Aortic stenosis (AS) can often coexist with other valvular diseases or be combined with aortic regurgitation (AR), leading to unique pathophysiological conditions. The combination of affected valves can vary widely, resulting in a lack of standardized diagnostic or therapeutic approaches. Echocardiography is crucial in assessing patients with valvular heart disease (VHD), but careful consideration of the hemodynamic interactions between combined valvular defects is necessary. This is important as it may affect the reliability of commonly used echocardiographic parameters, making the diagnosis challenging. Therefore, a multimodality imaging approach, including computed tomography or cardiac magnetic resonance, is often not just beneficial but crucial. It represents the future of diagnostics in this intricate field due to its unprecedented capacity to quantify and comprehend valvular pathology. The absence of definitive data and guidelines for the therapeutic management of AS in the context of multiple valve lesions makes this condition particularly challenging. As a result, an individualized, case-by-case approach is necessary, guided primarily by the recommendations for the predominant valve lesion. This review aims to summarize the pathophysiology of AS in the context of multiple and mixed valve disease, with a focus on the hemodynamic implications, diagnostic challenges, and therapeutic options. Multiple and mixed valvular heart diseases (VHD) are highly prevalent conditions, expected to increase in prevalence as the population gets older . The cliThe diagnostic algorithm should always start with the identification of the underlying etiology as well as the concomitant or VHD-induced cardiac structural changes. Moreover, in the presence of combined valvular defects, it is of pivotal importance to be aware of their hemodynamic interaction since this could affect the reliability of most of the echocardiographic methods, making the diagnosis very challenging. For this reason, in these complex scenarios, a multimodality approach using different imaging techniques, such as computed tomography (CT) or cardiac magnetic resonance (CMR), often represents the keystone of the management strategy. Apart from the definition of the appropriate diagnostic modalities, a case-by-case, individualized therapeutic management should always be chosen, mainly driven by the guideline’s recommendations for the predominant valve lesion ,2.The absence of clear data and, thus, guidelines for the management of AS in the context of multiple valve lesions makes this condition a great challenge for the clinician. In this review, we will discuss the pathophysiology of AS in the context of multiple valve disease, its diagnostic challenges, and therapeutic options.AS and mitral regurgitation (MR) are the most common VHDs in developed countries . The higMultiple valve diseases can arise from a variety of etiologies, including functional valve disease, rheumatic heart disease (RHD), degenerative processes, infiltrative cardiomyopathies, congenital heart diseases (CHD), and infectious endocarditis (IE), among others. Understanding the underlying cause of multiple valve disease is crucial for accurate diagnosis, management, and treatment of this complex scenario.Functional valve disease commonly co-occurs with AS and can arise from various mechanisms. Functional MR is observed in 63% of patients with AS , whereasRHD is a common cause of multiple valve disease, particularly in developing countries , but hasValvular thickening, restricted leaflet mobility, and nodularity along the length of the leaflet are typical morphological features . The mitDegenerative etiology is a prevalent cause of multiple valve disease, particularly in developed countries where aging is a significant contributing factor. It is estimated that approximately 10% of people over the age of 75 are affected by some form of VHD .The degenerative process in valve tissue is characterized by progressive calcification and thickening of valve leaflets. These changes result in increased stiffness of the valve tissue, leading to stenosis or regurgitation. The most affected valves are the AV and MV. Calcific AV disease is characterized by progressive thickening and calcification of the AV without commissural fusion, while degenerative MV disease involves progressive calcification of the mitral annulus at the base of the leaflets or degenerative changes of the MV causing prolapse .The presence of comorbidities such as hypertension, metabolic syndrome, or chronic kidney disease can also contribute to valve degenerative processes. These conditions cause mechanical stress on the valves, alterations of the metabolism with toxin accumulations, increased oxidative stress, and inflammation, ultimately accelerating valve dysfunction ,21. It iInfiltrative cardiomyopathies, including amyloidosis and Fabry disease, can also affect heart valves, leading to valve disease ,23,24. IIn CA, the extracellular deposition of amyloid fibrils can lead to thickening and stiffening of the heart valves. The infiltration of amyloid substances in the AV can result in stenosis, whereas infiltration in the MV typically leads to regurgitation . SimilarAS can be present alongside CHD, which can also impact other valves . The mosIE is a condition where the valvular endocardium is infected, with the AV being the most affected valve . The cauLess frequently, severe AV may be a long-term sequelae of mediastinal radiation therapy. Radiation damage affects more commonly left-sided heart valves, leading to their thickening and calcification, and it usually occurs after a latency period of several years .The coexistence of multiple VHDs represents one of the most challenging cardiovascular conditions for a cardiovascular imaging specialist . Indeed,Aortic Stenosis with concomitant Mitral Regurgitation. In patients with concomitant AS and MR, a quantitative approach to the estimation of MR severity is encouraged. As systolic intraventricular pressure is increased due to AS, concomitant MR is characterized by increased transmitral systolic velocity that results in a disproportional increase in color-flow jet area and regurgitant volume . TherefoAortic Stenosis with concomitant Mitral Stenosis. Similar to MR, severe mitral stenosis (MS) associated with AS leads to a great reduction in cardiac output, resulting in low flow rates and pressure gradients, with a possible underestimation of the severity of both valves if only Doppler measurements are considered . ParadoxAortic Stenosis with concomitant Aortic Regurgitation. The concomitant presence of significant AS and AR poses several diagnostic challenges. The impaired LV relaxation secondary to the pressure overload makes the PHT method unreliable for the evaluation of AR . Convers2 might reflect severe AS. Doppler velocity index  is not significantly affected by the presence of AR and, together with the effective AVA by the continuity equation method, represents the best parameters to grade AS severity in the context of mixed AV disease. The anatomic AVA measured by planimetry may help corroborate AS severity. Transesophageal echocardiography, with its superior image resolution compared to transthoracic echocardiography, offers an effective modality for direct planimetry of the AVA. This technique involves tracing the contours of the valve orifice during mid-systole, thereby providing a direct measure of the AVA. MDCT or CMR imaging can also accurately measure the anatomic AVA through planimetry. The choice of imaging modality depends on the specific clinical situation, availability of resources, and expertise [In mixed AV disease, the assessment of AVA remains accurate using the continuity equation; however, AVA may increase at high transvalvular flow rates, and, in some patients, an AVA greater than 1.0 cmxpertise ,42.Aortic Stenosis with concomitant Tricuspid Regurgitation. In the physiopathology of the AS, functional TR is present in one third of the patients, necessitating careful echocardiographic evaluation. While the evaluation of TR severity is not influenced by the coexistence of AS, when TR is chronic and severe, a low-flow condition may superimpose, making the classical continuity equation not reliable in the estimation of AS severity, with a tendency to be significantly underestimated ,44. AddiAs