The aim of this study was to determine how sacubitril/valsartan compared with valsartan in an outpatient setting affects left ventricular remodeling in heart failure with reduced ejection fraction and functional (or secondary) mitral regurgitation (SMR) due to the effect of dual inhibition of the renin-angiotensin system and neprilysin. The outpatient study included 90 patients with chronic SMR who were followed up for 12 months. They received sacubitril/valsartan or valsartan instead of the more commonly used angiotensin-converting enzyme inhibitor enalapril for heart failure, in addition to standard medical therapy for heart failure. The difference in NT-proBNP change between groups was the primary endpoint. Changes in effective regurgitation orifice area, left ventricular ejection fraction, left ventricular end-systolic and end-diastolic volume indices, left atrial volume index, E/e' index, and exercise tolerance on the 6-minute walk test were secondary endpoints. In the treatment efficacy analysis, NT-proBNP levels decreased significantly by 37% in the sacubitril/valsartan group and by 11% in the valsartan group (P<0.001). Ejection fraction and exercise tolerance  increased in the sacubitril/valsartan group (P<0.05). Also, in this group, the effective area of the regurgitation orifice, the left atrial volume index, the E/e' index, and the indices of the end-systolic and end-diastolic volume of the left ventricle (P<0.05) decreased more pronouncedly. Compared with valsartan, treatment with sacubitril/valsartan led to a significant improvement in cardiac remodeling in patients with SMR and heart failure with reduced ejection fraction. Heart failure (HF) is a multisystemic disease characterized by significant disturbances in cardiac physiology and a multitude of myocardial structural and functional changes . HF remaCommon diseases such as hypertension, coronary heart disease, diabetes mellitus, chronic kidney disease, and chronic heart failure may be accompanied by functional (or secondary) mitral regurgitation (SMR). Valvular heart disease accounts for 7-8% of HF cases. SMR occurs when normal or near-normal mitral leaflets fail to close adequately due to underlying left ventricular (LV) dysfunction or dilatation of the mitral annulus. SMR often occurs in CHF with reduced left ventricular ejection fraction as a result of LV remodeling that prevents coaptation of the valve leaflets. SMR has a worse prognosis than primary mitral regurgitation (MR). Despite the great diversity and improvements of drug therapy and surgical interventions, SMR continues to progress in most cases. This leads to further remodeling of the left ventricular myocardium and deterioration of the HF functional class in patients. The binary approach to MR, being either a primary valvular problem or valvular regurgitation secondary to ventricular dysfunction, should be considered, which may have therapeutic value. Drug therapy is limited for primary MR .The results of the COAPT study  have revived enthusiasm for transcatheter mitral valve repair in SMR . PatientThe Mitra-FR trial   is anothGuideline-based medical therapy is important because MR is dynamic and changes in response to medications, loading conditions, and hemodynamics.These studies highlight the importance of aggressive drug therapy for heart failure with reduced ejection fraction (HFrEF) and open the door to targeted therapy in patients with a significant burden of SMR that can contribute to left ventricular systolic dysfunction and volume overload. Effective drug therapy reverses LV remodeling and decreases the degree of mitral regurgitation in SMR .In the case of SMR and HF, the treatment of choice includes beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRA), which can partially attenuate LV dilatation and remodeling after myocardial injury. Recently, sacubitril, a new combination of valsartan and neprilysin inhibitor, which has more pronounced hemodynamic and neurohormonal effects, has been used as a replacement for ACE inhibitors or ARBs in HFrEF patients .The main objective of our study was to verify whether sacubitril/valsartan is better at reversing LV remodeling in HFrEF with SMR than valsartan alone in an outpatient setting because of the dual inhibition of the renin-angiotensin system and neprilysin.A single-center, controlled, prospective, non-randomized outpatient study was performed.2 lasting more than 6 months despite treatment with beta-blockers and ACE inhibitors (or ARBs). Patients were required to be on a stable dose of beta-blockers and ACE inhibitors (or ARBs) for at least 4 weeks prior to screening  at least 36 h before the appointment for sacubitril/valsartan medication).Screening inclusion criteria included age ≥40 years, stable HF with New York Heart Association (NYHA) class II or III symptoms, EF 35 to 40%, and duration of significant SMR >6 months, which were assessed using transthoracic echocardiography (EchoCG). Significant SMR has the following criteria: normal mitral valve leaflets and chords, regional or global LV wall motion abnormalities with leaflet fixation, and MR with an effective regurgitation orifice area of >0.1 cm2, serum potassium level >5.0 mmol/L, or a history of angioedema. Patients were also excluded from the study if they had any evidence of structural mitral valve disease, NYHA class IV symptoms, previous valvular intervention, hospitalization within the previous 6 weeks, a history of acute coronary syndrome, stroke, cardiovascular surgery or percutaneous coronary intervention within 3 months, significant myocardial ischemia requiring coronary revascularization, planned coronary revascularization, and mitral valve intervention.Screening exclusion criteria included systolic blood pressure <100 mmHg, glomerular filtration rate <30 mL·min·1.73 mThe study was conducted at the Clinical Diagnostic Center No. 4 (Russia) from December 2018 to December 2019, inclusive.The study protocol was approved by the Joint Ethics Committee . All necessary permits were received. Written informed consent was obtained from all participants prior to enrollment in the study. The study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki.The sample size was determined using an online statistical processing calculator for medical research