present in up to 50% of non-selected and asymptomatic patients . As a siThe ESC and American Heart Association (AHA) ACHD guidelines state that baffle leaks can be best diagnosed routinely with (contrast) echocardiography. Transesophageal echocardiography, cardiopulmonary exercise test, and/or cardiac MRI have an additive role in the diagnosis and evaluation of baffle leaks ,8. In a In the first two cases, a clinical suspicion of a baffle leak was present prior to diagnosis. Self-registered desaturation, objectified using an in-hospital bicycle exercise ergometry (exercise-associated cyanosis), played an important role in identifying the hemodynamic consequences of a baffle defect in a group of patients with a high a priori risk. Agitated saline contrast echocardiography and/or CT were used to confirm the diagnosis in our patients. While generally considered a safe procedure, patient B suffered from a transient ischemic attack directly after contrast echocardiography due to cerebral embolization of air bubble contrast. Transient visual disturbances have previously been described after agitated saline contrast echocardiography for baffle leak diagnosis . Cardiac MRI can provide more reliable and robust quantification of the interatrial shunt magnitude than echocardiography, although small shunts can easily be missed ,9. NeverAlthough, to the best of our knowledge, no data has been published on exercise catheterization of TGA patients with baffle defects, exercise hemodynamics have been described as being of incremental value in understanding functional limitations in patients with a Fontan circulation . Right hPatients A and C underwent the atrial switch procedure according to Mustard, and patient B according to Senning. A trend towards fewer baffle leaks after the Mustard compared with the Senning procedure has previously been described . As baffThe current AHA ACHD guidelines are less explicit in giving direct recommendations for the management of baffle leaks than the ESC guidelines ,8. JudgiThe decision was made to manage the baffle leak conservatively in this patient, as we expected closure to lead to further elevation of sRV end-diastolic pressures and aggravation of sRV dysfunction. A potentially positive effect of a baffle leak with “ASD-like physiology” has been described in the literature. By placing a volume load on the subpulmonary LV through the PVA to SVA shunt, the interventricular septum is splinted and might support the sRV function in a manner similar to retraining the LV with a pulmonary artery band or in cases with left ventricular outflow tract obstruction/pulmonary stenosis . NeverthThe ESC guidelines also suggest covered stents as an option for percutaneous baffle leak closure . The useWhile historically baffle complications were managed surgically, perioperative mortality for surgical baffle revision after the atrial switch procedure has been reported in up to 36% of cases . PercutaBaffle leaks are present in up to 50% of non-selected patients late after the atrial switch procedure, and while they initially may not cause clear symptoms, their existence can complicate the hemodynamic course and influence the prognosis in this complex patient group. Inherent to the nature of this case series, no conclusions can be drawn to advise specific treatment strategies for patients with a baffle leak. Nonetheless, this case series demonstrates the clinical considerations in an individual, patient-tailored approach when assessing baffle leak hemodynamics in the context of sRV failure. It illustrates the feasibility of a catheter interventional management strategy using septal occluder devices for successfully alleviating exercise-associated cyanosis. Moreover, it highlights the complexity of choosing a treatment strategy in “relatively” asymptomatic patients with signs of ventricular volume overload due to PVA to SVA shunting. Although intervention should be considered in these patients, this may not always be the best option. A clear evidence-based approach is currently missing to make these challenging treatment decisions. Future research should focus on defining more robust criteria for baffle leak closure and the optimal timing window, especially for seemingly asymptomatic patients.


Liver cirrhosis disrupts liver function and tissue perfusion, detectable by magnetic resonance imaging (MRI). Assessing liver function at the voxel level with 13‐b value intravoxel incoherent motion diffusion‐weighted imaging (IVIM‐DWI) could aid in radiation therapy liver‐sparing treatment for patients with early impairment. This study aimed to evaluate the feasibility of IVIM‐DWI for liver function assessment and correlate it with other multiparametric (mp) MRI methods at the voxel level.U test was employed to compare IVIM‐DWI parameters  between the healthy volunteer and patient groups. Furthermore, in the patient group, statistical correlations were assessed at a voxel level between LTR‐DCE MRI‐derived HEF, T1 post‐Gadoxetate administration, ΔT1%, and various IVIM parameters using Pearson correlation.This study investigates the variability of apparent diffusion coefficient (ADC) derived from 13‐b value IVIM‐DWI and B1‐corrected dual flip angle (DFA) T1 mapping. Experiments were conducted in‐vitro with QIBA and NIST phantoms and in 10 healthy volunteers for IVIM‐DWI. Additionally, 12 patients underwent an mp‐MRI examination. The imaging protocol included a 13‐b value IVIM‐DWI sequence for generating IVIM parametric maps. B1‐corrected DFA T1 pulse sequence was used for generating T1 maps, and Gadoxatate low temporal resolution dynamic contrast‐enhanced (LTR‐DCE) MRI was used for generating the Hepatic extraction fraction (HEF) map. The Mann‐Whitney pF and fastD were able to distinguish between healthy liver function and mild liver function impairment at the global level, with p = 0.002 for pF and p < 0.001 for fastD. Within the patient group, these parameters also exhibited a moderate correlation with HEF at the voxel level.For‐vitro measurements, the maximum coefficient of variation of the ADC and T1 parameters was 12.4% and 16.1%, respectively. The results also showed that fastD and pF for detecting liver function impairment at both global and pixel levels.Overall, the study highlighted the potential of  The progression of the disease is typically characterized by continuously increasing hepatic fibrosis, distortion of liver tissue architecture, loss of hepatocyte density, and regenerative nodule formation.Magnetic resonance imaging (MRI) is a non‐invasive imaging technique for chronic liver disease with the potential for both global and voxel‐level quantification of liver function. Gadoxetate dynamic contrast‐enhanced (DCE) MRI and T1 mapping have both been investigated to determine relative hepatocyte function globally and spatially with promising results.IVIM‐DWI has recently gained attention in liver function assessment. This imaging technique was initially described by Denis Le Bihan and colleagues in 1986.slowD) and pseudo diffusion (fastD) parameters derived from the IVIM‐DWI dataset were significantly decreased at two weeks and four weeks following carbon tetrachloride‐induced liver fibrosis, compared with that before the insult.pF) as an imaging biomarker in diagnosing liver fibrosis associated with a progressive increase in connective tissue.pF parameter derived from IVIM‐DWI data acquired with ten b‐values to characterize inflammation in chronic liver disease, and showed a strong correlation between pF and inflammation of the liver as measured by univariate analysis .Several studies have described the potential use of IVIM‐DWI in investigating global liver function and diseases. Chow et al. (2012) examined the contribution of molecular water diffusion and blood microcirculation in detecting apparent diffusion changes in early liver fibrosis in an animal model. They reported that the true diffusion Dslow and pseuAlthough there have been some investigations of the potential clinical use of IVIM in the assessment of liver function, the IVIM‐DWI map derived from the standard IVIM model using a least‐squares (LSQ) fit model at the pixel or voxel level results in very noisy estimates, particularly for the pseudo‐diffusion parameters which limits the applicability of the approach for assessing liver spatial features and heterogeneity.Therefore, this study aims to assess the feasibility of 13‐b value IVIM‐DWI maps derived from the Bayesian model to evaluate liver function in early liver function impairment patients with HCC who receiving liver radiotherapy. Firstly, the reliability of ADC and T1 value measurements in phantom and in‐vivo are assessed. Discrimination of global level liver function in healthy and early liver function impairment patients was then investigated. Then, a correlation between IVIM‐DWI, HEF, and T1 mapping at a voxel level was investigated to determine the relationship between IVIM‐DWI and the more common DCE technique for determining spatial liver function.22.1This study was ethically and scientifically reviewed and approved by the Hunter New England Human Research Ethics Committee, NSW, Australia. Twelve patients  were prospectively enrolled in the study with informed consent. All patients were diagnosed with HCC with Childs‐Pugh A (CP‐A) disease and received liver MRI simulation scans as a part of their routine clinical workflow for liver stereotactic body radiotherapy (SBRT) treatment planning. This included routine clinical DCE‐MRI scanning performed for tumor delineation. Informed consent was collected from all patients before participating. The inclusion criteria included age over 18 years old, HCC with underlying chronic liver disease, and eligibility for MRI scanning.A group of healthy volunteers was also recruited to participate in the same liver research project. They were included to ensure repeatability and to enable a comparison of IVIM‐DWI with the patient group. Inclusion criteria were age over 18 years and no clinical history of liver disease. Ten volunteers were recruited with a mean age of the volunteers of 32.4 ± 2.6 years. Volunteer scanning was conducted in accordance with ethical guidelines and with the explicit informed consent of participants. DCE‐MRI scanning with Gadoxetate administration was not performed for the healthy volunteers.2.2The liver mp‐MRI examination was undertaken on a 3T Skyra  MRI scanner with Syngo D13 software at the Radiation Oncology Department, Calvary Mater Newcastle hospital. Each patient was positioned head‐first supine on a top‐flat couch with raised arms using a T‐board as per the department's standard liver MRI simulation method. The Siemens 18‐channel body matrix phased‐array coil was positioned over the liver region. The body matrix coil was combined with the