previously described, the combination of AS with MR or MS is associated with a LF-LG state that makes the estimation of AS severity challenging. Low-dose (≤20 μg/kg per min) dobutamine stress echocardiography (DSE) may be helpful to distinguish true severe from pseudo-severe AS and to assess LV flow reserve when the pressure gradient is low and the LV ejection fraction is reduced. However, in the presence of significant MR, DSE may fail to induce a significant increase in LV outflow and may thus not allow the confirmation of AS severity.Again, in patients with concomitant AS and AR with reduced LV ejection fraction, a low-dose DSE may be helpful to assess the presence of LV contractile/flow reserve and confirm the overall hemodynamic severity of mixed AV disease. It has been suggested that an increase in peak jet velocity ≥4 m/s and/or a mean gradient ≥40 mm Hg with dobutamine stress could be indicative of severe AV disease .Currently, there is limited data on the use of stress echocardiography in patients with multiple and mixed VHD. Exercise echocardiography, performed using either a treadmill or bicycle ergometer, may be useful to discriminate symptoms in apparent non-critical valve disease at rest that worsen during stress, producing a disproportionate increase in the transvalvular pressure gradient or pulmonary arterial pressure . On the In the latest decade, cardiac CT has emerged as a valuable, complementary technique in the evaluation of AS severity through the calculation of the AV calcium score. The latter enables an accurate assessment of the burden of AV calcification and has been validated as a marker of AS severity . The AV Particularly, the latest international recommendations suggest the use of AV calcium scoring in patients with LF-LG AS in the two following scenarios: (1) LF-LG AS with preserved LV ejection fraction ; and (2) LF-LG AS with reduced LV ejection fraction (classic LF-LG AS), when there is a negative flow response on stress echocardiography.Despite not yet being widely used in daily clinical practice, AV calcium scoring may represent a faster and potentially easier tool than stress echocardiography, being both feasible and conclusive in many patients ,51,52. MOf importance, aside from its diagnostic value, the CT-derived AV calcium scoring has also been shown to be a strong prognostic marker as a predictor of disease progression and survival, independently from clinical and Doppler echocardiographic data ,54.The measurement of the anatomic AVA using planimetry on contrast-enhanced scans represents an alternative method for AS grading by cardiac CT. Although this approach demonstrated a good correlation with echocardiographic data obtained by the continuity equation, it is associated with a systematic overestimation of the AVA and thus should be used with caution .Finally, for patients being considered for surgery, CT offers precise measurement of the thoracic aorta and the capability to exclude coronary artery disease .To this end, CT represents an important, complementary tool in refining AS grading and may provide crucial diagnostic and prognostic information, especially in the setting of low-flow conditions and concomitant VHDs.Nowadays, there is limited evidence regarding the specific additive value of CMR in patients with AS and concomitant VHDs. However, CMR appears to be a promising tool in the setting of multiple VHDs since 1) it enables an accurate grading of VHDs, especially of regurgitant lesions, thus overcoming the well-known limitations of echocardiography in these patients; (2) it is the gold standard for the calculation of ventricular dimensions and systolic function; and (3) it has the key strength of myocardial tissue characterization [ it enablRegarding the grading of regurgitant lesions in patients with multiple VHDs, phase-contrast CMR imaging with flow quantification in the aorta or pulmonary artery should be the preferred method for calculating the regurgitant volume and regurgitant fraction . ConversIn patients with AS, peak velocity and mean pressure gradient may be derived by phase-contrast sequences, but they are often underestimated in comparison to Doppler data due to the partial volume averaging within the vena contracta . AdditioMore importantly, CMR allows for accurate assessment of serial changes in chamber dimensions and ventricular performance that reflect the overall burden of AS and concomitant valvular lesions . In addiIn patients with AS, the presence of replacement fibrosis on LGE imaging correlates with more severe valve stenosis and LV remodeling  and doesDecisions about treatment can only be made after conducting a thorough cardiac examination. It is crucial to acknowledge that treatment choices may not always be confined solely to the AV. In certain situations, such as IE or infiltrative diseases, treatment considerations may need to address issues beyond the AV itself. Should this comprehensive evaluation reveal that the patient’s primary condition is aortic stenosis, AV replacement (AVR) represents the only therapeutic option that has shown excellent long-term results in the management of severe AS . Indeed,SAVR can be performed through traditional medial sternotomy or using minimally invasive approaches that have the advantages of reducing the need for blood transfusion, the length of the intensive care unit stay, hospital costs, and the incidence of procedural complications such as renal failure and post-operative atrial fibrillation ,71. NeveDifferently from mechanical valves, bioprostheses can be implanted both surgically and with a transcatheter approach. The main advantage of bioprostheses is that they do not require long-term anticoagulation. Nevertheless, since they are composed of biological material , they undergo degeneration and are therefore less durable compared with mechanical valves . The traIn cases of concomitant VHD, clinical decision-making can be challenging, and an individualized, case-by-case multidisciplinary approach is necessary. There are essentially 2 possible scenarios: (1) AVR is indicated because of severe AS in the presence of concomitant mitral or tricuspid valve disease; and (2) mitral or tricuspid valve surgery is indicated in the presence of concomitant AS. In these two conditions, the physician should follow the current guidelines ,66 appliIn clinical practice, two commonly encountered scenarios involve AS accompanied by either MR or TR.Whether the presence of concomitant moderate MR is associated with worse outcomes after AVR remains a matter of debate . AVR red2), which has been associated with TR worsening [Concomitant significant secondary TR has been associated with worse outcomes in patients with severe AS in several observational studies . Neverthorsening , rather orsening ,85,86.Optimal grading for multiple or mixed VHDs still needs to be established. Nonetheless, the integration of multimodality imaging, including techniques such as CT and CMR, holds great promise for the future of diagnostics in this complex field. Despite the inherent challenges and costs associated with the utilization of multiple advanced imaging modalities, there is a justifiable rationale for employing multiple tests, given their unparalleled capabilities in quantifying and comprehending the intricacies of valvular pathology. Future research efforts should focus on validating the utility and effectiveness of these imaging techniques in clinical practice. Additionally, exploring novel imaging modalities, such as 4D flow CMR, particle image velocimetry, and vector flow mapping in echocardiography, could potentially enhance the accuracy of VHD diagnosis and management. Although these techniques are currently confined to research settings, their future application holds substantial potential to enhance patient care .In conclusion, AS combined with other valvular diseases or AR represents a complex and challenging clinical scenario. Echocardiography is crucial, but careful consideration of hemodynamic interactions between combined valvular defects is necessary. A multimodality imaging approach may also be required. Therapeutic management lacks definitive guidelines, making an individualized, case-by-case approach necessary. Further research and studies are needed to establish more standardized diagnostic and therapeutic approaches for this challenging condition.