data. Two groups matched for sex, age, and disease stage were recruited. The present study patients were divided into two groups: 46 patients took valsartan and 44 received sacubitril/valsartan (36 h after the last dose of ACE inhibitors). Patients started taking valsartan at 40 to 80 mg twice daily or sacubitril/valsartan at 24/26 to 49/51 mg twice daily. The dose was titrated based on tolerability at 4-week intervals up to the maximum dose of 160 mg twice daily for valsartan or 97/103 mg twice daily for sacubitril/valsartan. All other medications  were continued. Patients were treated for 12 months.The primary endpoint was the between-group difference in NT-proBNP change over 12 months of follow-up.The secondary endpoints included between-group differences in change in the effective regurgitation orifice area in SMR, left ventricular ejection fraction, left ventricular end-systolic and end-diastolic volume indices, left atrial volume index, E/e' index, and exercise tolerance  at 12 months of follow-up.The cardiac biomarker NT-proBNP was analyzed in the laboratory using stored samples collected prior to administration of the study medicines and after 12 months of treatment. The concentration of NT-proBNP in blood serum was determined by solid-phase chemiluminescence enzyme immunoassay (sandwich assay) using IMMULITE 2000 analyzer with commercial NT-proBNP kits .EchoCG is the gold standard in the diagnosis of SMR in HFrEF. Echocardiographic evaluation was performed at baseline and at the 12-month follow-up visit. EchoCG was performed in standard projections using ultrasonic devices Logiq 500 and Vivid 3 Expert  in greyscale, M- and B-modes. Color, continuous, and pulsed wave Doppler methods were used for quantitative and qualitative assessment of functional and organic changes in the heart and great vessels during standard EchoCG protocol. Severity of SMR should be assessed by one and the same experienced echocardiographer using an integrated multi-parametric approach. Comprehensive Doppler-echocardiographic examinations were performed at enrollment and at follow-up. The echocardiographic measurements were performed by an independent investigator who was blinded to the study group.End-diastolic and end-systolic volume of the left ventricle was measured on an apical 4-chamber image. End-systolic volume, end-diastolic volume, and ejection fraction of the left ventricular was calculated by the biplane Simpson method.The quantitative assessment is highly operator-dependent with limited reproducibility, inaccurate in the presence of an elliptical regurgitant orifice (observed frequently in SMR) or multiple jets, and often overlooked in everyday clinical practice. To mitigate the risk of error, multiple parameters should be assessed  radius, and the subsequently derived EROA and regurgitant volume) .2 × Nyquist limit, where r is the radius of the proximal isovelocity surface area, by the Nyquist limit, the peak regurgitation flow rate. The radius of the proximal isovelocity surface area was measured at early, middle, and late systoles with the most satisfactory proximal isovelocity surface area for the hemisphere and averaged. A significant change in the severity of mitral regurgitation was previously determined as the absolute value of the change in the effective area of the orifice regurgitation >0.1 cm2 or a >50% change in the effective area of the regurgitation orifice compared with baseline. The volume of regurgitation was estimated as the effective area of the orifice of regurgitation multiplied by the integral of the velocity from the mitral regurgitation jet. According to mitral valve hemodynamic parameters, patients were considered at risk of mitral regurgitation in the absence of a MR jet or the presence of a small jet in the central region in the Doppler mode, with a small isthmus of regurgitation (vena contracta <0.30 cm); with progressive MR, with an effective area of the orifice of regurgitation <0.20 cm2 and regurgitation volume <30 mL; and with severe MR, with an effective area of the regurgitation opening ≥0.20 cm2 and regurgitation volume ≥30 mL.The effective regurgitation orifice area was determined by dividing the regurgitation flow rate, calculated as 2πrThe E/e' index is defined as the ratio of the maximum early diastolic inflow of the left ventricle E to the maximum rate of early diastolic excursion of the mitral annulus e' . The avet-test at α=0.05 was used. Quantitative indicators were evaluated for compliance with the normal distribution using the Kolmogorov-Smirnov test. Quantitative indicators with a normal distribution were described using arithmetic means, standard deviations (SD), and upper and lower bounds of the 95% confidence interval (95%CI). Categorical data were described with absolute values and percentages. When comparing normally distributed scores calculated for two related samples, paired Student's t-test was used. A P value <0.05 was considered statistically significant for all tests. Statistical analysis was carried out using the StatTech v. 2.5.5 .The baseline mean NT-proBNP was assumed to be >125 pg/mL and the dropout rate, 10%. Based on these assumptions, a sample of 90 patients divided into 2 groups would provide 80% power if a two-tailed The study included 90 patients; 44 patients received sacubitril/valsartan and 46 received valsartan. The mean age of the patients was 61.5±5.3 years, and 63% were men. The cause of SMR was ischemic in 33 (36.7%) patients and non-ischemic in 57 (63.3%), while atrial fibrillation was present in 25 (27.8%) patients . Non-iscDuring the 12 months of follow-up, NT-proBNP level decreased by 37% in the sacubitril/valsartan group and by 11% in the valsartan group. Thus, a statistically significant difference was found between the groups in terms of change from baseline (P<0.001) .In a treatment efficacy analysis including 90 patients, the effective regurgitation orifice area decreased by 25 and 13% in the sacubitril/valsartan and valsartan groups, respectively (P<0.05) .2 for sacubitril/valsartan compared with 116.85±21.56 to 111.02±21.69 mL/m2 for valsartan; P=0.004) and LV end-systolic volume index , which led to an increase in LV ejection fraction and stroke volume. This improvement in systolic function and volumetric