posterior spine coil to receive MRI signals.The examination protocol began with a 13‐b value IVIM‐DWI pulse sequence. Due to the sensitivity of the echo‐planar imaging (EPI) pulse sequence to magnetic field inhomogeneity, external magnetic field shimming was enabled for the liver region before IVIM‐DWI scanning. The 13‐b value IVIM‐DWI image data was then acquired with a free‐breathing approach in the axial plane.1‐field inhomogeneity can cause image contrast variation and affect the measurement of T1 values. Therefore, the inbuilt B1‐field inhomogeneity correction sequence (turbo fast low angle shot T1‐weighted) provided by the vendor was utilized to acquire a correction map for the liver volume prior to the above images.Next, axial 3D dual flip angle (DFA) T1‐weighted imaging was then obtained before contrast injection with a single breath‐hold utilized for each volume acquisition. B1‐corrected T1 mapping acquisition to be used as a baseline liver volume image prior to contrast injection. This was followed by LTR‐DCE MRI image data, acquired during multiple breath‐holds using an axial 3D SPGR T1‐weighted Dixon pulse sequence. The LTR‐DCE MRI method was described in our previous study.Then, a non‐contrast axial 3D Dixon spoiled gradient recalled (SPGR) T1‐weighted pulse sequence was acquired after the completion of the pre‐contrast BFinally, post‐Gadoxetate administration DFA T1 mapping and hepatobiliary phase images were obtained at 900 s and 1200 s after injection, respectively. We acknowledge the consensus clinical protocol for gadoxetate DCE‐MRI in hepatocellular carcinomas, which recommends scanning the hepatobiliary phase (HBP) at 20 min after injection. This timing allows for the peak accumulation of gadoxetate in hepatocyte cells before a significant decrease occurs due to liver excretion processes. In accordance with this protocol, we performed T1 mapping for 900 s and conducted LTR DCE‐MRI, which lasted until 1200 s after injection.The IVIM‐DWI data were obtained from ten healthy volunteers, who underwent imaging protocols and techniques identical to those used in patients, as previously described.2.3http://www.slicer.org) using manual liver contour delineation and imported into Matlab for liver volume segmentation. The matrix size of each axial slice of the IVIM‐DWI dataset was down‐sampled from 340 × 218 to 128 × 128. Then, the Bayesian model was fit to each voxel independently to reduce computation time using Equation  using a MATLAB script developed by Oscar Jalnefjord.nS is the signal intensity of the diffusion image measured at b‐value n, S0b is the IVIM signal of non‐diffusion weighting (0b), pF is the perfusion fraction influenced by pseudo‐diffusionfast, D is the pseudo‐diffusion rate constant or blood perfusion‐driven diffusion, slowD is water molecule diffusion, and nξ is an error term based on Gaussian with variance (2yσ)The IVIM‐DWI datasets were imported into Matlab Version 2019b  to perform image post‐processing and generate IVIM‐DWI parametric maps. A median filter with a region size of 3 × 3 pixels was applied to each slice of the IVIM‐DWI dataset to reduce image noise. A binary image volume of the liver was created in 3D slicer software  and 15‐min post Gadoxetate administration (denoted as T1post), allowing for calculation of the differences in T1 relaxation time at a voxel level represented by delta T1 (ΔT1). The maximum percentage of T1 changes indicates healthy liver tissue due to shortening T1 relaxation induced by accumulated Gadoxetate in hepatocytes. The percent change of T1 can be calculated using the following Equation  T1 mapping is a method used in MRI to quantify liver function by measuring the T1 relaxation time of liver tissue. T1 relaxation time is a measure of the time it takes for hydrogen nuclei to return to their equilibrium state after being excited by a magnetic pulse. By using two different flip angles (three and 15 degrees) during the MRI acquisition, T1 mapping can produce a map of the T1 values across the liver tissue, which can provide information on liver function. In this study, voxelwise DFA T1 maps were generated in‐line on the MRI workstation with the Syngo platform  using non‐linear least‐square curve fitting. DFA T1 maps were obtained for both pre  maps were generated from the LTR‐DCE MRI image data using the voxelwise truncated singular value decomposition‐deconvolution analysis (TSVD‐DA) method similar to that described by Nilsson et al.2.52.5.1The variability of two acquisition protocols, 13‐b value IVIM‐DWI and B1‐corrected DFA T1 mapping, was assessed using the QIBA diffusion phantom (standard model 128) and NIST/ISMRM system phantom. To obtain diffusion images, the QIBA diffusion phantom was imaged three times consecutively over four sessions, resulting in a total of 12 phantom image datasets. For the DFA T1 variability measurement, the NIST phantom was imaged in two sessions. The apparent diffusion coefficient (ADC) values and T1 values across all tubes and datasets were measured using an ROI approach. The average ADC value and T1 values were compared to the reference value and the percentage difference (%ΔADC and %ΔT1), calculated across all tubes. Both intra‐ and inter‐session coefficient of variations (intra‐session CV and inter‐session CV) were measured. Further details can be found in Supplementary material 2.2.5.2slowD, fastD, and pF maps were generated for the entire liver volume, and the average and SD of all parameters were computed for within‐subject coefficient of variation (WCV) analysis.The scan‐rescan repeatability of identical 13‐b value IVIM acquisition protocol in the ten healthy liver volunteers was assessed. Two MRI scan sessions were performed, with an average interval of 37.6 days  without fasting. 2.6slowD, fastD, and pF values were averaged from all voxels within the segmented liver volume and compared between the two groups. In addition, all subjects were classified as healthy = 0 or disease = 1 to assess the diagnostic performance of the IVIM‐derived parameters in discriminating liver dysfunction from a healthy liver.IVIM‐derived parameters were compared between the healthy volunteer group and the HCC patient group with CP‐A level disease. Global pre, T1post, slowD, fastD, and pF maps to extract parametric values. T1pre and T1post values were used to calculate the percentage of T1 decrease (∆T1%). Voxel values of HEF, T1post, ∆T1%, slowD, fastD, and pF were utilized to evaluate voxel wise correlation through linear correlation for individuals within the patient group.To examine the relationship between the parameter values at a voxel level from the different MRI techniques, rigid image co‐registration across HEF maps, T1 maps, and IVIM parametric maps was performed using 3D slicer software before exporting to MATLAB for quantification. Then, a single 2D ROI  was manually drawn over segment VIII of the liver HEF map on one slice that exhibited a high level of registration agreement to create a binary mask image before applying it to the T12.7slowD, pF, and fastD between the mild liver function impairment patient and healthy volunteer groups. Furthermore, a receiver operating characteristic or ROC curve was used to assess the diagnostic performance of the slowD, pF, fastD parameters in discrimination of patient and healthy volunteer groups. The area under the ROC curve was reported as a diagnostic performance index. Internal validation was performed using Bootstrapping . A p‐value less than 0.05 was considered statistically significant in all tests.SPSS Statistics Version 27.0 was used to analyze the patient data. IVIM‐DWI values were expressed in mean, median, max, min, and SD. The nonparametric Mann‐Whitney test was used to compare the global p < 0.001). However, as the sample size was larger than 100 voxels, the violation of the normality assumption would not be expected to cause significant issues.r, is between +1 and −1. When r = 0, it suggests that there is no connection between the two variables. If r is greater than 0, it indicates a positive association, meaning that as one variable increases, so does the other variable. On the other hand, if r is less than 0, it suggests a negative association, which means that as one variable increases, the other variable decreases. a correlation coefficient of r between 0.1 and 0.3 (or −0.1 to −0.3) suggests a small strength of association, whereas a coefficient between 0.3 and 0.5 (or −0.3 to −0.5) implies a medium strength of association. A coefficient between 0.5 and 1.0 (or −0.5 to −1.0) indicates a large strength of association. The larger the absolute value of the correlation coefficient (r), the stronger the relationship between the two variables. The Fisher Z transformation was employed to calculate the average correlation coefficient (r) across patients, which involved transforming the r‐value to Fisher's Z value and then calculating an averaged r.SPSS software (IBM® SPSS® Statistics 27) was utilized to test normality using the Kolmogorov–Smirnov test. The data were non‐normally distributed , 10.4% (1.9%–25.2%), and 8.6% (2.6%–13.5%) for ly Table 3.2slowD, pF, and fastD parameters in healthy volunteers were 1.02 ± 0.15 × 10−3 mm2/s, 29.2% ± 5.1%, and 73.5 ± 25.5 × 10−3 mm2/s, respectively. In comparison, the values in the patient group with mild liver function impairment were 0.96 ± 0.13 × 10−3 mm2/s, 21.6 ± 4.0%, and 36.4 ± 14.2 × 10−3 mm2/s respectively. A significant difference in the pF and fastD parameters between the two groups was observed . In contrast, there was no significant difference between the two groups for the slowD parameter.The quantitative results are given in Table slowD (a), pF (b), and fastD (c) between the two groups. The blue boxplot shows the healthy volunteer results, and the green is the patient group. The results show that the parameters significantly decreased (p < 0.05) in the liver mild function impairment patients except for slowD (p = 0.075) which did not meet statistical significance.Figure 3.3slowD, pF, and fastD. The area under the ROC curve for pF and fastD is higher than that for slowD, indicating that they are better parameters for discriminating global liver function.Figure pF, and fastD for discriminating the healthy liver from the CP‐A liver were found to be 25.3%  and 58.5 × 10−3 mm2/s , respectively.The optimal cutoff values for slowD, fastD, and pF maps of a healthy volunteer and a patient.Figure 3.4r‐values with 95% CI between HEF, slowD, fastD, pF, T1post, and ∆T1% for the 12 patients. For the HEF parameter, the r‐value between HEF and other parameters varied across patients, from low to moderate positive and negative correlations.The average dice similarity score between binary masks of all parametric maps, which estimates the quality of the image