Homografts and bovine jugular vein are the most commonly used conduits forright ventricular outflow tract reconstruction at the time of primary repairof truncus arteriosus.We reviewed all truncus patients from 1990 to 2020 in two mid-volume centers.Inclusion criteria were primary repair, age under one year, and implantationof either homograft or bovine jugular vein. Kaplan-Meier analysis was usedto estimate survival, freedom from reoperation on right ventricular outflowtract, and freedom from right ventricular outflow tract reoperation orcatheter intervention.P=0.002). Freedom from reoperation on rightventricular outflow tract at one, five, and 10 years in the homograft groupwere 100%, 83%, and 53%; and in bovine jugular vein group, it was 100%, 85%,and 50% (P=0.79). There was no difference in freedom fromreoperation or catheter intervention (P=0.32).Seventy-three patients met the inclusion criteria, homografts were implantedin 31, and bovine jugular vein in 42. There was no difference inpreoperative characteristics between the two groups. There were 25/73 (34%)early postoperative deaths and no late deaths. Follow-up for survivals was17.5 (interquartile range 13.5) years for homograft group, and 11.5(interquartile range 8.5) years for bovine jugular vein group(Bovine jugular vein was equivalent to homografts up to 10 years in terms ofsurvival and freedom from right ventricular outflow tract reoperation orcatheter intervention. The choice of either valved conduit did not influencethe durability of the right ventricle-pulmonary artery conduit in truncusarteriosus. TA is a rare disease with incidence of< 0.35% of all congenital heart diseases, but it accounts for 4% of all critical congenital heartdiseases. Because of its specific anatomical and hemodynamic features, earlydevelopment of severe pulmonary hypertension and truncal valve (TV) dysfunction,natural evolution results in high mortality — up to 80% until the age of one year. The contemporarytreatment of TA is a single-staged surgical repair in the neonatal period, or in thefirst few months. One of the most challenging parts remains the right ventricularoutflow tract (RVOT) reconstruction. Since the first successful surgical repairusing aortic homograft (HG) in 1968 by McGoon, a lot of improvements in surgical technique andperioperative management has occurred. Nevertheless, the overall mortality remainshigh — 3-20% with long-term survival of approximately 75% at 20 years. Concerning the RVOTreconstruction, various surgical methods without an accepted standard are currentlyused — direct right ventricle to pulmonary artery (RV-PA) anastomosis, HG, or othertype of valved conduit implantation,6,7,8. In 2021, aconsensus document on optimal management of patients with TA was issued. Regardless the type of conduit atthe time of initial repair, a reoperation is required for its replacement when childgrows up. The reasons are small sizes used in the first weeks of life, limiteddurability, and degeneration. The most widely used valved conduits nowadays are HGs,followed by bovine jugular vein (BJV) . The BJV is reported to have good handlingcharacteristics but inferior freedom from degeneration and reintervention. This study aims to analyzepatients after primary repair of TA with HG or BJV implantation, in terms ofsurvival, freedom from RVOT reoperations, and freedom from RVOT reoperation orcatheter intervention.Truncus arteriosus (TA) was first reported by Wilson in 1798 in an autopsy case. In1864, BauchananThe medical records of all patients in the congenital heart surgery of NationalHeart Hospital  and La Timone Children Hospital  who underwent primary truncus repair under one year of age, from January1990 to December 2020, were retrospectively reviewed (n=80). Additionalinclusion criterium was the implantation of either HG or BJV. Seven patientswere excluded . Follow-up echocardiographyand exam reports were obtained from hospital record systems.The study was approved by institutional review boards in both hospitals (TPL7AP)and the need for patient consent was waived due to the study’s retrospectivenature. Derived data supporting the findings are available from thecorresponding author on request.Early in-hospital mortality was defined as occurring within 30 days of surgery orbefore hospital discharge. All other deaths were considered late. Intensive careunit (ICU) length of stay was calculated as the number of calendar days from theday of admission (counted as one day) to the day of ICU discharge. The time fromthe surgery date to the date of death, or last follow-up, was considered thepatient survival time. This study focused on longevity of RV-PA conduits,therefore only conduit associated reinterventions were included. Reoperationsincluded all RVOT surgical procedures, regardless TV surgery. Catheterinterventions included all catheter-based procedures related to RVOT. The timefrom the surgery date to the date of reoperation/catheter intervention wasconsidered the time of freedom from RVOT reoperation or catheterintervention.. In almost all of the cases, smallest conduitsavailable were used.All patients underwent median sternotomy, standard cardiopulmonary bypass (CPB)with mild hypothermia, or deep hypothermic circulatory arrest. Intracardiacrepair was performed during aortic cross-clamping with cold blood cardioplegia (Marseille) or crystalloid cardioplegia(Sofia). All BJV conduits were washed in normal saline at least three timesbefore implantation. The pulmonary artery was separated from the truncal rootand extensively mobilized. The distal end was cut as short as possible in orderto proper positioning the conduit, while a right ventriculotomy was thenperformed as high as possible within a safe distance of the main coronaryarteries. The ventricular septal defect closure was performed using aheterologous pericardial patch or Dacron® patch through the rightventriculotomy or through the TV. In HG implantation, the proximal anastomosiswas augmented with a hood of autologous pericardium, Gore-Tex®, oranterior mitral leaflet in aortic HGs. All HGs were cryopreserved with the sameconservation technique during the study periodAll patients were assessed preoperatively, postoperatively, at discharge andannually after surgery. Routine baseline diagnostic examination included:Clinical examination – oxygen saturation, blood pressure, heart murmur,and signs of heart failureElectrocardiogram – standard 12-lead electrocardiogramTransthoracic echocardiography with focus on the RV-PA conduit dimensionsand function, assessed in the parasternal long-axis, parasternalshort-axis, and subcostal view. Conduit stenosis was assessed bymeasurement of peak velocity across the pulmonary valve usingcontinuous-wave Doppler and applying the modified Bernoulli equation tocalculate the peak gradient. Trace of the full envelope was used tocalculate the mean pressure gradient. Color Doppler and pulsed-waveDoppler were used to evaluate the pulmonary regurgitation. In all of thecases in which reintervention was considered, a cardiovascular magneticresonance imaging and/or cardiac catheterization was done..As stated in the 2021 consensus, the timing for conduit replacement in TA is nodifferent than in other situations, and is based on a composite indication ofraised right ventricular (RV) pressures (> 67% systemic pressure in the rightventricle), impaired RV function, and the development of exercise limitationassociated with conduit stenosis or impaired functionPrimary endpoints of interest were defined: survival, freedom from RVOTreoperation, and freedom from RVOT reoperation or catheter intervention in bothgroups.Secondary endpoints were focused on patients’ perioperative variables — CPB time,aortic cross-clamping time, delayed sternal closure (DSC), ICU length of stay,mechanical ventilation time, conduit size, and conduit size/body surface area(BSA) index.P-values < 0.05 were considered statisticallysignificant. All data were analyzed using statistical software IBM Corp.Released 2011, IBM SPSS Statistics for Windows, version 20.0, Armonk, NY: IBMCorp.Data are expressed as mean ± standard deviation for normally distributedcontinuous variables, or median and interquartile range (IQR) for non-normallydistributed continuous variables; frequency and percentage (%) were used forcategorical variables. The Kolmogorov-Smirnov test was used to determine normaldistribution. For continuous variables, comparisons between the groups were madeusing Student’s t-tests or Mann-Whitney U test, as appropriate. Fisher’s exacttests were used for comparisons of categorical variables. Survival, freedom fromRVOT reoperation, and freedom from RVOT reoperation or catheter interventionwere displayed graphically using Kaplan–Meier curves, and log-rank test was usedfor comparison between groups. An adjustment for multiple tests was not used.A total of 73 patients met the inclusion criteria; 31 patients had HG implanted,compared to 42 patients with BJV. HGs were the preferable option in Marseille(n=30/31 HG patients). BJV was most commonly used in Sofia (n=30/42 BJV patients),due to lack