remodeling was associated with a decrease in visually graded mitral regurgitation valve.Compared with participants treated with valsartan, participants treated with sacubitril/valsartan experienced a greater decrease in the index of the LV end-diastolic volume . On ultrasound from the apical four-chamber position and along the short axis of the heart from the parasternal and subcostal positions after detecting tricuspid regurgitation, color Doppler mapping can accurately measure the velocity of the transtricuspid regurgitation jet. Knowing the maximum rate of regurgitation, using the simplified Bernoulli equation (ΔP=V2), it is possible to calculate the pressure difference between the right ventricle and the right atrium. By adding to this value the value of right atrial pressure corresponding to the central venous pressure, one can determine the systolic pressure in the right ventricle, which, in the absence of pulmonary valve stenosis, corresponds to the systolic pressure in the pulmonary artery. Using this method, we found a tendency for a decrease in systolic pressure in the right ventricle, which could be measured in the availability of tricuspid regurgitation. In addition, diastolic function improved. The E/e' index decreased  (The volume index of the left atrium decreased (from 29.95 to 27.7 mL/mlsartan) .Ejection fraction increased by 8.2% in the sacubitril/valsartan group and by 3.8% in the valsartan group.During the follow-up period, an increase in exercise tolerance was noted  from 297.48±47.57 m to 400.52±48.41 m after 12 months of treatment with sacubitril/valsartan (P<0.05), i.e., there was an increase of 20%. In contrast, in the valsartan group, the distance increased by 11% (P<0.05).In this outpatient study of participants with HFrEF, treatment with sacubitril/valsartan resulted in a reduction in NT-proBNP level after 12 months of therapy compared with valsartan alone. Also, there was a significant reduction in secondary echocardiographic endpoints, including effective regurgitation orifice area, end-diastolic and end-systolic left ventricular volumes, left atrial volume, and E/e' index in the sacubitril/valsartan group. There was also a significant increase in LV ejection fraction in the sacubitril/valsartan group and in the 6-minute walk test distance. The data obtained indicated improvement of cardiac remodeling in the sacubitril/valsartan group.Mitral regurgitation is a volume overload lesion that over time causes LV dilatation and eccentric hypertrophy. These size changes and LV remodeling is accompanied by changes in diastolic and systolic functions. SMR, which alters normal blood flow to and from the heart, may also increase LV end-diastolic volume . AdaptatNT-proBNP is secreted primarily by the ventricular myocardium in response to increased wall stress with increased LV filling pressure  . ElevateSurgical correction of SMR is in great demand and includes endovascular treatment, mitral valve plastic surgery or prosthetics, LV plastic surgery, LV mechanical aid devices, and coronary artery bypass grafting for ischemic MR. However, given the etiological factors and despite the surgical treatment of MR, the outcome of the disease may be unfavorable . In our In addition to cardiac biomarkers, echocardiography provides a significant contribution to the evaluation of patients with HF and SMR. Changes in the level of NT-proBNP in our study correlated with greater changes in the effective area of the regurgitation orifice , LVEF, and size of the LV and left atrium of the group taking sacubitril/valsartan compared to the valsartan group. An increase in EF when taking sacubitril/valsartan was also found in other studies , as was The study population included the minimum number of participants. Another limitation of this study was the lack of patient randomization. For treatment, larger studies including randomized ones are needed. It is known that echocardiography is the standard imaging modality for evaluating mitral regurgitation, especially in outpatient settings, but echocardiography is not as accurate as magnetic resonance imaging in terms of measuring heart parameters and LV volumes.Among patients with SMR and HFrEF, treatment with sacubitril/valsartan resulted in a significant improvement in cardiac remodeling compared with valsartan alone.


A 24-year-old Moroccan patient was admitted to the cardiology department. He had a history of Behcet’s disease (BD) complicated by a large left ventricular pseudoaneurysm for which, 9 years before, he underwent surgical repair with patch closure with favourable post-operative results. He presented with acute heart failure; clinical symptoms included Class IV New York Heart Association dyspnoea alongside bilateral leg oedema. On chest auscultation, bilateral crackles were heard. The rest of the physical examination found specific signs of BD such as oral aphtosis and inflammatory oligoarthritis.Figure 1, Cardiac magnetic resonance imaging revealed hypokinetic dilated cardiomyopathy with severe systolic dysfunction. The left ventricular ejection fraction was 20%. There was a rupture of the left ventricle’s inferior wall due to patch dehiscence creating a giant 85 × 52 mm bi-lobed pseudoaneurysm (1 Cardiac involvement is present in ∼6% of patients according to the results of a large Tunisian cohort.2 Left ventricular pseudoaneurysm is one among many reported complications,3 and it is explained by myocardial fragility caused by coronary ischaemia. Cardiovascular surgery in the active inflammatory stage often results in severe post-operative complications such as patch dehiscence. Immunosuppressive therapy and colchicine may help manage such events.4 Careful follow-up is required, even for patients with successful initial patch repair. This is, to our knowledge, the first case of recurrent left ventricular pseudoaneurysm associated with BD. This disease should always be suspected in the aetiological workup of pseudoaneurysm, especially in young male patients.Behcet’s disease is a systemic vasculitis affecting young adults with mostly cutaneous and articular manifestations. The diagnosis and classification of BD should be made using the 2014 International Criteria for Behcet’s Disease.ytad544_Supplementary_DataClick here for additional data file.