registration index, was 0.85 ± 0.02. Table slowD and T1post parameters with the average correlation coefficients for the patients being . However, no significant correlation was found in a patient (P9) for HEF and slowD and three patients  for HEF and T1post . In contrast, HEF had a moderate positive correlation with fastD , pF , and ∆T1% . No significant correlation was found in a patient (P6) for HEF and fastD.HEF had a moderate negative correlation with slowD exhibited a weak positive correlation with T1post , however, no significant correlation was found in a patient (P9). In addition, slowD had a moderate negative correlation with ∆T1 . All patients showed a significant correlation between slowD and ∆T1.fastD was correlated with pF , but it had a weak correlation with T1post and ∆T1% , respectively. No significant correlation was found in one patient (P2) for fastD and ∆T1%.pF had weak relationships with T1post and ∆T1% , respectively. No significant correlation was found in P10 for pF and T1post and in P2 for pF and ∆T1%. Figure p‐values table are provided in the Supplementary material 2 (Table  2 Table .slowD (d), fastD (e), and pF (f), as well as B1‐corrected T1 maps, including T1pre (g) and T1post (h), in an HCC patient with CP‐A disease. The asterisk indicates the tumor region.Figure 4post, and ∆T1% parametric maps are contrast‐based functional parameters and were used to determine relative hepatocyte function. On the other hand, IVIM‐DWI derived slowD, fastD, and pF are non‐contrast based functional parameters. Therefore, they were used here to estimate liver tissue diffusivity (slowD) and liver tissue blood perfusion (fastD and pF).This paper deployed multiparametric MRI for liver function quantification for multiple liver tissue features, including tissue diffusivity, liver tissue blood perfusion, and hepatocellular function. DCE‐MRI–derived HEF, T1The 13‐b value IVIM‐DWI and B1 corrected DFA T1 mapping acquisition protocols were assessed for accuracy and repeatability using phantom testing. For IVIM‐DWI, the agreement to reference values and repeatability of the ADC value was assessed. The 50% PVP concentration in the diffusion phantom showed a greater difference to the reference value than the other concentrations. This was possible due to the high PVP concentration tube containing air pockets that can cause outlier ADC values in a high PVP concentration phantom as described by Wagner et al. (2017).2 concentration. The increased T1 variation with the increased NiCl2 concentration is probably due to increased magnetic susceptibility in higher NiCl2 concentrations.For the T1 mapping the measured T1 difference to reference values was a maximum of 13.6%. This problem can potentially be ameliorated by using the difference in T1 values pre‐ and post‐ Gadoxetate injection (∆T1%). However, this is still affected by intra‐session repeatability which was in general low but for some concentrations was of a similar magnitude to above. For the repeatability measurements, both intra‐ and inter‐session variability increased with increasing NiCI2 concentrations. Additionally, a recent study by Keenan et al.’s study (2021)2 concentration tubes.Keenan et al. (2016)slowD parameter had the lowest variability followed by pF. In comparison, the fastD parameter had a higher variability with an average wCV of 10.4% and a range of 1.9%–25.2%. The largest uncertainty in IVIM is attributed to fitting error resulting in higher variability in the fastD parameter.fastD in this investigation was lower than that reported by Cieszanowski et al.,For in‐vivo repeatability testing of the 13‐b value IVIM‐DWI acquisition protocol on ten healthy volunteers, the fastD parameter could distinguish between healthy volunteers and mild liver function impairment patients. Global fastD and pF were significantly lower in patients compared to the healthy liver function group, although only mild liver function impairment patients were recruited. slowD tended to be lower in patients compared with the healthy volunteers, but no significant difference was found in this study owing to small sample size. The decrease of pF and fastD in the cirrhotic patients in this study is consistent with a previous study by Lefebvre and colleagues, reporting a negative correlation between pF and increased liver dysfunction grade .pF and fastD had a high diagnostic performance in the discrimination of healthy and mild liver function impairment when assessed with ROC analysis.Despite higher variability than the other parameters, the global fastD and pF) and hepatocyte function‐associated parameters (∆T1%) in almost all patients, however, the correlations were not strong. A relationship between HEF and the ∆T1% value was also seen in a study by Haimerl et al., who reported that ∆T1% in normal liver function was significantly higher than that in cirrhotic patients at a global level.pF, fastD, and ∆T1% than voxels with reduced liver function.Besides global liver function analysis, this study also investigated the feasibility of voxel wise analysis of IVIM maps derived from the Bayesian model. Using this method, noise can be reduced to improve voxel‐based comparison. The results from voxel‐based analysis illustrated that HEF was significantly correlated with liver tissue perfusion‐related parameters Dfast and Fp slowD parameter associated with tissue diffusivity in most patients; however, some patients exhibited positive correlations. This might be caused by uncertainties in image registration. Additionally, the observed weak and heterogeneous correlation between HEF and slowD values could also stem from subtle alterations in tissue architecture within this patient cohort. The slowD parameter was not found to clearly distinguish liver dysfunction in this study where normal volunteers were compared to CP‐A dysfunction patients. A study by Koinuma et al. reported a negative relationship between ADC value and grade of liver function impairment. Wang et al. (2018) also reported that liver tissue stiffness due to fibrosis positively correlated with CP class.HEF was negatively correlated with the post parameter. HEF values decrease for cirrhotic patients, whereas higher T1 values would be expected due to lower Gadoxetate uptake. The T1 value of normal hepatocyte function voxels decrease 15‐min post‐Gadoxetate administration due to Gadoxetate‐induced shortening of the T1 relaxation time.fastD and pF are related to liver tissue perfusion, fastD was positively correlated with the pF parameter, as would be expected.HEF was also negatively correlated with the T1slowD parameter in distinguishing between normal and cirrhotic liver. Thirdly, the study did not validate IVIM‐DWI with different grades of liver dysfunction as all patients were diagnosed with the same liver dysfunction grade of CP‐A disease. However, the results showed the capability of global fastD and pF parameters in discriminating the early stages of liver dysfunction from healthy function.There are several limitations to this study. First, in‐vivo repeatability of T1 values was not investigated in this study, and this study was not able to acquire mp‐MRI data in the normal volunteers due to the Gadoxetate administration required for DCE‐MRI and T1 mapping. Thus, only the IVIM‐DWI data were acquired in healthy volunteers and compared with the patient group. Secondly, the number of patients was small, mainly due to the COVID‐19 pandemic, resulting in limited patient recruitment. This could reflect the low diagnostic performance of the Another limitation is that the IVIM‐DWI scans were acquired with free breathing while the LTR DCE‐MRI was acquired in breath‐hold. This is necessary due to the long imaging time of the sequence. This, combined with the poor anatomical visualization for the DWI imaging technique results in image registration uncertainties when registering to the DCE‐MRI scans. Furthermore, interpolating voxel sizes to match the reference HEF map, particularly in the slice direction could potentially misalign IVIM map voxels with the reference voxels. To minimize registration uncertainty, only a single slice of the registered data was used for the parameter comparisons. Moreover, motion of the patient during the IVIM‐DWI scan can also reduce the image quality. This will affect the voxel wise comparison results and may explain the lack of strong correlations. Therefore, an IVIM‐DWI acquisition protocol incorporating a novel motion‐insensitive technique would be suggested to improve image quality for further study. This will also be beneficial for clinical implementation of this imaging technique if combined with DCE‐MRI to determine spatial liver function.5pF and fastD parameters could distinguish healthy liver function and mild liver function impairment at the global level and showed correlation with the Gadoxetate LTR‐DCE MRI‐based HEF parameter at the voxel level within the patient group despite the small number of patients and differences in patient motion and position. The results from this study suggest that the addition of the IVIM‐DWI acquisition and fastD and pF parameters could potentially be useful in assessing liver tissue perfusion however greater patient numbers are required, and methods to consolidate patient positioning. Furthermore, results from this work also found a positive relationship between ∆T1% and HEF parameters, which are associated with hepatocyte function at the voxel level. However, further study is required to determine whether T1 mapping would improve liver function quantification or could be an alternative method.This pilot study investigated the feasibility of 13‐b value IVIM‐DWI and B1‐corrected dual flip angle T1 mapping acquisition protocols in quantifying liver function. The IVIM‐derived Peter Greer, Saadallah Ramadan, and John Simpson supervised the work and contributed to the guarantors of integrity of entire study, study concepts/study design, approval of final version of submitted manuscript, and manuscript drafting or manuscript revision for important intellectual content. Monchai Phonlakrai performed literature research, the experiments, and data/statistical analysis. Kate Skehan performed data acquisition and manuscript drafting and manuscript revision for important intellectual content. Jonathan Goodwin, Yuvnik Trada, Jarad Martin, Swetha Sridharan, Lay Theng Gan, and Sabbir Hossain Siddique contributed to the manuscript drafting and manuscript revision for important intellectual content. All authors provided critical feedback and helped shape the research, analysis, and manuscript.The authors declare no conflicts of interest.Supporting InformationClick here for additional data file.Supporting InformationClick here for additional data file.Supporting InformationClick here for additional data file.