of availability of small HG in Bulgaria.P=0.15), weight(P=0.07), sex (P=0.18), type of TA(P=0.15), presence of coronary anomalies(P=0.26), DiGeorge syndrome (P=0.23), severity ofTV regurgitation (P=0.96), or in the anatomy of TV cusps(P=0.58).Patient preoperative characteristics are summarized in vs. 12 mm (IQR 2) for BJV . Whencomparing conduit size/BSA, HG group showed a mean of 60 mm/m2 ±14 in the BJVgroup, it was 54 mm/m2 ±16 (P=0.004). There were nosignificant differences in CPB time (P=0.51), aortic cross-clampingtime (P=0.99), DSC (P=0.98), ICU length ofstay(P=074), hospital length of stay (P=0.44),and mechanical ventilation time (P=0.39).Perioperative variables are summarized in P=0.45).Mortality was comprised only of early postoperative mortality at primary repair.Causes of in-hospital mortality include low cardiac output syndrome (n=9), pulmonaryhypertension (n=5), coronary ischemia (n=2), hemorrhagic shock (n=1), and unknown(n=8). There were no late deaths.Overall in-hospital mortality was 34.2% (n=25/73) — 39% in HG group (n=12), 31% inBJV group (n=13) — with no difference between the groups (P=0.45)  .A total of 19 survivals  required conduit replacement .There were no deaths at time of replacement, and there were no reinterventions dueto infective endocarditis.P=0.79)  years for all survivals. Freedom from reoperation was 83±8%and 85±6% at five years and 53±12% and 50±11% at 10 years forHG and BJV, respectively (P=0.79) .P=0.32)  were inserted. Freedom from RVOT reoperation or catheter intervention was94±5% at one year, 72±10% at five years, and 49±11% at 10 yearsin the HG group, and 91±4%, 70±8%, and 51±10% at one, five, andat 10 years, respectively, in the BJV group (P=0.32) .P=0.002). At the last follow-up,all patients were in New York Heart Association (or NYHA) functional class I orII.Follow-up for survivals was 17.5 (IQR 13.5) years for the HG group and 11.5 (IQR8.5) years for the BJV group . This favored a study comparing RVOT conduits used at the time of primaryrepair. Contegra™ became available in Europe in 1999, which means there wereno BJV patients in the first decade of our study. This time difference resulted insignificant follow-up difference and limited our study to a 10-year comparison.. No evidence supports valvedstrategy over direct anastomosis in terms of survival or operativeoutcome. Althoughrecently Derridj et al. showedstrong evidence with excellent results with direct RV-PA anastomosis using leftatrial appendage, valved conduits are still the most prevalent technique used in theliterature. Naimo etal. published a40-year experience with 239 patients who underwent conduit repair and 16 directanastomosis. The rate of RVOT reoperations was high with freedom from reoperation at10 years, 28.5% for conduit and 35.5% for direct anastomosis. After its firstdescription by McGoon in 1968, HG were thought to be the ideal conduit for RVOTreconstruction. In the recent consensus, pulmonary and aortic HG have been qualifiedas best and second-best performance, while BJVs perform “generally good but inferiorto homografts”. First everretrospective comparison of BJV conduit and down-sized pulmonary HG byBove showed comparableresults between two conduits. In 2008, Protopapas reviewed 17 articles with 767patients related to RVOT reconstruction with BJV and found contradictory results. Insome series, patients with BJV had higher incidence of stenosis and short-termreintervention when small sizes were used (12-14 mm), while other authors were veryBJV-enthusiasthic.Myens reported unsatisfactory results with excessive proliferation of neointima atthe level of the distal anastomosis and stopped utilizingContegra™,while Fiore recommend BJV conduit as a first choice for conduit replacement inpatients < 2 years of age.In a similar European/American two-center study, BJV showed inferior toaortic/pulmonary HGs in time to conduit failure. Center, conduit modification, and bypass orcross-clamping time at implantation did not influence conduit longevity. Our studyconfirms these results with no difference in perioperative data. These contradictoryresults may be partially explained by the heterogeneity of the series, surgerytechniques, and variety of indications.Implantation of any type of RVOT conduit under one year of age will always questionits durability, since in a growing child several reoperations are inevitable toadjust the graft size. Recently published consensus on truncus patients managementby task forces of the European Association for Cardio-Thoracic Surgery andAssociation for European Paediatric and Congenital Cardiology encompassed the fullspectrum of the disease, including the reconstruction of RVOT.Both conduits have their advantages and disadvantages. Small HGs have very limitedavailability, and in Bulgaria, HG lack in general. Preservation and storagetechnique of HGs could influence the strength of immune response, as well as theirquality. HG degeneration and calcification result from reaction of tissuerejection, orchronic trauma to neointima, resulting in different series from 6% to 50% ofhemodynamically significant supravalvular stenosis,19.Nevertheless, distal anastomotic stenosis was also reported with HG in the Rossseries and when usingGore-Tex® non-valved conduits in TA repairs.In BJV, the length of a jugular vein valve is much longer, which is an issue inneonates where the distance between RV and PA is very short. The principal site ofBJV conduit obstruction has been proven to be at the distal anastomosis withneointimal proliferation. The origin is suggested to be inadequate glutaraldehyderemoval, immune response2were identified as an independent risk factor increasing five-fold mortality byMastropietro et al.; both ofour groups showed a median diameter > 50 mm/m2. Oversized conduitsrequire larger ventriculotomy and could increase risk for coronary arterycompression. Unfortunately, small-sized conduits aren’t always available.In our series, after successful postoperative hospital discharge, survival wasexcellent. The high early mortality was probably related to late indication forsurgery — median age of primary repair was about two months. With the methods ofprenatal and early diagnosis we have in most cases today, we aim to performexclusively neonatal surgery. Also, RV-PA conduit diameter > 50 mm/mWe were not able to prove any influence of age, body weight, length of CPB, and typeof conduit to mortality. Furthermore, during the study period, Sofia center had noopportunity to utilize extended mechanical circulatory support. Use of ECMO inpatients with low cardiac output might improve the reported mortality.. While freedom from redo/catheterintervention did not differ significantly between the two groups, it revealed thatabout 30% of conduits will be changed by the 5th year. Theoretically,timely catheter interventions could postpone surgery and increase lifespan of aconduit.Since the fate of TV will be a subject of a different review, in our study weincluded only reinterventions associated to RV-PA conduit. Timing for conduitreplacement was no different from in other situations, and was based on indicationsof raised RV pressure, impaired RV function, or other conduit dysfunction. Fortunately, we didn’t observe anyreintervention due to infective endocarditis.According to current guidelines, antibiotic infective endocarditis prophylaxis isrecommended in all types of cyanotic congenital heart disease, moreover in patie ntsrepaired with a prosthetic material like RV-PA conduits,23,24,25. Particularemphasis in echocardiography examination should be conduit valve function and anygradients on proximal or distal anastomotic site.We have demonstrated comparable results between HG and BJV groups. As both conduitsshowed gradual deterioration with time, regular follow-up and timely referring tosurgery or intervention is an important detail in management in thesepatientsOur small number of cases and small number of events might generate certainbiases. Data were acquired retrospectively; however, this is an accepted studydesign when dealing with low-incidence disease. The operations were performed bydifferent surgeons in Marseille and Sofia, who chose the conduit type by theirpreference or availability, not by randomization. Perioperative managementstrategies in both centers were standardized but could have significantdifferences with impact on patient outcome. Aortic and pulmonary HG data havebeen collected in the same group, however, they could perform with differentresults.Our two-center independent results add to the current knowledge surrounding the RVOTreconstruction in truncus patients, showing that BJV conduit was equivalent to HG upto 10 years for survival, freedom from RVOT reoperation, and freedom from RVOTreoperation or catheter intervention. Commercially available Contegra™ is agood alternative to HGs, when the latter are unavailable. The choice of eithervalved conduit did not influence the durability of the RV-PA conduit in truncusarteriosus. A randomized multi-center controlled trial with long-term follow-up isstill needed to solve the HG/BJV debate.