When modifying HI and CI for the individual’s pulmonary valve position, those indices are present with greater sensitivity and specificity regarding the maximum oxygen-pulse as a pathophysiological correlate of reduced cardiac function . Conclusion: The indexed lateral deviation of the pulmonary valve seems to be a valuable cofactor for HI and CI, allowing for an improved description of cardiopulmonary impairment in PE patients.Background: The severity of pectus excavatum is classified by the Haller Index (HI) and/or Correction Index (CI). These indices measure only the depth of the defect and, therefore, impede a precise estimation of the actual cardiopulmonary impairment. We aimed to evaluate the MRI-derived cardiac lateralization to improve the estimation of cardiopulmonary impairment in Pectus excavatum in connection with the Haller and Correction Indices. Methods: This retrospective cohort study included a total of 113 patients (mean age = 19.03 ± 7.8) with pectus excavatum, whose diagnosis was verified on cross-sectional MRI images using the HI and CI. For the development of an improved HI and CI index, the patients underwent cardiopulmonary exercise testing to assess the influence of the right ventricle’s position on cardiopulmonary impairment. The indexed lateral position of the pulmonary valve was utilized as a surrogate parameter for right ventricle localization. Results: In patients with PE, the heart’s lateralization significantly correlated with the severity of pectus excavatum ( Pectus excavatum (PE), defined as the posterior positioning of the sternum and costal cartilages, is the most frequent congenital anterior chest wall deformity, with an incidence of 1 in 300–400 births and an m:f ratio of 2:1 . The patThe aim of this case-control study was to adjust HI and CI to cardiac lateralization, using this as a cofactor to improve the determination of cardiopulmonary impairment in cross-sectional imaging.ins, and CIins  underwent CPET and thoracic MRI in hold end-inspiration, both of which were performed within 1 week. Nine additional patients who were diagnosed with additional cardiac, pulmonary, and neurologic diseases, leading to impaired CPET results, were excluded prior to enrollment in this study. A total of 36 otherwise healthy subjects  who received an MRI on account of long-term follow-up after lymphoma therapy in childhood were used as controls regarding the position of the right ventricle, HInd CIins .insp and CIinsp, as well as the modHI and modCI. Both the lateral position of the pulmonary valve, reaching from the midline of the chest to the middle of the pulmonary valve (a) and the diameter of the inner chest wall at the level of the pulmonary valve (b), were measured to calculate the indexed position of the pulmonary valve (All patients underwent MRI scans on a 1.5-Tesla (T) scanner  or a 3-T scanner  with a gradient strength of 45 mT/m and a 32-channel body coil for signal detection. At the University of Mainz, pre-operative PE-diagnostic enclosed MR-imaging. A standard T2-weighted half-Fourier acquisition single-shot turbo spin echo sequence with an acquisition time of 25–30 s in hold end-inspiration was used to calculate the HIry valve .The lateral position of the pulmonary valve (a) measured from the midline  to the middle of the pulmonary valve and the inner thoracic diameter at the same level (b). Haller Index and Correction Index were calculated in standard fashion (Sectra Imaging Software Version 24.1).The indexed pulmonary valve position was calculated by dividing the distance of the center of the pulmonary valve from the midline according to half the internal thoracic diameter at the level of the pulmonary valve.The subject depicted above shows the pulmonary valve located from the midline of 4.88 cm, with an inner thoracic diameter at the pulmonary valve level of 23.66 cm. This results in an indexed pulmonary valve position of 0.41. The indexed pulmonary valve position serves as a reciprocal cofactor for the calculation of the modHI and modCI.The HI of 4.34 results in a modHI of 10.59, and the CI of 35.67 results in a modCI of 87 are shown.2max% [%]) and percentage of predicted oxygen pulse (O2-pulsemax% [%]) were evaluated and compared against calculated reference values based on age, sex, height, and weight. Cardiopulmonary impairment in CPET was defined as a reduction in VO2max% of less than 85% of the predicted value and a reduction in oxygen-pulse of less than 80% of the predicted value.CPET was performed on an H/P/cosmos treadmill using CareFusion MS-CPX 5.70 software  combined with GE-electrocardiogram (ECG) Cardiosoft 6.7 . The exercise protocol was an altered, improved treadmill protocol recommended by the German Society of Pediatric Cardiology. According to this protocol, the test started with at 2 km/h on a flat treadmill, increasing stepwise in increments of 0.5 km/h and 3% inclination every 90 s to a maximum incline of 21%. Beyond this inclination, only speed continued to increase, in increments of 0.5 km/h. The testing was stopped when the calculated target heart rate  was reached or when exhaustion occurred, as indicated by the patient. The percentage of predicted oxygen uptake . The Mann–Whitney U test was used to compare age, ratio of pulmonary valve position, HIt-tests were performed to compare CPET results at different grades of severity based on modHI and modCI.Receiver operating characteristic (ROC) analysis was performed to evaluate the sensitivity and specificity of the four different indices in relation to the defined cardiopulmonary impairment. Unpaired Student X2-Test. A p-value of less than 0.05 was considered significant in all statistical analyses.Additionally, a Kruskal–Wallis Test was performed to compare CPET results with modHI and modCI after dividing pectus patients into quartiles. Contingency tables were calculated at different grades of modHI and modCI to evaluate the positive predictive value, negative predictive value, sensitivity, and specificity of the defined cardiopulmonary impairment. Significance was determined by Our patient collective comprised a total of 113 patients with PE  and 36 age-matched controls . Further biometric data of the entire