Regional nodal irradiation (RNI) for breast cancer yields improvements in disease outcomes, yet comprehensive target coverage often increases cardiac radiation (RT) dose. Volumetric modulated arc therapy (VMAT) may mitigate high-dose cardiac exposure, although often increases the volume of low-dose exposure. The cardiac implications of this dosimetric configuration  remains uncertain.Eligible patients receiving adjuvant RNI using VMAT for locoregional breast cancer were prospectively enrolled on an IRB-approved study. Echocardiograms were performed prior to RT, at the conclusion of RT, and 6-months following RT. Echocardiographic parameters were measured by a single reader (AY) and measures were compared pre- and post-RT via the Wilcoxon rank sum test. Changes in echocardiographic parameters over time were compared to mean and max heart doses via the Spearman correlation test.Among 19 evaluable patients (median age 38), 89% (n=17) received doxorubicin and 37% (n=7) received trastuzumab/pertuzumab combination therapy. All patients received VMAT-based whole-breast/chest-wall and regional nodal irradiation. Average mean heart dose was 456cGy (range 187–697cGy) and average max heart dose was 3001cGy (1560–4793cGy). Among salient echocardiographic parameters, no significant decrement in cardiac function was observed when comparing pre-RT to 6-months post-RT: mean left ventricular ejection fraction (LVEF) was 61.8 (SD 4.4) pre-RT and 62.7 (SD 3.8) 6-months post-RT (p=0.493); mean global longitudinal strain (GLS) was −19.3 (SD 2.2) pre-RT and −19.6 (SD 1.8) 6-months post-RT (p=0.627). No individual patient exhibited reduced LVEF or sustained decrement in GLS. No correlations were observed for changes in LVEF or GLS when compared to mean or maximum heart doses .VMAT for left-sided RNI yielded no significant early decrement in echocardiographic parameters of cardiac function, including LVEF and GLS. No patient exhibited significant LVEF changes, and none exhibited sustained decrements in GLS. VMAT may be a reasonable approach to cardiac avoidance in patients requiring RNI, including those receiving anthracyclines and HER2-directed therapy. Larger cohorts with longer follow-up will be needed to validate these findings. Moreover, whereas the traditional understanding of RT-associated cardiotoxicity assumed a long latency period for the manifestation of cardiac events via accelerated fibrotic changes, recent studies suggest that early cardiotoxicity can be observed3.Over 3 million cancer survivors in the United States have undergone treatment comprising some measure of cardiac radiotherapy (RT) exposure. Several series have demonstrated that chest/breast radiotherapy may result in increased cardiovascular (CV) morbidity, including cardiomyopathy, coronary disease, and valvular dysfunction9. Moreover, with the implementation of advanced RT delivery technologies , improvements in cardiac dose reduction remain of hypothetical benefit with limited clinical indications of long-term superiority10. Further elucidation of RT-associated CV toxicity is of particular importance given a series of landmark studies that prompted increased utilization of regional nodal irradiation (RNI)12. This comprehensive breast RT approach typically yields elevated cardiac exposure due to proximity of the internal mammary nodal (IMN) target to the heart.Many epidemiologic analyses that associate RT with CV toxicity are based on outdated RT delivery techniques  and systemic therapies. The applicability of these findings to current RT approaches and systemic agents remains unknown, and uncertainty persists regarding the mechanisms and predictors of cardiotoxicity15, yet the cardiac implications of this technique are unknown. Indeed, while VMAT improves the conformality of high-dose RT regions, it necessarily exposes more non-target tissue to low-doses of radiation. This typically reduces the maximum heart dose as intended, while simultaneously increasing the mean heart dose (MHD) with, as yet, indeterminate consequences.Volumetric modulated arc therapy (VMAT) is one of several approaches designed to reduce cardiac exposure from RNI (and thereby mitigate putative CV risk)16 Myocardial strain parameters such as global longitudinal strain (GLS) are more sensitive compared with left ventricular ejection fraction (LVEF) for detecting early stages of cardiotoxicity related to radiotherapy and have established prognostic value in multiple treatment settings.19 Myocardial work indices are novel echocardiography-based measures that have been proposed to provide complementary assessment of cardiac function over GLS, however the value of MW indices to detect the cardiotoxic effects of radiotherapy is unknown.Echocardiography is a primary modality for assessing structural and functional changes secondary to the cardiotoxic effects of RT. Myocardial strain imaging using speckle-tracking echocardiography is an established tool for quantitative measurement of cardiac contractile function.Thus, we undertook a prospective single-arm cohort study to quantify the longitudinal change in myocardial strain and myocardial work indices among breast cancer patients receiving RNI via VMAT. Imaging was conducted pre-RT, at the end of RT, and 6-months following RT, to assess for putative subclinical changes in cardiac function arising from treatment.This was a single-arm prospective cohort study designed to evaluate changes in myocardial function based on 2D echocardiographic indices among breast cancer patients receiving left-sided RNI using VMAT. Patients with invasive locoregional breast cancer (i.e. non-metastatic) were prospectively screened and approached for participation on this IRB-approved study by the treating physician(s). Eligible and consenting patients were enrolled at the time of treatment consent for adjuvant RNI using VMAT . Thereafter, echocardiograms were performed at three timepoints: prior to RT , at the conclusion of RT , and 6-months following RT. All study patients provided fully-informed written consent prior to participation. This study protocol was approved by the Memorial Sloan Kettering Cancer Center institutional review board and was compliant with the Health Insurance Portability and Accountability Act.20 During the standard 2D echocardiogram, apical 2-, 3-, and 4- chamber views and short-axis views at the midpapillary level were acquired at a frame rate of 40–80 frames per second. Speckle tracking strain analysis was performed offline to calculate peak systolic global longitudinal (GLS), circumferential (GCS) and radial (GRS) strain  as previously described.21 All strain analysis was performed by a board-certified cardiologist (A.Y.), independent of the clinical interpretation of the 2D echocardiogram. Strain analysis was conducted in a manner blinded to patient radiotherapy plan or dosimetry.2D and Doppler echocardiography was performed using a Vivid E9 ultrasound scanner  at the following timepoints: pre-RT, post-RT, and 6 months post-RT. LVEF was calculated from the apical 4- and 2-chamber views using a modified Simpson biplane method according to the American Society of Echocardiography guidelines.22 The peak systolic LV pressure was estimated based upon brachial systolic blood pressure measurement. Timing of mitral and aortic valve opening and closure, measured by pulse-wave Doppler and confirmed by 2D assessment in the apical long axis view, were used to define isovolumic and systolic ejection periods. The software then used the peak systolic LV pressure, valvular timing events, and GLS measurements to automatically generate left ventricular pressure strain loops. The following indices were then calculated: 1) global work index (GWI), which represents the total area of the pressure strain loop from mitral valve closure to opening; 2) global constructive work (GCW), which represents myocardial work during systolic shortening and negative work (i.e. work performed by the blood on the ventricle) during lengthening in isovolumic relaxation; 3) global wasted work (GWW), which represents negative work during lengthening in systole and myocardial work during shortening in isovolumic relaxation; and 4) global work efficiency (GWE), which is calculated as GCW divided by the sum of GCW and GWW.Myocardial work indices were measured with commercially available software (GE Echopac), as previously described.Inter-observer and intra-observer variability for MW indices was assessed in 20 randomly selected studies by the intraclass correlation coefficient (ICC) and standard error of measurement. For inter-observer variability, studies were remeasured by two observers blinded to one another’s findings (A.Y. and J.L.). For intra-observer variability, studies were remeasured by the same observer at different points in time.Continuous measures were summarized as mean and standard deviation, and categorical measures were summarized as frequency and percent. Differences in echocardiographic parameters between timepoints  were explored by analysis of variance for repeated measures. Differences between the pre-RT and post-RT timepoints were further compared using the Wilcoxon rank sum test. The Spearman correlation test was used to assess the effect of mean and max heart doses on changes in echocardiography-based parameters from pre-RT to 6 months post-RT.From 2018 to 2020, 19 patients were enrolled on this prospective study  . Of thesEchocardiographic parameters of cardiac structure and function over time are shown in 23 There were no significant differences in GWI, GCW, GWW, or GWE from pre-RT to 6-months post-RT.Myocardial work indices of the study population over time are shown in We evaluated for associations between cardiac dosimetry and longitudinal changes in echocardiographic parameters of cardiac function during the study period (from pre-RT to 6-months post-RT). There was no correlation between change in LVEF (pre-RT to 6 months post-RT) and mean  or max  heart dose. Similarly, we found no correlation between change in GLS (pre-RT to 6-months post-RT) and mean  or max  heart dose.We then evaluated for associations between cardiac dosimetry and longitudinal changes in myocardial work indices. There was a significant correlation between mean heart dose and decline in GWI from pre-RT to 6 months post-RT , but not max heart dose and GWI . GWI declined from pre-RT to 6 months post-RT for participants in the highest quartile of mean heart dose (1787 mmHg% to 1732 mmHg%) but was stable or increased for participants in the first (1750 mmHg% to 1904 mmHg%), second (1937 mmHg% to 2114 mmHg%), and third (1883 mmHg% to 1880 mmHg%) quartiles. There was no correlation between mean or max heart dose with other myocardial work indices including GCW, GWW, or GWI.Inter- and intra-observer variability for myocardial work indices as measured by ICC and standard error of measurement (SEM) are summarized in In this prospective study of women with breast cancer receiving multimodal treatment including regional nodal irradiation with VMAT, we observed no early reductions in echocardiographic parameters of LV systolic