Due to the heterogeneity of anatomic anomalies in Ebstein’s anomaly (EA), particularly in the subset of patients with atrial septal defect (ASD), hemodynamic changes, which ultimately cause left ventricular (LV) deterioration remain unclear. The current study aimed to investigate the effect of concomitant ASD on LV function using cardiovascular magnetic resonance (CMR) imaging in patients with EA.This study included 31 EA patients with ASD, 76 EA patients without ASD, 35 patients with simple ASD and 40 healthy controls. Left/right ventricular  volumes and functional parameters, LV strain parameters, and echocardiogram indices were compared among the four groups. Associations between variables were evaluated via Spearman or Pearson correlation analyses. The association between risk factors and LV ejection fraction (EF) was determined via multivariate linear regression analysis.Both EA patients and ASD patients had a higher RV/LV end-diastolic volume (RVEDV/LVEDV) as well as lower LV and RV ejection fractions (LVEF/RVEF) compared to healthy controls . Moreover, the EA patients with ASD had a significantly higher RVEDV/LVEDV and a lower LVEF and RVEF than those without ASD . Multivariate linear regression analysis revealed that the presence of ASD was independently associated with LVEF . The RVEDV/LVEDV index was associated with LVEF . Furthermore, the LV longitudinal peak diastolic strain rate (PDSR) was lower in EA patients with ASD than those without ASD, patients with simple ASD, and healthy controls (p < 0.05).Concomitant ASD is an important risk factor of LV dysfunction in patients with EA, and diastolic dysfunction is likely the predominate mechanism related to LV dysfunction.The online version contains supplementary material available at 10.1186/s12968-023-00976-3. Ebstein’s anomaly (EA) is a rare congenital malformation caused by tricuspid valve (TV) delamination failure. The dysplastic and tethered TV  is offset toward the apex of the right ventricle (RV), with subsequent atrialization of the RV inlet. Any remaining inlet portion below the tethered TV, the trabeculated RV, and the RV outflow tract comprise the functional right ventricle (fRV) . These aCardiovascular magnetic resonance (CMR) imaging is a complementary imaging modality to echocardiography. Furthermore, it has emerged as the gold standard for evaluating the function and size of the LV and RV, which can help in risk stratification and treatment decision-making in patients with EA , 8. TherPatients diagnosed with EA based on echocardiogram results in our registry database from July 2013 to November 2022 were evaluated . This stThe current study was approved by the Biomedical Research Ethics Committee of our hospital. The electronic medical records of the patients were reviewed, and data on the New York Heart Association (NYHA) functional classification and echocardiographic parameters  were recorded.2; matrix size 256 × 166/256 × 144). Late gadolinium enhancement (LGE) imaging was conducted for 10–15 min after the intravenous administration of gadolinium contrast (0.15 mmol/kg) using a T1-weighted inversion recovery turboFLASH sequence .CMR imaging was performed using a 3 T MR scanner . All participants were examined according to the standardized imaging protocol for congenital heart disease . Cine imAll CMR imaging data were analyzed using a commercially available software . The LV volume and functional parameters including end-diastolic volume, end-systolic volume, stroke volume, and ejection fraction (EF) were acquired, as described in a previous study , 13. To All statistical analyses were performed using SPSS statistical software  and GraphPad Prism . Continuous variables were presented as means ± standard deviations or as medians and interquartile ranges. Normality was evaluated using the Kolmogorov–Smirnov test, and the homogeneity of variance was assessed using the Levene’s test. One-way analysis of variance was used to compare variables among the healthy control, ASD, EA with ASD, and EA without ASD groups. Then, post hoc analysis was performed using the Bonferroni’s correction. Binary variables were analyzed using the cross tabs chi-square test. Associations between variables were investigated via Spearman or Pearson correlation analyses. Further, univariate factors related to the LVEF with a p-value of < 0.1 were then included in the stepwise multivariate analysis. A p-value of < 0.05 was considered statistically significant.The final study cohort comprised 107 patients with EA, 35 patients with simple ASD, and 40 healthy controls. Atrial septal defects were confirmed on echocardiogram in patients with EA . Among 1As shown in Table On CMR images, LGE was identified in 30/107 28%) of EA patients, mainly occurred at subendocardium of the RV and/or basal and middle septum . However, CMR imaging is more effective in quantifying the size and function of the right ventricle , 8. It iOur study revealed that EA patients with ASD had a significantly higher RVEDV/LVEDV index than those without ASD, indicating that those patients with ASD had a more severe LV compression caused by an enlarged RV. Further, the RVEDV/LVEDV index was associated with LVEF. However, EA patients with ASD had a significantly higher rate of severe TR, which also increased the volume load of the RV. In addition, EA patients with ASD had a more severe tricuspid valve leaflet displacement and a higher incidence of LGE +, which indicated a more severe disease. Thus, it was challenging to conclude that differences in RV/LV size and function between the two EA subgroups were attributed to the presence of ASD. These variations might be caused by the fact that EA patients with ASD also had a more severe anatomic variant with more severe TR. To correct confounding factors affecting the LVEF, we conducted a multivariate linear regression analysis. The results showed that the presence of ASD was independently associated with LVEF, confirming that the presence of ASD is an extremely important risk factor of LV dysfunction.TR and left-to-right shunt caused by ASD can lead to RVVO. In this study, the RVEDVI were significantly greater in EA patients and in ASD patients, which was not surprising. In some patients with EA, ASD was found, and could cause a right-to-left shunt owing to increased right heart pressures and compliance deterioration, which can contribute to right-side overload discharge . HoweverInterestingly, EA patients with ASD had a significantly lower LVEDVI than healthy controls and EA patients without ASD. However, there was no significant difference in LVEDVI between healthy controls and EA patients without ASD. This might be attributed to the fact that the LV filling pressure of patients with EA generally remains within the normal range due to compensatory effects, and the LV filling pressure is impaired if the RVVO increases to a certain extent. Further, the EA with ASD group had a significantly lower LVEF and RVEF than the EA without ASD group. Although the patients without ASD had a lower LVEF than healthy controls, its average is still within the normal range (> 55%). We believe that RVVO coupled with RV pump dysfunction leads to a diminished RV output, thereby resulting in a reduced effective preload on the LV and a compromised LV cardiac output, which is consistent with the previous concept .A previous study found that the presence of LV dysfunction could independently predict late mortality. Further, it was considered a high-risk factor for mortality after surgery , 23. TheThe current study had several limitations. First, our cohort only comprised a small number of patients with EA with ASD, and the statistical power was limited. However, the number of patients with EA in this study was relatively larger than that in other published studies. Second, this was a retrospective study with all its inherent limitations. Not all patients with EA on echocardiography had data on the ASD size, which inhibited the further investigation of ASD effects on LV function. Finally, our patient groups might be biased because we studied only adult patients with EA and with ASD who were referred to CMR. As this was a cross-sectional study, larger studies with a longer observation period must be performed to evaluate the CMR-derived indices believed to be associated with specific outcomes.In conclusion, concomitant ASD is an important risk factor of LV dysfunction in patients with EA. Based on the LV strain parameters of patients with EA, mainly the PDSR decreased, indicating that the diastolic dysfunction is likely the predominate mechanism related to LV dysfunction. Hence, the normalization of loading conditions at end-diastole can mainly improve LV function in patients with EA.Additional file 1: Table S1. CMR Parameters between non-cyanotic EA + ASD Patients and cyanotic EA + ASD Patients. Table S2. Left Ventricle Strain Parameters Difference between non-cyanotic EA + ASD Patients and cyanotic EA + ASD Patients.