collective are given in p < 0.001). Further, a significant difference between the PE and the control group regarding HIinsp, modHI, CIinsp, and modCI could be established, with less favorable results being found in the PE collective. After dividing the entire collective into quartiles according to HIinsp and CIinsp, a Kruskal–Wallis Test was performed to compare these quartiles regarding the pulmonary valve position index. The indexed position of the pulmonary valve differed significantly between the quartiles of HIinsp and/or CIinsp values (p ≤ 0.001). The data and distribution are depicted in The position of the pulmonary valve was significantly more lateral in pectus patients than in the control group . Only modHI and modCI showed a highly significant difference regarding their reduced O2-pulsemax% . The O2-pulsemax% reduction did not reach a level of significance in HIinsp and CIinsp . ROC curves are depicted in All indices depicted below displayed a cardiopulmonary impairment with regard to a reduced VO2max% were reduced to less than 85%, while those for O2-pulsemax% were reduced to less than 80%. These can be seen in the results of the contingency tables, given in 2 according to the reduced cardiopulmonary function, as described by reduced VO2max% or reduced O2-pulsemax%.The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of modHI and modCI used in the detection of VO2max% of less than 85% of the predicted value and a total of 24 patients had an O2-pulsemax% of less than 80% of the predicted value. The sensitivity and specificity in the detection of impaired cardiopulmonary function according to a reduced VO2max% for modHI were 92% and 40% at an index of 12. For modCI, the sensitivity and specificity were 77% and 57%, respectively. Both had a high negative predictive value of 91% and 90%. The sensitivity and specificity in the detection of impaired cardiopulmonary function according to a reduced O2-pulsemax% for modHI were 92% and 40% at an index of 12; for modCI, they were 71% and 74%, respectively, at an index of 120. Both had a high negative predictive value of 94% and 89%. An unpaired t-test revealed a significantly reduced O2-pulsemax%, reaching maximum statistical significance at a modHI of 12, with a reduction of 101.75 ± 17.94% to 89.89 ± 18.90% (p = 0.003). The VO2max% was reduced, reaching its maximum statistical significance at a modHI of 13 with a reduction from 101.3 ± 13.83% to 92.56 ± 14.85% (p = 0.003). O2-pulsemax% was reduced, reaching its maximum statistical significance at a modCI of 120 with a reduction from 98.95 ± 18.49% to 84.78 ± 17.56% (p ≤ 0.001), and VO2max% was significantly reduced, reaching its maximum statistical significance for a reduced VO2max% at 100.A total of 22 probands had a VO2max% (p = 0.024) and in O2-pulsemax% (p = 0.002). The same analysis regarding modCI revealed statistically significant differences between the quartiles in VO2max% (p = 0.029) and O2-pulsemax% (p = 0.016). Data for VO2max% and O2-pulsemax%, according to quartiles of modHI and modCI, are depicted in Regarding modHI, a statistical significance could be observed between the quartiles in VO2max% and O2-pulsemax% occurred with rather low sensitivity and specificity [2-pulsemax% shows severe PE. We recommend using the oxygen pulse as an indicator for cardiopulmonary impairment, since it is an accepted surrogate parameter for stroke volume while being independent from heartrate [2max% to be achieved in PE, could be further evaluated in Holter-ECG-Studies. The modified HI and CI are easy to obtain using cross-sectional imaging and can be calculated by acquiring only two variables . We utilized MRI (T2w-HASTE-sequence) to measure thoracic deformities without radiation and focused on the inner thoracic areas with a short acquisition time of 25–30 s and adequate spatial resolution [Although the Haller and Correction indices are the two most commonly used indices for the classification of chest wall deformities, they do not adequately describe the actual cardiopulmonary function in patients with PE ,21,22,27cificity . Some pacificity ,23. Explcificity . An anatcificity ,30. Thereartrate . The heaeartrate . In preveartrate ,33. The solution .2-pulsemax% and VO2max% at an MRI-derived inspiratory modified HI, with a value ranging from 11.5 to 12. O2-pulsemax% and VO2max% were continuously reduced in all modified CI, reaching their maximum statistical significance at a modified CI of 120 and 100, respectively. These findings suggest a possible link between the degree of PE, lateralization, and reduced cardiopulmonary function. When considering that both modified indices show a respective overlap between pectus patients and healthy controls, we recommend the use of HI or CI for the initial diagnosis and morphologic description of pectus excavatum. The presented modifications can also be used to estimate the grade of cardiopulmonary impairment with a high degree of sensitivity and specificity (2max% or O2-pulsemax%. These are defined in the literature using threshold values [Previous studies described significant differences in the HI-index when measured during in- and expiration ,36. As acificity . There ad values ,37. Due d values ,40,41,42Our study has several limitations, which are mainly based on the retrospective design and small sample size. At our department, PE is routinely verified by MRI; however, we are aware that this does not represent the standard in other institutions, particularly in adult patients, who mostly receive CT scans. MRI scans are often believed to be time-consuming and expensive, and are not readily available at every location. The MRI sequence was applied in our study; hence, the T2-weighted, half-Fourier acquisition, single-shot, turbo spin echo sequence has an acquisition-time of 25–30 s and does not need a contrast medium ,34. Our The findings of the present study display modifications to HI and CI for the lateral position of the pulmonary valve. These allow for an accurate correlation between the severity of pectus excavatum and the respective cardiopulmonary impairment. These indices can be readily obtained from any cross-sectional imaging and easily integrated in the preoperative workflow of PE.