function including LVEF, GLS, or MW indices. The absence of significant changes in echocardiography-based measures of cardiac contractile function early after RNI with VMAT support further investigation of this contemporary RT technique which is being increasingly adopted. In addition, we found no correlation between mean or max cardiac RT dose and longitudinal changes in LVEF or GLS. Finally, we observed an association between mean heart dose and change in global work index from pre-RT to 6months post-RT. The utility of assessing myocardial work  to detect subclinical cardiotoxicity from breast RT may therefore warrant further investigation.7. More recently, as the multidisciplinary management of breast cancer has improved in lockstep with radiotherapeutic technologies, several studies now support the increasing benefit of comprehensive RT for a variety of breast cancer presentations24. Two landmark trials, MA.20 and EORTC 22922, both demonstrated that RNI confers a significant 10-year disease-free survival benefit for those presenting even with a limited axillary disease burden. In parallel, the DBCG-IMN study affirmed the importance of including the internal mammary nodal (IMN) basin as a component of RNI, demonstrating an overall survival benefit when this region was encompassed in the radiotherapeutic target despite the elevated cardiac dose with this approach. Thus, an increasing proportion of breast cancer patients now receive RNI, along with the concomitant elevation in cardiac RT exposure, although without impinging on cardiac outcomes. And while none of these studies demonstrated elevated cardiac mortality with IMN coverage, the balance of literature to date suggests that increasing cardiac dose can only be detrimental to long term outcomes. To that end, the VMAT approach studied here is being increasingly employed for RNI, although as discussed above, lowering of the maximum heart dose as afforded by VMAT often comes at the expense of raising the mean heart dose with unclear implications that require further study.The cardiac implications of adjuvant treatment have been studied intently since the early days of postmastectomy RT. Indeed, owing to the limited precision of RT in prior eras, several reports raised the specter of significant RT-associated CV toxicity25 We further extend these results in the current longitudinal cohort study with inclusion of patients treated with RNI using VMAT. Studies assessing the subclinical cardiotoxicity of RT have previously demonstrated radiation-induced global and segmental changes in myocardial strain and strain rate in patients with breast cancer, however breast radiotherapy in these studies was delivered using tangential photon beams with typical 3D-conformal dosimetry.28 More advanced breast radiotherapy techniques, such as VMAT, intensity modulated radiotherapy (IMRT), and proton therapy are now available and are increasingly used in standard care.Overall, the present findings are consistent with those from our previous study which showed no evidence of early subclinical LV systolic dysfunction after contemporary breast RT in women with HER2 positive breast cancer.30 This study further contributes to the current literature by assessing for changes in myocardial work in the setting of breast radiotherapy. Overall, no significant change in MW indices was observed in our patients throughout the radiotherapy treatment period. However, among participants in the highest quartile of mean heart dose, there was a decline in GWI. These findings possibly suggest that GWI can detect early subclinical changes in myocardial function related to radiotherapy. Further studies are needed to replicate these findings and determine whether GWI provides incremental diagnostic and prognostic value to established echocardiographic parameters.Myocardial work indices, which are measures of left ventricular mechanics that incorporate myocardial deformation with afterload and are less susceptible to fluctuations in blood pressure, have diagnostic and prognostic significance in several cardiovascular conditions including chemotherapy related cardiac dysfunction.These findings must be interpreted in the context of the study design. While our prospective cohort study was of limited size, it nonetheless provides novel data on the potential role of myocardial work for assessment of radiation-induced cardiotoxicity. Whether changes in myocardial work indices are associated with clinical cardiovascular outcomes will require larger studies with longer follow-up. In addition, most patients in this study were treated with anthracyclines and/or HER2-targeted therapies which can cause short- and long-term effects on cardiac function. Therefore, we cannot exclude the potential confounding effects of prior/concurrent breast cancer treatments on echocardiographic changes during radiotherapy. However, the absence of significant changes in LVEF or GLS within 6 months of radiation in the context of other cardiotoxic cancer treatment exposures suggest that radiation with VMAT does not enhance the cardiotoxic effects of other cardiotoxic breast cancer treatments.In conclusion, in this small prospective study, VMAT for patients requiring regional nodal irradiation yielded no observable early decrement in echocardiographic parameters of cardiac function including LVEF and GLS. The cardiac implications of VMAT for patients requiring RNI merit further study, including among those receiving anthracyclines and HER2-directed therapy. Assessment of myocardial work indices such as GWI may be useful to identify subclinical cardiotoxicity in patients receiving among the highest allowable mean heart doses and warrants further consideration. Larger cohorts with longer follow-up will be needed to validate these findings.This study was supported by a grant from the Imaging and Radiation Sciences Program at Memorial Sloan Kettering Cancer Center, the Lois Green Fund, and in part by NIH/NCI Cancer Center Support Grant No. P30CA008748.


Heart failure is one of the main morbidity and mortality factors in the general population and especially in elderly patients. Thus, at the European level, the prevalence of heart failure is 1% in people under 55 years of age but increases to over 10% in people over 70 years of age. The particularities of the elderly patient, which make the management of heart failure difficult, are the presence of comorbidities, frailty, cognitive impairment and polypharmacy. However, elderly patients are under-represented in clinical trials on the diagnosis and treatment of heart failure. The need for complementary methods (biomarkers) for differential and early diagnosis of heart failure is becoming more and more evident, even in its subclinical stages. These methods need to have increased specificity and sensitivity and be widely available. Natriuretic peptides, in particular B-type natriuretic peptide (BNP) and its fraction NTproBNP, have gained an increasingly important role in the screening, diagnosis and treatment of heart failure in recent years. Heart failure is one of the main morbidity and mortality factors in the general population and especially in elderly patients. Thus, at the European level, the prevalence of heart failure is 1% in people under 55 years of age but increases to over 10% in people over 70 years of age [With life expectancy increasing to an average of 73 years, the geriatric population is becoming increasingly representative, leading to an increasing incidence of heart failure. In recent years, in developed countries, heart failure has become a growing public health problem, generating higher costs for the diagnosis, treatment and follow-up of these patients ,3,4,5,6.Advances in medicine, easier access to medical and care services have led to an increase in the elderly population and consequently its share of heart failure cases. More than a quarter of heart failure patients are over 80 years of age, and among decompensated cases requiring emergency hospitalization, about 1 in 7 are over 80 ,11,12,13Age plays an important role in the deterioration of cardiovascular function, thus the risk of cardiovascular disease among the geriatric population is very high. The prevalence of cardiovascular disease increases with age ,16,17,18-To analyze the role of brain natriuretic peptides in the diagnosis of heart failure in the elderly and in the differential diagnosis between cardiac failure and respiratory failure.-To understand the way age and other factors influence BNP/NTproBNP levels in geriatric patients, and how this affects the specificity and sensibility of these biomarkers in identifying heart failure in this category of patients.-To analyze the correlation between natriuretic peptides and myocardial left ventricular dysfunction.This is a systematic review of the most relevant clinical studies and trials conducted in the last 20 years addressing the topic of heart failure in the elderly population. The patients included in these studies were over 65 years old, with a mean age of 75 years, and they were diagnosed with heart failure according to the current guidelines of medical practice. Clinical and imaging data and natriuretic peptides  were obtained for all patients.The majority of these trials were relatively small, retrospective and registry-based trials, including a mean number of 1500 patients per trial, each study reflecting the experience of one medical center see .Several clinical trials such as “Study of the Role of Plasma NTproBNP in the Diagnosis of Heart Failure” by Bahaar Athavale et al., “Use of NTproBNP Testing to Guide Heart Failure Therapy in the Outpatient Setting”, and “Long-Term Results of Intensified, N-Terminal-Pro-B-Type Natriuretic Peptide-Guided Versus Symptom—Guided Treatment in Elderly Patients with Heart Failure-2013” showed that the NTproBNP is a hormone produced by the heart and that it is a strong prognostic factor for adverse events, hospitalization and mortality in heart failure patients ,36,37,38Natriuretic peptides are also a good predictor of short-term mortality in patients with acute decompensated heart failure. Comparing BNP to NTproBNP, the latter has a longer biological half time than BNP, thus being a more stable molecule with fewer fluctuations. These characteristics make NTproBNP a better marker for screening of heart failure ,39,40,41The first clinical trial that investigated the use of brain natriuretic peptide serum levels as a marker of heart failure was conducted by Mark Richards in the Cardio-Endocrine Research Group. In a population of 205 patients, it was demonstrated that NTproBNP is as useful as BNP in the diagnosis of heart failure. At that time, the standard biomarker of heart failure was BNP, but in recent years the N-terminal fragment of BNP (NTproBNP) was recognized as an important indicator of heart failure ,42,43,44Another research study, the PRIDE trial, including 600 patients, showed that NTproBNP was a good marker for the diagnosis of heart failure and also for ruling out heart failure in the emergency department .Recent medical practice guidelines