In patients with heart failure, empagliflozin offers significant cardiovascular benefits. However, its exact mode of action is unknown. Understanding the way by which empagliflozin works in heart failure may uncover additional therapeutic targets or identify other classes of drugs that may be useful to clinicians and patients. This literature review aims to unravel the mysteries by which empagliflozin reduces cardiovascular death, cardiovascular events, and heart failure hospitalization in diabetic and non-diabetic patients. Three researchers conducted the data collection. We incorporated research that used human models, animal models, patients with diabetes, and patients without diabetes. Pathology, pathophysiology, metabolism, physiology, empagliflozin, heart failure, and cardiovascular were the search terms used to probe the mesh database on PubMed. This study showed that the mechanisms by which empagliflozin could lead to positive clinical outcomes in heart failure (HF) are as follows: down-regulation of the mammalian target of rapamycin complex 1 signaling (mTORC), decreasing sarcoplasmic reticulum calcium loss, increasing cytosolic calcium loss, inducing electrolyte-free osmotic diuresis, improving fuel efficiency, and protecting the endothelial glycocalyx. These findings were inconsistent, with no generally accepted hypotheses within the scientific community. Hence we conclude that further research is required to determine the function of Empagliflozin in heart failure and the degree to which the aforementioned mechanisms of action contribute to cardiac protection. Heart failure (HF) continues to pose a significant threat to the US healthcare system. As the population ages, the number of newly diagnosed cases, already approaching one million per year, is expected to rise ,2. CurreThe goal of the empagliflozin cardiovascular outcome event trial in type 2 diabetes mellitus patients-removing excess glucose (EMPA-REG) outcome was to assess the safety of empagliflozin (EMPA) in patients with type 2 diabetes who were at high risk of cardiovascular (CV) events. HF deaths with EMPA were calculated to be 3.7%, compared with 5.9% with placebo. Hospitalization rates were also lower in patients taking EMPA (2.4% vs. 4%) . The empAim of studyWhile there seems to be consensus on the benefit of SGLT2 inhibitors in HF patients, the mechanism of action by which it exerts this effect is not clearly understood. It is the aim of this study to examine the literature on the proposed mechanisms by which EMPA exerts its effect in improving heart failure outcomes.Research methodTo gather information for this literature review, only one database-PubMed-was used. We used the Mesh database tool, and our search terms included mixtures of the following words: pathology, pathophysiology, metabolism, physiology, empagliflozin, heart failure, and cardiovascular. We included articles that dealt with both diabetic and non-diabetic subjects, but we left out any details about other medications in the same class. No additional inclusion or exclusion criteria were used. Ninety-eight papers, all published between 2013 and 2023, were found in our search. Three researchers independently reviewed each article as part of the data-gathering process.DiscussionEmpagliflozin Suppression of the mTORC PathwayIn the study conducted by Pabel et al., myocardial tissue from patients with HFpEF exhibited decreased phosphorylation of the myofilament proteins titin, troponin I (TnI), and myosin binding protein C (MyBPC) compared to non-failing heart myocardium . PatientEMPA also increased the expression of the CD 36 cluster of differentiation, which aids in fatty acid oxidation and energy availability -19. ThesEmpagliflozin Regulation of Calcium Within MyocytesDuring heart failure, calcium (Ca2) levels increase. When Ca2 binds to troponin C it activates the actin/myosin filaments, resulting in myocardial stiffness and diastolic dysfunction in susceptible individuals. EMPA is able to combat these effects through its inhibition of the myocardial Na-H exchanger that decreases Ca and Sodium (Na) cytosol levels . AnotherEmpagliflozin Natriuretic and Diuretic EffectsImpaired diastolic function is present at an early stage of heart failure pathophysiology and is characterized by high left ventricular filling pressure and increased preload. EMPA's ability to regulate pressure inside the heart and blood vessels is one mode of action by which it may exert its beneficial cardiovascular effects in patients with heart failure. Electrolyte-free osmotic diuresis is caused by glycosuria when EMPA inhibits SGLT2 receptors on proximal convoluting tubules . HyponatAlthough the diuretic effects of EMPA are well established, the extent to which this explains the beneficial cardiac effects observed with the use of EMPA in HF treatment needs further investigation. The diuretic effects of empagliflozin make this medication dangerous in patients with a glomerular filtration rate (GFR) is less than 20mL/min/1.73 m2.Figure Empagliflozin and the Efficient Fuel HypothesisAccording to the efficient fuel hypothesis, left ventricle ejection fraction (LVEF) can decrease and Left ventricle (LV) mass can increase when fuel is scarce . CardiovSantos-Gallego et al.'s findings that EMPA-treated non-diabetic pigs had increased myocardial ATP content and improved myocardial work efficiency supported this theory . CompariEmpagliflozin Effects on the Endothelial GlycocalyxProteoglycans and glycoproteins hold the endothelial glycocalyx, a layer rich in carbohydrates that resembles a gel, to the vascular endothelium. It guards blood vessels against moving inflammatory cells, serves as a transducer for fluid shear stress, and controls nitric oxide release. Damage to the endothelium's glycocalyx from hyperglycemia results in endothelial dysfunction, which in turn causes atherosclerotic cardiovascular disease. As a result, there is increased vascular permeability in the presence of hyperglycemia as well as increased activation of the coagulation cascade and increased expression of SGLT1 and SGLT2 receptors . The ideEmpagliflozin is thought to prevent atherosclerotic cardiovascular disease and maintain the health of the endothelial glycocalyx by bringing the level of senescence markers, including Endothelial nitric oxide synthase (eNOS), tissue factor, vascular cell adhesion molecule 1 (VCAM-1), and SGLT1 and 2, to levels comparable to those in the outer aortic arch curvature . We willDespite the long list of cardio-protective benefits of EMPA in heart failure the cost and availability of the drug pose a challenge to its use worldwide. Figure Scientific QuestionCan knowledge of EMPA's mechanism of action in the treatment of heart failure aid in the identification of new therapeutic targets or identify other drug classes that may be useful to clinicians in treating heart failure?LimitationsIt is important to draw attention to this study's flaws. First off, not all potential mechanisms by which EMPA has cardioprotective effects may be covered in this research article. This is due to the investigators' bias in trying to discuss mechanisms of action that they felt were well-researched and described. Additionally, the scope of our study was restricted to a single database and a single, clearly defined search strategy. Outside of these restrictions, there may be a large number of other published and unpublished articles putting forth various possible mechanisms of action by which EMPA protects the heart in heart failure patients. Therefore, our study should be viewed as a summary of some of the numerous hypotheses that have been put forth regarding the therapeutic effects of EMPA in heart failure. It should encourage additional studies to determine how and to what extent these hypotheses account for the observed excellent clinical outcomes of EMPA in HF patients.We concluded that the mechanism by which EMPA is beneficial in heart failure remains unknown. Some proposed modes of action include suppression of the mTORC1 pathway, regulation of calcium in the sarcoplasmic reticulum and in the cytosol, electrolyte-free osmotic diuresis, improved fuel efficiency, and protection the the endothelial glycocalyx. As more studies are conducted we are confident that the mysteries by which EMPA is helpful in heart failure will be unrevealed.


Myocardial injury assessment from delayed enhancement magnetic resonance images is routinely limited to global descriptors such as size and transmurality. Statistical tools from computational anatomy can drastically improve this characterization, and refine the assessment of therapeutic procedures aiming at infarct size reduction. Based on these techniques, we propose a new characterization of myocardial injury up to the pixel resolution. We demonstrate it on the imaging data from the Minimalist Immediate Mechanical Intervention randomized clinical trial (MIMI: NCT01360242), which aimed at comparing immediate and delayed stenting in acute ST-Elevation Myocardial Infarction (STEMI) patients.We analyzed 123 patients from the MIMI trial . Early and late enhancement images were transported onto a common geometry using techniques inspired by statistical atlases, allowing pixel-wise comparisons across population subgroups. A practical visualization of lesion patterns against specific clinical and therapeutic characteristics was also proposed using state-of-the-art dimensionality reduction.p-value <0.05, mainly in these regions). In contrast, global measurements were comparable for all territories , although immediate stenting resulted in more subjects without reperfusion injury.Infarct patterns were roughly comparable between the two treatments across the whole myocardium. Subtle but significant local differences were observed for the LCX and RCA territories with higher transmurality for delayed stenting at lateral and inferior/inferoseptal locations, respectively (15% and 23% of myocardial locations with a Our approach substantially empowers the analysis of lesion patterns with standardized comparisons up to the pixel resolution, and may reveal subtle differences not accessible with global observations. On the MIMI trial data as illustrative case, it confirmed its general conclusions regarding the lack of benefit of delayed stenting, but revealed subgroups differences thanks to the standardized and finer analysis scale. The lon (MVO) –6, whichon (MVO) , but areComputational tools inspired by statistical atlases can overcome the main bottleneck to a finer analysis of such lesions, namely anatomical differences across subjects and acquisitions . First, In this paper, we re-examined the delayed enhancement images from the Minimalist Immediate Mechanical Intervention (MIMI) trial  with suc2.2.1.This study retrospectively analyzed the imaging data from the MIMI study , which was a multicenter, prospective, randomized, open-label trial with blinded endpoint evaluation. The study protocol was approved by the local ethics committee (IRB 2010–048), and complied with the Declaration of Helsinki and French laws. All subjects gave written informed consent.The included patients were adults with symptoms consistent with STEMI ≤12 h, with ST-segment-elevation ≥1 mm in ≥2 contiguous limb leads or >2 mm in ≥2 precordial leads on the electrocardiogram, intended for primary percutaneous coronary intervention. The clinical and