Transthoracic echocardiography (TTE) offers a measurement method for the determination of pulmonary hypertension (PH) in patients with severe aortic valve stenosis (AS) with determination of maximal tricuspid regurgitation velocity (TRVmax) and systolic pulmonary artery pressure (sPAP). Radiological parameters for noninvasive detection of PH, most importantly computed tomography (CT) based PA/AA-ratio = ratio of pulmonary artery diameter (PA) and ascending aorta diameter (AA), are also included in the latest ESC guidelines. The aim of the present study was to define cut-off values for PA/AA-ratio taking also into account cardiovascular biomarkers to determine criteria for noninvasive diagnosis of PH.194 patients with severe AS undergoing transcatheter aortic valve replacement (TAVR) underwent pre-procedural TTE and CT with measurement of PA/AA-ratio. Additionally, common cardiovascular biomarkers were determined.TAVR patients with an sPAP ≥ 40 mmHg or a TRVmax ≥ 2.9 m/s had a PA/AA-ratio ≥ 0.80 in an AUROC analysis. The cut-off value of ≥ 0.80 resulted in a significantly higher mortality rate (log-rank test: p = 0.034) in these patients in a Kaplan–Meier analysis regarding 1-year survival after TAVR. Significant differences in biomarker expression between patients with a PA/AA-ratio ≥ 0.80 or < 0.80 occurred for BNP (p = 0.001), cTnI (p = 0.032), GDF-15 (p = 0.002) and H-FABP (p = 0.015).PA/AA-ratio ≥ 0.80 is a promising radiological parameter that can provide information about mortality in patients with severe AS undergoing TAVR; combined with biomarkers it may contribute to noninvasive detection of PH in patients with severe AS. Pulmonary hypertension (PH) due to severe aortic valve stenosis (AS) is a frequently diagnosed sequelae in the clinical setting, which occurs pathophysiologically due to chronic pressure load initially on the left ventricle and subsequently on the left atrium and pulmonary circulation . ClinicaIn order to still provide patients with noninvasive options for PH detection, imaging plays an increasingly crucial role. It was already shown in a previous work  that theTherefore, the aim of the present study was to calculate a cut-off value for PA/AA-ratio based on echocardiographic sPAP data, to further investigate this value with respect to mortality, and finally to further underline PH determination based on this radiological criterion with serum biomarker analyses of various common cardiovascular biomarkers.Originally, this study population included 221 patients just before transcatheter aortic valve replacement (TAVR) procedure between 2016 and 2018 at Paracelsus Medical University Hospital Salzburg and Kepler University Hospital Linz. 27 patients had to be excluded due to missing weight or height data, missing CT data or inadaquate CT quality. At last, 194 patients were recommended for inclusion in the study. Relevant exclusion criteria even before study recruitment were patients with a bicuspid aortic valve, acute cardiac decompensation at the time of TTE or at the time of TAVR, as well as patients with any history that might indicate a pre-capillary component of pulmonary hypertension . Therefore, in this selected patient population, a post-capillary cause [severe AS and possibly limited left ventricular ejection fraction (LVEF)] is assumed for the pulmonary hypertension.The study protocol was approved by the local ethics committees of Paracelsus Medical University Salzburg (415-E/1969/5-2016) and Johannes Kepler University Linz (E-41-16) and conducted in accordance to principles of the Declaration of Helsinki and Good Clinical Practice. Written informed consent to participate in the study was available from all patients before study inclusion.2 for definition of severe AS. Patients with low-flow, low-gradient AS situation were excluded. Via Simpson’s method LVEF was calculated. To graduate mitral, aortic and tricuspid valve regurgitation in minimal, mild (I), moderate (II) and severe (III) spectral and color-Doppler images were used. Maximum tricuspid regurgitant jet velocity (TRVmax) was obtained by continuous wave Doppler over the tricuspid valve. The probability of the presence of PH was considered medium at a threshold of ≥ 2.9 m/s and high at a threshold of ≥ 3.4 m/s. Pulmonary artery pressure (PAP) was calculated using the formula 4 × TRVmax2 and adding the estimated right atrial pressure (RAP). The latter corresponds to the central venous pressure and was determined by the diameter of the inferior vena cava (IVC). With an IVC diameter ≥ 21 mm and a respiratory caliber fluctuation < 50%, a RAP of 15 mmHg was assumed. For an IVC diameter < 21 mm as well as a respiratory caliber fluctuation ≥ 50%, a RAP of 3 mmHg was calculated. Other scenarios not corresponding to these constellations were provided with an intermediate value of 8 mmHg [2) + RAP was applied to obtain a sPAP result. Different TRVmax (≥ 2.9 m/s and ≥ 3.4 m/s) values and sPAP  values were used to determine PH in accordance with the current literature [Common ultrasound devices  were used for performing TTE as routinely diagnostic on average 1–4 weeks before TAVR. These examinations were each conducted by experienced clinicians with more than 4 years of training in echocardiography. Severe AS was classified according to current guidelines of European Society for Cardiology measuring using an AV Vmax  of 4.0 m/s, an AV dpmean  ≥ 40 mmHg and an aortic valve area ≤ 1.0 cmf 8 mmHg . Finallyterature .The included study patients at both centers routinely received a pre-interventional, ECG triggered CTA of the whole aorta and femoral arteries to asses, among others, the aortic annulus size, the aortic anatomy and vascular access. Scans were performed on multidetector CT scanners  with a patient size-adapted tube voltage (80–120 kVp) and active tube current modulation. A bolus-tracking technique was applied with a 100 mL bolus of non-ionic iodinated contrast media followed by 70 mL saline solution injected at a flow rate of 3.5–5 mL/s. This imaging, as well as TTE, was completed in a separate inpatient stay approximately 1–4 weeks before the TAVR procedure.A stationary workstation  was used for image analysis. Two experienced