support the use of B-type natriuretic peptide in the diagnosis, prognosis and determination of the severity of heart failure, as well as being useful in guiding treatment ,17,18,41In the latest European Society of Cardiology practice guidelines on heart failure 2021), there is a class I level B evidence indication for the use of BNP/NTproBNP as a diagnostic tool. Plasma levels of natriuretic peptides are recommended as a first-line diagnostic test in patients suspected of heart failure for differential diagnosis. An elevated level of natriuretic peptides supports the diagnosis of heart failure and may also guide the investigation algorithm and prognostication ,40,41,47, there iIn elderly patients, serum BNP levels may be influenced by a variety of factors in addition to heart failure, with clinical studies showing an increase with age in serum BNP values. Because of the higher basal BNP levels in elderly patients, its negative predictive value in detecting heart failure is lower in the geriatric population.In an analysis of the Pianoro study, which included patients over 65 years of age and followed parameters that may correlate with mortality and their biological age, it was found that BNP and in particular the precursor NTproBNP correlates best with mortality ,48,49,50Mortality increased from BNP age values above 69 years and peaked at values above 85 years (from 7.9% to 22.8%). Correlating these values with the chronological age of the patients, mortality increased starting from a difference of at least 11 years between chronological age and BNP age ,50.Several clinical studies have shown the importance of changes in the dynamics of serum natriuretic peptide levels. Thus, a study published in the Journal of the American College of Cardiology in 2010 included about 2900 patients over 75 years of age, measuring baseline BNP levels at the time of inclusion and at 2–3-year intervals. The results of the study showed an increased incidence of heart failure and cardiovascular mortality with increasing NTproBNP values over time. Cardiovascular risk began to increase from serum NTproBNP values of 190 pg/mL. Patients who had an increase of more than 25% in natriuretic peptide values had the highest risk of heart failure and cardiovascular mortality, regardless of baseline natriuretic peptide levels. What this study demonstrates is that serum NTproBNp values are in a continuous dynamic, and this is reflected in cardiovascular risk .In a study led by Passantino and colleagues, published in the Journal of the American Geriatrics Society, a cohort of elderly patients hospitalized for heart failure was analyzed, identifying prognostic factors associated with short- and long-term mortality . This reDespite the positive predictive value of BNP for mortality in elderly patients with heart failure, intensification of treatment in high-risk patients based on increased serum natriuretic peptide values, although resulting in improved symptomatology and quality of life, had no influence on mortality. This is probably also due to the high proportion of non-cardiovascular mortality among elderly patients due to multiple associated pathologies ,40,41,45Several clinical trials have evaluated the efficacy of heart failure therapy guided by serum BNP/NTproBNP values, but without favorable results ,52,53,54In an article published in the European Heart Journal by Richard W. Troughton and co-workers, a meta-analysis of BNP-guided therapy in patients with heart failure was proposed. The data were compared and analyzed according to various criteria, including age, with patients being divided into two age categories: under 75 and over 75. It was found that in patients under 75 years of age, NTproBNP-guided therapy led to a decrease in mortality and hospitalization rates, benefits that were not found in patients over 75 years of age .Its previous meta-analyses also suggested a possible 20–30% reduction in all-cause mortality when using natriuretic peptide-guided heart failure therapy.However, the European Society of Cardiology considered the evidence insufficient for a firm recommendation of BNP-guided therapy in heart failure .In the BED (BNP Usefulness In Elderly Dyspnoeic Patients) study published by Plichart et al. in the European Journal of Heart Failure , 383 eldIn the HFinCH study, led by James Mason et al., published in 2013 , 405 eldThe Breathing Not Properly study , was a mIn a smaller study, on a cohort of 64 patients with a mean age of 84 years, a cut-off value for BNP of <129 ng/L showed a 90% negative predictive value in excluding heart failure .In another study of 201 patients admitted for dyspnea, 45% of whom were over 75 years of age, BNP and NTproBNP values played an important role in discriminating acute heart failure from other conditions. In elderly patients, the cut-off values for BNP were higher than in younger patients, and the specificity of natriuretic peptides decreased with age .In the British Medical Journal in 2018, Kathryn Taylor et al. published a meta-analysis on the diagnostic accuracy of natriuretic peptides for chronic heart failure in ambulatory care. At thresholds >100 pg/mL, BNP had a sensitivity of 0.95 reduced between 0.46 and 0.97 and a specificity between 0.31 and 0.98 at a threshold <100 pg/mL. For NTproBNP, the specificity was 0.99 and the specificity was 0.60 at a threshold >136 pg/mL. There was no significant difference in diagnostic accuracy between BNP and NTproBNP .More recently, in 2021, Nevis et al. published the study Use of B-Type Natriuretic Peptide (BNP) and N-Terminal proBNP (NT-proBNP) as Diagnostic Tests in Adults With Suspected Heart Failure: A Health Technology Assessment, to evaluate the diagnostic accuracy, clinical impact and cost-effectiveness of BNP/NTproBNP testing in heart failure. Natriuretic peptides had a high sensitivity (80–96%) and low likelihood value . In one The mean values for the specificity of BNP/NTproBNP in the diagnosis of heart failure are 80–85% and the mean sensibility is 75% (with NTproBNP being a stronger marker of heart failure), but there was a great variation of cut-off values between these trials ,55,56,57Each study attempted to find cut-off values for BNP/NTproBNP that discriminated the cardiac and respiratory etiology of dyspnea in geriatric patients. At present, there is no general consensus on these cut-off values. Although a high specificity has been achieved at higher BNP values, no cut-off BNP value has been found that presents a sufficient probability for a definite diagnosis of cardiac insufficiency.Factors underlying the reduced specificity of natriuretic peptides in geriatric patients are age, atrial fibrillation, high prevalence of preserved left ventricular systolic function in elderly patients, renal dysfunction, chronic lung disease and other comorbidities.Additionally, in geriatric patients, the diagnosis of heart failure is more difficult because of the multiple comorbidities present, which interfere with the diagnosis. Elderly patients are more likely to be less investigated in emergency departments, mainly because of the severity of symptoms at presentation, so their classification into a particular diagnosis is more difficult.In elderly patients, unlike younger patients, BNP does not yet discriminate between the cardiac or respiratory origin of dyspnea as the main form of heart failure see More clinical trials including geriatric patients are needed to establish the exact role of natriuretic peptides in the diagnosis of heart failure.Elderly patients are under-represented in clinical trials on the diagnosis and treatment of heart failure. These studies underlie the development of treatment guidelines and form the foundation of modern evidence-based medicine. On average, less than 30% of the patients selected in these clinical trials were over 70 years of age. Many of these patients are excluded from clinical trials because of comorbidities.The particularities of the elderly patient, which make the management of heart failure difficult, are the presence of comorbidities, frailty, cognitive impairment and polypharmacy ,50,55,58Approximately 60% of elderly patients with heart failure have at least three comorbidities. Among these comorbidities, the most common are hypertension and heart rhythm disorders, and among non-cardiac conditions these include chronic renal failure, diabetes mellitus and anemia . All theAlthough the benefits of standard therapies in heart failure, as evidenced by subgroup analyses in clinical trials, are present in the elderly population, these drugs have been found to still be underutilized ,14,24,39In addition to drug treatment, heart failure requires invasive interventions on the heart, such as coronary angiography followed by possible coronary revascularization by percutaneous angioplasty or coronary artery bypass grafting, pacemaker implantation, intramyocardial resynchronization devices, intracardiac defibrillator and radiofrequency ablation for heart rhythm disorders. All of these therapies lead to improved quality of life and survival, but the decision to perform them on an individual geriatric patient requires a thorough assessment. This requires multidisciplinary teams of cardiologists, neurologists, geriatricians, psychiatrists, etc. Assessment of comorbidities, frailty, life expectancy, risk/benefit ratio, etc., must be taken into account ,17,18,41The main symptoms of heart failure, such as exercise intolerance and dyspnea, can also be interpreted in the context of older age and the functional disability of geriatric patients, which is why the diagnosis of heart failure may be overlooked.In a study of the distribution of risk factors for the development of heart failure according to age, a higher proportion of known classical risk factors was found in the younger population compared to the elderly. In other words, traditional predictors of heart failure were less common in elderly patients. For example, the presence of smoking as a risk factor was 21% in younger patients versus 13% in older patients and diabetes was present in 14% of younger patients versus 7% of geriatric patients ,33,34.Under these conditions, there is a growing interest in developing effective methods for the diagnosis, screening, prognosis and treatment guidance of heart failure. These methods need to be as specific and sensitive as possible to be clinically relevant.Although the scientific data on the etiology and pathophysiology of heart failure are substantial, the imaging methods used are increasingly more powerful with high sensitivity, and diagnostic criteria are constantly being revised in guidelines for medical practice.The concept of biochemical tests, using various biomarkers such as natriuretic peptides and troponin, is increasingly taking shape in current clinical trials.The diagnosis of heart failure is based on the patient’s clinical history, the physical examination of the patient performed by the doctor and the results of the complementary imaging tests: chest radiography and echocardiography. About 30–50% of patients presenting in emergency departments for