angiographic inclusion criteria and the intervention procedure were detailed in Belle et al. .Patients were randomized between two different strategies: immediate stenting or 24–48 h delayed stenting. The primary endpoint was MVO [% of left ventricular (LV) mass] on cardiac magnetic resonance performed 5 days (interquartile range 4–6) after inclusion.2.2.The MRI protocol was performed in multiple centers 3 to 8 days after inclusion on 1.5 T systems. The analysis performed in this paper focused on EGE and LGE images for which LV and lesion segmentation was feasible , obtaineThe myocardial and lesion contours were manually segmented offline by one experienced observer (LP) and controlled by two other experienced observers  using commercial software . They consisted of the endocardium, epicardium, infarct (from LGE), and early and late MVO  . The infThe LV-RV junction was manually identified by one experienced observer (ND) using a single landmark on each slice. The myocardial borders around the LV outflow tract were marked by two landmarks to exclude this region on the concerned slices. Finally, the slice locations corresponding to the endocardial apex and the mitral level  were identified. These locations were extrapolated in case the acquisition did not cover such slices.2.3.We first parameterized the myocardium by defining radial, circumferential, and long-axis coordinates on each slice, for each individual. They were estimated on images oversampled by a factor 4 to prevent artifacts in case few pixels covered the myocardium, in particular along the radial direction. Their values ranged from 0 to 1, corresponding to endocardium-to-epicardium , apex-to-base (long-axis), and the anticlockwise direction starting from the LV-RV junction , as illustrated in Then, we arbitrarily defined a common reference geometry onto which standardizing the image data, as a semi-ellipsoid with maximal endocardial and epicardial radii of respectively 30 and 50 pixels, represented on 21 slices of 80 × 80 pixels each  . No extr2.4.p-value from the Hotelling t-squared test (performed on the pixel map), displayed in a logarithmic color scale.Once standardized onto a common geometry, lesions can be compared at each pixel of the myocardium in the EGE and LGE images. We first estimated the representative (average) infarct pattern for each coronary territory and each treatment subgroup, and visualized it at each slice of the reference geometry . A Bull’2.5.Despite being standardized onto a common geometry, the infarct patterns still contain a lot of information, which is challenging to visualize and relate to other patient characteristics. We therefore estimated a simplified representation of all the individual subjects in the studied population that can be visualized in two dimensions. To do so, we used the t-SNE (T-distributed Stochastic Neighbor Embedding) algorithm , a widesOn our data, t-SNE provided a two-dimensional cloud of points where each point corresponds to a sample in the population, while forcing similar patterns to be represented by nearby points, and conversely dissimilar patterns to be represented by distant points. Then, we examined the link between infarct patterns and other variables of interest by coloring each point according to the value of the variable we inspect. We focused on a subset of relevant clinical and therapeutical variables related to patients’ risk: coronary artery of concern, ejection fraction, stenting strategy, delay from onset of symptoms to coronary intervention, sex, age, diabetic status, smoking status, and body mass index.This was implemented in Python, using a public open-source version of t-SNE from the scikit-learn libraryBefore applying t-SNE, infarct patterns were realigned to the left anterior descending (LAD) territory, to better focus on the pattern shape without being confounded by different infarct localizations and analyse all the population at once. This was achieved by rotating all infarct patterns along the circumference such that the average infarct center of a given coronary territory is aligned to the average infarct center for the LAD territory, as previously reported .2.6.We also estimated commonly-used global descriptors of the main lesion characteristics: the proportion of damaged myocardium , the average transmurality over the infarcted myocardium , and the endocardial surface area (in %). These characteristics were both estimated before and after standardization to the reference geometry to quantify the consistency of global observations regarding standardization .2.7.The identification of the LV-RV junction on each slice, and the identification of the apex and mitral valve slice locations were repeated by the same operator and another experienced operator (LP). The reproducibility of these measurements  and its 2.8.P-values below 0.05 were considered statistically significant. All the patient and the global lesion characteristics were analyzed using the SPSS software .Standard statistical analysis was performed in complement of the pixel-wise analyses exposed in the previous sections, as follows. Continuous variables were expressed as median and interquartile range, with Mann-Whitney U-test used for inter-groups comparisons. Categorical variables were expressed in percentage over the number of samples, with Fisher’s exact test used for inter-groups comparisons. 3.3.1.The original MIMI study enrolled 160 patients between June 2011 and December 2012, of which 140 patients had interpretable MRI scans . In the The median resolution of the analyzed images was 1.5625 × 1.5625 × 5 mm. The LV ranged over 17 ± 2 slices, with 1 ± 1 extra slices lying out of the acquired stack of slices.3.2.p-value” Bull’s eye, which quantified statistical differences between the two treatment groups at each location. The LAD mid and LAD proximal groups respectively had 9% and 13% of myocardial locations with a p-value <0.05, but rather sparsely distributed across the ventricle and not necessarily matching the infarct zone. In contrast, the LCX and RCA groups respectively had 15% and 23% of myocardial locations with a p-value <0.05, including marked statistical differences grouped over a portion of the infarct zone.Infarct patterns  were roughly comparable between the two treatments for all territories and across all slices. However, for the left circumflex (LCX) infarcts, higher transmurality was observed with delayed stenting at the lateral locations  vs. 53% (delayed)). A similar trend was observed for the right coronary artery (RCA) infarcts at the inferior/inferoseptal locations  vs. 38% (delayed)). These subtle observations were confirmed by the “Early MVO was absent in 28/117 patients: 16/61 (28%) with immediate stenting and 12/56 (23%) with delayed stenting. Late MVO was absent in 48/123 patients: 32/65 (49%) with immediate stenting and 16/58 (28%) with delayed stenting. No infarct was observed in one patient .3.3.We first observe that even when this anatomical alignment was performed, the shapes of infarct patterns showed anatomical consistency across subjects from the same coronary artery. The shapes of LAD infarcts were quite similar, while RCA and LCX infarcts showed more dissimilar shapes that are likely related to broader anatomical and collaterality variations across patients having RCA and LCX culprit arteries. A more subtle grouping of patterns was observed regarding ejection fraction, which might reflect the varying impact of each coronary artery on the cardiac function. In contrast, no specific grouping of patterns was observed for the stenting strategy, confirming the main finding of the MIMI study. The lack of grouping of patterns for all the other selected variables  indicated the lack of bias and the quality of randomization.Similar observations were obtained by multiple launches of the t-SNE algorithm, which confirmed results against the random state intrinsic to this algorithm.3.4.3.5.p-value quantifying statistical differences between the two treatment groups, for identification of the LV-RV junction and basal/apical slices repeated by the same operator or by a second one. Patterns are very similar to the ones in Finally, 4.We proposed a fresh look at the characterization of myocardial lesions (infarct and early/late MVO) to go beyond global assessment with quantitative and standardized comparisons up to the pixel resolution. On the delayed enhancement imaging data from the MIMI study, which aimed at assessing acute myocardial infarction patients while comparing different reperfusion strategies, our results not only confirmed at a much finer resolution and in a more standardized manner that immediate and delayed stenting led to comparable infarct and reperfusion lesions, but revealed a deleterious effect of delayed stenting at specific locations. They also indicated that the infarct shape was not related to other clinical and therapeutic variables of interest.Comparing delayed vs. immediate stenting highly depends on the chosen MRI endpoints . In the In the literature, the lack of clear differences between treatment options may also come from the simplicity of global descriptors  to assess lesions of complex shapes. Many studies investigating the cardiac function, not necessarily with MRI, already underlined the value of regional or local descriptors of the observed diseases , 16. OurStatistical atlases have been widely used to quantify shape differences across of a population , as rece4.1.Seventeen patients were not analyzed due to technical issues related to the image quality. Besides, our population size was moderate, and the statistical analysis of lesion patterns may be affected by this sample size, in particular in case of small or unbalanced subgroups as observed for some territories. We therefore supported as much as possible our observations with complementary measurements .Spatial alignment required the semi-automatic segmentation of the myocardium and the manual identification of few landmarks on each slice, which is time-consuming and needs careful quality control in the current implementation. This could be solved by considering recent advances in the automatic segmentation of delayed enhancement MRI, when its accuracy reaches acceptable ranges on all slices on routine imaging data , 24.Non-linear statistical analysis techniques may overcome some limitations of the techniques we used here to estimate representative lesion patterns , 25, but5.Our methodology allows assessing the acute myocardial infarction lesions much beyond commonly used global descriptors while delivering a synthetic picture of a population, and could be used for standardized reporting in many cardiac MRI clinical research studies. This approach provides quantitative finer insights into how lesions differ between subgroups of subjects, and enables to locate a given subject within the population/group response in a logic of personalized medicine. On the MIMI study, it confirmed at a much finer scale the comparable myocardial damage between immediate and delayed stenting, and even suggested a deleterious effect of delayed stenting visible at some locations. This strategy appears highly promising to analyze in a much more integrated manner the multi-parametric and longitudinal data from ischemia-reperfusion studies, and better state on potential therapies to reduce myocardial loss after myocardial infarction.