radiologists—one board certified with nine years of experience in vascular imaging (radiologist 1), one in the fourth year of training (radiologist 2)—independently performed the following measurements on axial sections in mediastinal window settings on the end-diastolic phase: (1) Main pulmonary artery (PA) diameter was measured perpendicular to the vessel axis at the widest point within 3 cm of the bifurcation of the pulmonary trunk. (2) At the same level as the main PA measurement, the widest diameter of the ascending aorta (AA) was measured , growth/differentiation of factor-15 (GDF-15: pg/ml), heart-type fatty-acid binding protein (H-FABP: ng/ml), insulin like growth factor binding protein 2 (IGF-BP2: pg/ml) and soluble urokinase-type plasminogen activator receptor (suPAR: pg/ml) were analyzed using enzyme-linked immunosorbent assay (ELISA) kits . Manufactures’s instructions were performed for adequate preparation of reagents. Therefore, serum samples and standard protein were placed onto the wells of ELISA plates  and incubated for 2 h. The plates were treated with Tween 20/PBS solution . Afterwards, a biotin-labeled antibody was added and incubated for another two hours. A washing process was performed and streptavidin-horesradish-peroxidase solution was added to the wells. A color reaction was generated after adding tetramethylbenzidine . Optical density was determined at 450 nm on an ELISA plate-reader .Statistical analysis was performed using SPSS . Graphical representations were created using GraphPad Prism  in addition to SPSS.Kolmogorow–Smirnow–Lilliefors test was carried out to test variables for normal distribution. Normally distributed metric data was expressed as mean ± standard deviation (SD) and analyzed using an unpaired student’s t-test. Not-normally distributed metric data was expressed as median and interquartile range (IQR); Mann–Whitney-U-test was applied for statistical analysis here. Frequencies/percentages were used for categorial data and compared using the chi-square test.Area under the receiver operator characteristics (AUROC) curves with area under the curve (AUC) and separate analysis of Youden Index (YI) were performed using different sPAP values (sPAP 40–45–50 mmHg) and TRVmax values (TRVmax ≥ 2.9 m/s and ≥ 3.4 m/s) to determine the respective cut-off for the PA/AA-ratio.For the analysis of inter- and intra-observer variability, the Pearson correlation coefficient with 95% confidence interval (CI) was reported for two independent investigators  or two measurements taken 4 weeks apart by one investigator .Correlation analyses were absolved using Pearson correlation coefficient (metric data) or Spearman’s rank-correlation coefficient  to determine the strength between PA/AA or PA/AA ≥ 0.80 to further variables .p < 0.100 in the univariate analysis were entered and a backward variable elimination was carried out.To detect possible influencing factors regarding the presence of a potential PH with a PA/AA-ratio ≥ 0.80, a univariate, binary logistic regression analysis was figured out. For better comparability, a z-transformation was absolved for metric data. Multivariate, binary logistic regression was performed to assess independent factors regarding the prediction of a PA/AA-ratio ≥ 0.80. Therefore, covariates with A Kaplan–Meier curve with a corresponding log-rank test was generated to determine whether there were differences in 1-year survival between patients with different sPAP values , TRVmax values  and a PA/AA-ratio ≥ 0.80 compared with PA/AA-ratio < 0.80.p < 0.100) were entered and a backward variable elimination was performed.Univariate Cox proportional hazard regression model was used to calculate hazard ratio (HR) and 95% CI for several influencing factors associated with 1-year-mortality. Again, the z-transform was applied for metric data. Afterwards, multivariate Cox regression was performed to assess independent predictors of mortality. Therefore, again, covariates associated with mortality in the univariate analysis .Subsequently, AUROC analyses were carried out to determine an optimal cut-off value of examined cardiovascular biomarkers according to a prediction of PA/AA-ratio ≥ 0.80.In order to investigate not only the effect of a singular biomarker, biomarkers were examined in combinations of two or three. For this purpose, a binary logistic regression was completed and the obtained values were again submitted to an AUROC analysis.A p-value < 0.050 was considered statistically significant.In Figs. TRVmax analysis demonstrated similar results with a PA/AA-ratio of 0.80 Fig. a or 0.83Therefore, a value of 0.80 was used for the PA/AA-ratio in the following.194 patients with primary, severe AS from the Paracelsus Medical University Hospital Salzburg and Kepler University Hospital Linz were included in the study. 72 patients (37.11%) had a PA/AA-ratio < 0.80 in the performed ECG triggered CTA, which corresponded to the absence of PH in this study. In contrast, 122 patients (62.89%) had a PA/AA-ratio ≥ 0.80 and were listed as subjects with potential PH.A flow chart regarding study inclusion and relevant exclusion criteria is shown in Fig. Table A strong and statistically highly significant (p ≤ 0.001) inter- and intra-observer correlation was found. Inter-observer variability for the pulmonary artery diameter was 0.98 (95% CI 0.96–0.98), for ascending aortic diameter 0.98 (95% CI 0.97–0.98) and for PA/AA-ratio 0.96 (95% CI 0.95–0.97). Intra-observer variability for a repeated evaluation of 50 scans for PA/AA-ratio was 0.99 (95% CI 0.99–1.00) (data not shown).To investigate relationships between PA/AA-ratio or PA/AA-ratio ≥ 0.80 and other patients’ characteristics, correlation analysis using Pearson or Spearman correlation coefficient was performed Table .Table 2TOverall, both the PA/AA ratio and the PA/AA ratio ≥ 0.80 generally showed no pronounced correlations with the investigated clinical variables. The highest positive correlation was found for BNP  and sPAP .In order to verify a relevant statistical relationship between the potential presence of PH via PA/AA-ratio ≥ 0.80 and other factors , a univariate as well as a multivariate binary logistic regression was