decompensated heart failure are misdiagnosed, because of the atypical manifestations, lack of imagery and the clinical signs that are not always obvious . Thus, tDiagnosis of heart failure, especially in elderly patients, is difficult because symptoms such as fatigue and dyspnea on exertion, as well as clinical signs such as swollen jugular veins or tibial edema, are not specific to heart failure, but may be caused by a range of comorbidities. Differential diagnosis between cardiovascular disease and other pathologies is difficult in geriatric patients.Additionally, the clinical symptoms and signs of heart failure often become apparent in the later stages of the disease, so diagnosis is made late and the therapeutic benefits are greatly reduced.As for dyspnea, the most common complaint of patients with heart failure, studies show uncertainty about its etiology. For example, the “Breathing not Properly” study reports diagnostic errors in about half of the cases presented for dyspnea. The difficulty of diagnosing heart failure is even greater in patients presenting for the first time with symptoms of dyspnea. Clinical examination of the patient is often not sufficient in developing an accurate diagnosis, and imaging methods such as chest radiography have neither the necessary sensitivity nor specificity. Echocardiography can detect changes in left ventricular ejection fraction, but for heart failure with preserved ejection fraction, it is not as useful.The need for complementary methods (biomarkers) for differential and early diagnosis of heart failure is becoming more and more evident, even in its subclinical stages. These methods need to have increased specificity and sensitivity and be widely available.Natriuretic peptides, in particular B-type natriuretic peptide (BNP) and its fraction NTproBNP, have gained in recent years an increasingly important role in the screening, diagnosis and treatment of heart failure.The B-type natriuretic peptide is released by myocardial cells in response to increased parietal stress under the conditions of volume or intramyocardial pressure overload that occur in heart failure. BNP has a natriuretic and peripheral vasodilator effect, thus reducing this intramyocardial overload.Geriatric patients show an increased prevalence of heart failure with preserved left ventricular ejection fraction, which makes diagnosis more difficult, especially in the presence of comorbidities and predominant symptoms, such as dyspnea on exertion and reduced functional capacity, which is often attributed to simple ageing. Natriuretic peptides could be useful in the diagnosis of heart failure for this type of patient, but the interpretation of their serum values may be influenced by several factors such as chronic kidney disease, sepsis, hyperthyroidism, chronic anemia, atrial fibrillation and others. All these comorbidities, very common in elderly patients, modifying basal natriuretic peptide values independently of the presence of heart failure lead to the need to establish different cut-off values of these biomarkers in geriatric patients. Age and chronic kidney disease appear to be the major determinants of serum BNP/NTproBNP values. It was also found that even patients without a diagnosis of heart failure, but with elevated serum natriuretic peptide values, showed increased cardiovascular events and mortality. This raises the possibility of using natriuretic peptides to screen for silent heart disease in elderly patients ,47.Most clinical studies have shown that natriuretic peptides have low discriminatory power for the diagnosis of heart failure in elderly patients. The importance of these peptides is still the subject of debate and research, and more clinical studies are needed to provide data on their usefulness in the diagnosis, treatment and prognosis of heart failure in elderly patients. In general, natriuretic peptides have been more sensitive in diagnosing forms of heart failure with left ventricular systolic dysfunction and less sensitive in forms with preserved systolic function.


However, in approximately one in three cases, we can observe a discordant AVA < 1 cm2 with a peak velocity < 4.0 m/s or a mean gradient <40 mmHg. This is due to reduced transvalvular flow associated with LV systolic dysfunction (LVEF < 50%) defined as “classical” low-flow low-gradient (LFLG) AS or normal LVEF “paradoxical” LFLG AS. SE has an established role in evaluating LV contractile reserve (CR) patients with reduced LVEF. In classical LFLG AS, LV CR distinguished pseudo-severe AS from truly severe AS. Some observational data suggest that long-term prognosis in asymptomatic severe AS may not be as favorable as previously thought, offering a window of opportunity for intervention prior to the onset of symptoms. Therefore, guidelines recommend evaluating asymptomatic AS with exercise stress in physically active patients, particularly those younger than 70 years, and symptomatic classical LFLG severe AS with low-dose dobutamine SE. A comprehensive SE assessment includes evaluating valve function (gradients), the global systolic function of the LV, and pulmonary congestion. This assessment integrates considerations of blood pressure response, chronotropic reserve, and symptoms. StressEcho 2030 is a prospective, large-scale study that employs a comprehensive protocol (ABCDEG) to analyze the clinical and echocardiographic phenotypes of AS, capturing various vulnerability sources which support stress echo-driven treatment strategies.Rest and stress echocardiography (SE) plays a pivotal role in the evaluation of valvular heart disease. The use of SE is recommended in valvular heart disease when there is a mismatch between resting transthoracic echocardiography findings and symptoms. In aortic stenosis (AS), rest echocardiographic analysis is a stepwise approach that begins with the evaluation of aortic valve morphology and proceeds to the measurement of the transvalvular aortic gradient and aortic valve area (AVA) using continuity equations or planimetry. The presence of the following three criteria suggests severe AS: AVA < 1.0 cm Aortic valve stenosis (AS) is the most common primary valve disease. The disease has a higher incidence of occurrence in the United States and Europe, and a growing prevalence due to the ageing population ,2.Stress echocardiography (SE) is an established method for assessing patients with coronary artery disease ,4. The cThe American Society of Echocardiography, the European Association of Cardiovascular Imaging, and the general cardiology guidelines of the American College of Cardiology (ACC), American Heart Association (AHA) and the European Society of Cardiology (ESC) ,2,7 recoThe purpose of this review is to evaluate the role of ABCDEG SE in AS patients and, in addition, to analyze the role of SE in specific subgroups: in asymptomatic severe AS patients and in discordant severe AS.A systematic approach typical to all applications is outlined in the valve SE protocol of execution, as are other parameters must be defined specifically for valvular disease in a certain limelight . With imPatients referred to the SE lab are studied with semi-supine bicycle SE. In patients unable to exercise, a pharmacological test with dobutamine is indicated in selected patients. Due to the risk of severe hemodynamic compromise, stress testing is not typically recommended to symptomatic patients with severe AS on account of it being harmful ,9.Caution regarding exercise testing is also recommended in cases of AS with peak velocity > 5 m/s or mean gradient > 60 mmHg .High-gradient AS;Low-flow low-gradient (LFLG) AS with reduced LVEF;LFLG AS with preserved LVEF;Normal-flow, low-gradient AS with preserved LVEF.Patients with reduced aortic valve area can be classified into four categories, as defined by the guidelines :High-graAS patients undergo comprehensive transthoracic echocardiography at rest conditions before SE .AS patients undergo physical or pharmacological SE according to the protocol recommended by the European Association of Cardiovascular Imaging  and the Severe chest discomfort, diagnostic ST–segment shift, and excessive blood pressure increase, may limit dyspnea, maximal anticipated heart rate, and substantial arrhythmias, all of which are all fundamental grounds for discontinuing the test. During times of stress, there are some basic general rules and acquisition patterns to be considered. The ideal acquisition order, however, should be customized for each patient and distinct research issue. In most cases, the digital capture proceeds in four stages: rest; intermediate stage; peak stress; and recovery (after the conclusion of exercise). Normally, no measurements are required during the image capture phase, while images are saved and examined offline after the performance of the test. This is due to initial expansion of LV end-diastolic volume being a measure of preload reserve and, if impaired, being required to contribute to the decrease in stroke volume and cardiac reserve during periods of stress. Conversely, the intermediate stage is fundamental to assessing changes within a preload reserve.Concerning B-lines, the recovery stage is decisive. Since pulmonary congestion continues after a stress interruption, B-lines require <1 min acquisition time with a simplified 4-site scan, allowing for information loss during the startling recovery period ,15,16.The traditional 2-dimensional echocardiography, the parasternal long-axis view, short-axis view, and the apical 4- and 2-chamber views are deployed in echocardiographic imaging.All patients underwent Step A. This included an evaluation of anomalies related to wall motion. In a 17-segment model of the left ventricle, the wall motion score index (WMSI), which is a four-point scale ranging from 1  to 4 (dyskinetic), was determined for every patient involved at baseline and at a time of peak stress .Step B of the methodology involved scoring each site from 0  to 10  for B-lines using lung ultrasonography and the 4-site streamlined scan on the third intercostal space . The comThe LV CR was assessed in a force-based fashion in step C of the procedure using the stress/rest ratio of force, a factor was computed as systolic blood pressure/end-systolic volume ,18.The left anterior descending coronary artery (LAD) and wall motion were imaged intermittently throughout the conventional SE examination. This was performed with the aim of determining the coronary flow velocity reserve (step D) . ConsequThe ratio of the peak assessment to the rest value of a high diastolic flow velocities was used to quantify coronary flow velocity reserve.Indeed, the peak/rest heart rate ratio from a 12-lead electrocardiogram was used to compute the heart rate reserve (step E) ,21.Step G included the evaluation of the trans-aortic maximal and mean gradients using continuous-wave Doppler techniques and the evaluation of integral flow in the LV outflow tract using pulsed-wave Doppler methods. Data stroke volume and AVA were calculated using the continuity equation method. If needed, the steps were repeated after 5 min