Recent evidence underlined the importance of right (RV) involvement in suspected myocarditis. We aim to analyze the possible incremental prognostic value from RV global longitudinal strain (GLS) by CMR.Patients referred for CMR, meeting clinical criteria for suspected myocarditis and no other cardiomyopathy were enrolled in a dual-center register cohort study. Ejection fraction (EF), GLS and tissue characteristics were assessed in both ventricles to assess their association to first major adverse cardiovascular events (MACE) including hospitalization for heart failure (HF), ventricular tachycardia (VT), recurrent myocarditis and death.Among 659 patients , RV GLS was impaired (> − 15.4%) in 144 (21.9%) individuals, of whom 76 (58%), 108 (77.1%), 27 (18.8%) and 40 (32.8%) had impaired right ventricular ejection fraction (RVEF), impaired left ventricular ejection fraction (LVEF), RV late gadolinium enhancement (LGE) or RV edema, respectively. After a median observation time of 3.7 years, 45 (6.8%) patients were hospitalized for HF, 42 (6.4%) patients died, 33 (5%) developed VT and 16 (2.4%) had recurrent myocarditis. Impaired RV GLS was associated with MACE , HF hospitalization , and death , but not with VT and recurrent myocarditis in univariate analysis. RV GLS lost its association with outcomes, when adjusted for RVEF, LVEF, LV GLS and LV LGE extent.RV strain is associated with MACE, HF hospitalization and death but has neither independent nor incremental prognostic value after adjustment for RV and LV function and tissue characteristics. Therefore, assessing RV GLS in the setting of myocarditis has only limited value.The online version contains supplementary material available at 10.1186/s12968-023-00957-6. Myocarditis is an important cause of heart failure (HF) that has recently gained attention due to the increasing number of patients undergoing high-sensitive noninvasive imaging modalities for myocardial tissue characterization such as cardiac magnetic resonance imaging (CMR). Both, clinical presentation and long-term outcomes of patients with myocarditis vary and can range from asymptomatic, mild and benign course to patients that suffer from a large spectrum of adverse cardiac events including HF with need for hospitalizations, ventricular tachycardia (VT), recurrent myocarditis, and death –3. This The design of the ‘Inflammatory Cardiomyopathy Bern Registry’ (FlamBeR) NCT04774549) and the ‘CMR Features in Patients With Suspected Myocarditis’ (CMRMyo) (NCT03470571) registry was previously described 49 and th. The ind2 and > 123 ml/m2) were defined according to Kawel-Boehm et al. as the lower limit of the mean in healthy volunteers [CMR was performed at 1.5- or a 3.0 Tesla scanner  as previously described , 9. Patilunteers   in both2 and compared to the subsequent model by a likelihood ratio test. Variables with > 10% missing values  were excluded. Time to event curves were plotted according to the Kaplan–Meier method. Results were considered to be statistically significant if the two-sided p-value was < 0.05.Statistical analysis was performed with IBM SPSS Statistics 25  and R software version 4.1.3 . Results are presented as absolute frequencies (percentages) or as mean ± standard deviation (SD) whenever appropriate. Non-normally distributed variables were provided as the median with the corresponding interquartile range (IQR). Bivariate Pearson correlation was used to describe a correlation between RV GLS and other parameters of LV and RV function. Uni- and multivariate Cox regression was used to investigate associations to primary and secondary endpoints. The prognostic capability of stepwise models with sequentially included variables was evaluated by the goodness of fit, indicated by χ1125 patients referred to CMR for suspected myocarditis were screened for eligibility. Of those, 75 patients were excluded due to known  or suspected (according to CMR) coronary artery disease, 40 patients due to evidence of other structural cardiomyopathy and 4 patients due to known pulmonary artery hypertension. Among the remaining 941 patients, 162 did not meet ESC-criteria for clinically suspected myocarditis, in 114 RV strain analysis was not possible due to poor image quality, RV foreshortening, or breathing or arrhythmic artefacts and 6 0.53%) were lost to follow-up. Finally, 659 patients  male) were included . Implementing RV GLS in addition (model 1b) or instead of LV GLS (model 1c) did not significantly improve prognostication .During the observation time of median 3.7 (IQR 2.1 to 6.3) years, first MACE occurred in 115 patients (17.6%), of whom 45 (6.8%) patients were hospitalized due to HF, 42 (6.4%) patients died, 33 (5%) developed VT and 16 (2.4%) suffered from recurrent myocarditis. A total of 21 patients experienced more than one event type. Univariate Cox regression analysis demonstrated the significant association of female gender, elevated N-terminal pro-hormone brain natriuretic peptide (NT-proBNP), LV LGE and LV LGE extent, reduced LVEF and RVEF, LV strains and RV GLS to the combined endpoint (Table model 2a) as reported previously [model 2b) did not improve prognostication . However, implementing RV GLS instead of LV GLS in the newly constructed model 2c achieved comparable prognostic capability, as reflected by a significant model χ2 of 80.8 (p = 0.048 vs. without RV GLS). RV GLS remained independently associated with the occurrence of HF hospitalizations, adjusted to the effects of the other variables in the model . Regarding the other secondary endpoints, RV GLS was univariately associated with death , but not after adjustment for LVEF and RVEF or LV GLS  which makes it acquisition less time-intensive, but on the other hand also prone to impaired image quality. In our study, a relevant number of patients had to be excluded from RV based image analysis due to arrhythmia, breathing artefact, or foreshortening in the RV which limited the interpretation of our findings.Improvement of RV image acquisition with dedicated RV focused views  and RV adapted inversion time, could minimize the exclusion of images and help to exploit the additional information from RV tissue characteristics and RV function, including biplane RV GLS and radial or circumferential RV strain in future studies.As previously discussed , impaireRegarding other imaging parameters, this study confirmed the high prognostic power of LV LGE and LV GLS in suspected myocarditis, which were both independently associated with MACE. The sole presence of LV LGE was associated with the composite of MACE and VT, but not with death, which contrasts prior studies , 36. MyoOur findings underline the important role of CMR in suspected myocarditis. CMR does not only allow to accurately assess LV dimension/function and tissue characteristics, but also proved to inherit important information from RV function. Echocardiography represents a reproducible method to derive RV GLS and RVEF but may be challenging in patients with impaired echo window , and RV The retrospective design of this observational study inherits several limitations. The lack of standardized blood sampling protocols goes along with a relevant number of missing values for biomarkers such as NT-proBNP and troponin and their prognostic relevance could not be fully assessed. The prognostic implications of features that were incorporated in our inclusion criteria (e.g. sole presence of LGE or elevated biomarkers such as NT-proBNP) might be underestimated. Secondly, in order to cover the full spectrum of myocarditis, we included patients with clinically suspected myocarditis according to standardized criteria, which is one of the most common reasons for referral to CMR . NeverthRight ventricular global longitudinal strain determined by CMR feature tracking is associated with first MACE, heart failure hospitalizations and death in the univariate analysis, but has neither independent nor incremental prognostic value after adjustment for LV/RV-function and tissue characteristics. Although RV GLS may provide some prognostic value for heart failure hospitalizations, its overall utility as a predictor of adverse cardiovascular events in the clinical setting of myocarditis remains limited.Additional file 1: Table S1. Baseline characteristics in patients with and without major adverse cardiovascular events (MACE).