in the recovery phase .Beyond SE, adjunctive imaging studies can potentially increase our pathophysiology knowledge of the AS process, contributing additional diagnostic and prognostic information . More sp2), indicative of pseudo-severe AS, and a lack of increase in AVA, indicative of true severe AS. During the last decade, the evidence supporting the optimal cut-off for the trans-aortic gradient augmentation has not increased as expected. Therefore, major scientific research needs to evaluate the positivity criteria cut-off of this parameter.Every positive criterion is predetermined in advance. When two contiguous segments of the same vascular territory of the LV exhibit an increase in at least one point of the segmental score during SE , the A cSome observational data suggest that long-term prognosis in asymptomatic AS stenosis may not be as favorable as previously thought, suggesting that there exists a window of opportunity for intervention prior to the onset of symptoms. Recent data indicate that there is an increased risk of mortality in asymptomatic severe AS, even when LVEF is >50% . MoreoveWhen exercise testing causes symptoms, the patient is deemed to be symptomatic and qualifies for an aortic valve replacement class 1 recommendation. Symptoms are considered symptoms if they are reported deliberately by the patient or detected by exercise testing. Normally, in patients without overt symptoms who exhibit (1) a drop of >10 mm Hg in systolic blood pressure from baseline to peak exercise or (2) a significant decrease in exercise tolerance compared to age and sex normal standards, the rate of symptom onset is elevated within the bounds of 1 to 2 years (roughly 60% to 80%) .Therefore, guidelines recommend evaluating asymptomatic AS with exercise stress in physically active patients, particularly those younger than 70 years. A decreased exercise tolerance indicates intervention for the 2020 ACC/AHA  and 2021The 2021 ESC recommendations state that, if the resting LVEF is lower than 55% without evidence of an additional cause, intervention should be considered in patients with severe AS who are asymptomatic. Additionally, this is advised if the LVEF is less than 50% (class of recommendation 1) [The incidence of the abnormal stress test in asymptomatic severe AS has ranged from 28% to 67%, with a pooled average of 49% .Therefore, recording abnormal aortic valve hemodynamics with exercise echocardiography is of limited additive value and is no longer recommended for decision making.The predictive value of the test is diminished in older adults despite the fact that a negative exercise test result may seem comforting in younger patients. Combining them with the echocardiographic evaluation of LV function, transvalvular pressure gradients and pulmonary arterial pressure can be useful.In this case, the application of ABCDE SE in asymptomatic AS patients has the potential to identify the presence of latent coronary artery disease (Step A+); the presence of B lines at peak stress (Step B+), indicative of a preclinical decompensation which may precede the onset of dyspnea and symptoms by days or months; a latent LV dysfunction with reduced LV CR (Step C+); and an impaired coronary flow velocity reserve (Step D+). This is particularly the case in in patients who have angiographically normal coronary arteries and severe AS. When a valve is replaced prior to the regression of LV hypertrophy in these patients, the degree of coronary microvascular disease, which is reflected in a reduction in coronary flow reserve during stress testing and is related to exercise capacity, is reversible and foresees outcomes better than the severity of AS ,32,33,34There are invasive and more reproducible invasive tests to assess absolute coronary flow and coronary flow reserve in patients with severe AS candidate to TAVI/SAVR. In patients with severe AS and non-obstructive coronary artery disease, an invasive study demonstrated that the compensatory mechanism of increased resting flow maintains adequate perfusion at rest, but not during hyperemia, with a consequent reduction in coronary flow reserve .The management of patients with moderate AS is very important, particularly in terms of the choice between early intervention versus watchful waiting. The correct diagnosis of true moderate AS is of primary importance. For an accurate measurement of the trans-aortic jet velocity, multiple acoustic windows should be used in order to determine the highest velocity, In fact, alignment errors in the Doppler beam led to an underestimation of the true velocity, and consequently to the calculated gradients underestimating AS severity. In addition, an echocardiographic evaluation of valve morphology and aortic valve calcium scoring can be performed using computer tomography (CT) to confirm the diagnosis of true moderate AS. Paolisso et at.  demonstr2, LV EF < 50%, and stroke volume index ≤ 35 mL/m2.The evaluation of classical LFLG AS is the main indication of SE in valvular heart disease . ClassicDue to the difficulty of separating patients with severe AS from those who have pseudo-severe AS, this entity poses a diagnostic challenge ,2,9,39. The primary objective of using dobutamine SE is to boost the transvalvular flow rate without causing myocardial ischemia. In response to an increase in transvalvular flow rate, patients with pseudo-severe AS will have an increase in the AVA and little change in gradient, whereas patients with severe AS will possess a fixed valve area but undergo an increase in stroke volume and gradient ,13,39,40Evaluation of the LV CR is a critical component of classical LF-LG AS because patients with reduced LV CR have a higher risk of unfavorable events ,13,39. TAn imbalance between the severity of the stenosis and myocardial reserve, an inadequate increase in myocardial blood flow because of associated coronary artery disease, irreversible myocardial damage from a previous myocardial infarction or extensive myocardial fibrosis can all contribute to the lack of stroke volume increase during dobutamine SE .A noninvasive method of assessing LV CR can be inferred to add another modality ,42,43 beThe LV CR measured by LV force, however, significantly varies from LVEF when the situation is viewed from a conceptual, methodological, and clinical perspective. It only requires the measurement of systolic blood pressure by cuff sphygmomanometer and end-systolic volume by 2D echocardiography, rather than the assessment end-diastolic and end-systolic volume . It is iAdditionally, with all modalities of SE, LV CR is more prognostically effective than LVEF changes in identifying patients at higher risk, including both those with normal and those with noticeably abnormal resting LV function ,45,46. SPatients with an increased indexed stroke volume of at least 20%, an unchanged AVA, and an unchanged transvalvular gradient have indeterminate AS severity. Up to 30% of patients lack CR, indicating a high risk of perioperative mortality following surgical aortic valve replacement ,49. ProjThis parameter’s goal is to predict the AVA would be at a standard normal flow rate of 250 mL/s. When compared to conventional DSE parameters, it has been discovered that in patients with LG-AS, the AVAProj more accurately foresees underlying AS severity, the impairment of myocardial blood flow, LV pump reserve, and survival [2 [In discordant severe AS, the confirmation of the actual AS severity is essential. Both the American and European guidelines recommend performing non-contrast CT to quantitate aortic valve calcification and therefore differentiate true severe vs. non-severe AS, and this is particularly true in the case of patients with paradoxically low flow and LG-AS. Additionally, CT cut-offs have been defined to identify patients who likely have an AVA <1 cm2 .In patients with classical LF-LG AS, severe impairment of LV longitudinal systolic function at rest or during dobutamine SE, very low LVEF (35%), and the absence of LV CR are the main factors that have been linked to an increased risk of mortality under conservative management, as well as following aortic valve replacement ,48,49,50SE has an important diagnostic and prognostic role in evaluating LV CR patients with heart failure patients and reducing LV EF ,53.The prognostic role of LV CR for AS patients who are candidates for transfemoral aortic valve implantation (TAVI) or surgical aortic valve replacement (SAVR) remains to be clarified ,52.In LF-LG AS patients undergoing SAVR, the peri-procedural risk is considered greater if LV CR is absent .Patients with LV CR have a significantly better results with percutaneous or surgical aortic valve replacement than with medical therapy in LF-LG traditional severe AS ,42,49,50However, the outcome and management of classical LFLG AS has changed: the operative outcome of SAVR has improved in LF-LG AS, with much lower operative mortality and less frequent severe prosthesis–patient mismatch ,55,56. TThe prognostic role of SE in LF-LG AS remains uncertain and needs to be clarified with further scientific evidence. Ribeiro et al.  showed tConversely, when working on LFLG AS patients undergoing TAVI, Barbash et al.  showed tBased on this evidence, the current ESC guidelines  suggest AS is a common valvular disease, especially affecting the elderly. As for atrial fibrillation, the incidences of this issue increase with age. Many studies in different subgroups of AS have shown that atrial fibrillation is associated with worse outcomes ,66,67. IFinally, AS should be considered in the bleeding risk assessment of patients with atrial fibrillation with an increased risk of gastrointestinal bleeding .SE, when combined with exercise or dobutamine, has essential applications in the assessment of patients with AS. Its potential is, however, underused ,70.In asymptomatic patients with AS, it is possible to have the presence of LV hypertrophy LV systolic dysfunction, left atrial enlargement, mitral and tricuspid regurgitation, and right ventricular dysfunction. Aortic valve replacement does not affect prognosis in asymptomatic patients; only after the patient develops symptoms is a benefit obtained with aortic valve replacement since it improves the outcomes of these issues. However, a new and increasingly accredited hypothesis supports the concept that cardiac damage identifies patients with poor prognosis, despite the absence of symptoms, when imaging shows parameters of cardiac damage related to poor outcome .An innovative concept of staging AS, centered on the patient rather than imaging, has been proposed in order to assist with the decision to potentially intervene more quickly This is an alternative to simply categorizing the severity of the valve lesion based on echocardiographic data .In this framework, the comprehensive approach with the ABCDEG protocol may refine the AS phenotype identification and it may play an important role in its practical use: in fact, ABCDEG SE contributes to the risk stratification of AS patients characterized by numerous vulnerabilities beyond coronary artery stenosis : myocard