performed Table .Table 3Up < 0.100), so multivariate analysis was performed with these variables. None of the clinical characteristics finally showed a p value ≤ 0.050.In the univariate analysis, gender, weight, height, STSScore, sPAP, hemoglobin, hematocrit, BNP, cTnI and GDF-15 showed a relevant association . In the group of patients with a PA/AA-ratio < 0.80, 15/72 (20.83%) died within one year. In contrast, 44/122 (36.07%) from the group with a PA/AA-ratio ≥ 0.80 passed away.p < 0.100) with atrial fibrillation, mitral valve insufficiency and PA/AA-ratio ≥ 0.80. After inclusion of these data in a multivariate analysis, atrial fibrillation (p = 0.045) and PA/AA-ratio ≥ 0.80 (p = 0.042) remained independent factors for estimation of mortality after 1 year.To investigate influencing factors concerning 1-year mortality after TAVR, a univariate and multivariate Cox proportional hazard regression was figured out Table . The resFigure BNP Fig. a demonstOther biomarkers studied, such as sST2 Fig. c, IGF-BPTo analyze potential biomarkers for prediction of a PA/AA-ratio  ≥ 0.80 in patients with severe AS before TAVR, AUROC-curves regarding plasma level concentration of BNP, cTnI, sST2, GDF-15, H-FABP, IGF-BP2 and suPAR were figured out. Therefore AUC, cut-off values with YI as well as sensitivity and specificity were extracted Fig. ; Table 5AUROC analyses showed significant values for BNP, cTnI, GDF-15 and H-FABP showing the best AUC on the side of BNP . The 3-way biomarker analysis was promising when combining cTnI, GDF-15 and IGF-BP2 .In the current clinical setting, diagnosis of PH as a sequelae of severe AS is mainly performed by TTE by determination of TRVmax or sPAP. However, not only echocardiography offers a noninvasive way of PH detection, but also computed tomography. In the context of procedure-planning CTA before TAVR, the main pulmonary artery diameter with a cut-off value of 29 mm and the PA/AA-ratio with a cut-off value of 1.00 (2015) and 0.90 2022), respectively, found their way into the ESC guidelines so far , 13. Rec, respectThe current ESC guidelines of August 2022  state a Due to only 51% specificity of PA/AA-ratio for PH at sPAP ≥ 40 mmHg or to 53% at TRVmax ≥ 3.4 m/s, the aim of the study was to additionally support or optimize the diagnosis by common cardiovascular biomarkers. Comparative studies combining radiological criteria of PH with laboratory chemical markers are practically scarce. One of few papers was published by the working group of Gumauskiene et al. , who demIn contrast to PA/AA-ratio, the main pulmonary artery diameter could not contribute to an early detection of pulmonary hypertension in a recently published study of our own working group , even inFinally, the noninvasive, radiological determination of PA/AA-ratio  ≥ 0.80 provides a diagnostic tool that can not only provide valuable information regarding 1-year mortality after TAVR but can also further delineate the risk for pulmonary hypertension with common cardiovascular biomarkers such as cTnI or GDF-15.A summary of the study design and the results obtained is presented in a graphical abstract in Fig. The present, retrospective study design is based on data from a small cohort over a circumscribed time period (2016–2018). Biomarker levels were only measured at baseline without statement regarding expression after TAVR procedure. Technical pitfalls in echocardiographic and radiological measurements which lead to misclassifications should always be conceded, even if examinations were performed by experienced clinical investigators. Additionally, invasive right heart catheterization, the gold standard of for accurate diagnosis regarding the genesis of PH (pre-capillary vs. post-capillary) was neither performed in Salzburg nor in Linz, because it is no longer a routine, diagnostic procedure before TAVR, since the findings are not a contraindication for TAVR and thus the mostly elderly and multi-morbid patients experience more risks than actual benefits from the invasive procedure. This final point also addresses the fact that, despite exclusion of obvious factors for pre-capillary pulmonary hypertension , we did not include with absolute certainty a pure cohort of only left heart-related, post-capillary pulmonary hypertension patients and thus isolated pre-capillary, but also combined pre-capillary and post-capillary patients, may also be found in this noninvasive study.With a PA/AA-ratio  ≥ 0.80, an underlying, quick and easily measurable radiological parameter can provide information about mortality in patients undergoing TAVR. The excellent inter- and intra-reader agreement (ICC > 0.98) for CT-measured diameters underlines the reproducibility and robustness of this ratio. Combination of CT, TTE and cardiovascular biomarkers offers a potential way of noninvasive risk stratification regarding pulmonary hypertension in patients with severe aortic valve stenosis.


The identification of heart failure (HF) patients at risk for arrhythmic sudden cardiac arrest (SCA) is a major challenge in the cardiovascular field. In addition to optimal medical treatment for HF, implantable cardioverter defibrillator (ICD) is currently recommended to prevent SCA in patients with reduced left ventricular ejection fraction (LVEF). The indication for an ICD implantation, in addition to HF etiology, New York Health Association (NYHA) class and life expectancy, mainly depends on LVEF value at echocardiography. However, the actual role of LVEF in the prediction of SCA has recently been debated, while newer multimodality imaging techniques with increased prognostic accuracy have been developed. Speckle tracking imaging allows the quantification of mechanical dispersion, a marker of electrophysiological heterogeneity predisposing to malignant arrhythmias, while advanced cardiac magnetic resonance techniques such as myocardial T1-mapping and extracellular volume fraction assessment allow the evaluation of interstitial diffuse fibrosis. Nuclear imaging is helpful for the appraisal of sympathetic nervous system dysfunction, while newer computed tomography techniques assessing myocardial delayed enhancement allow the identification of focal myocardial scar.This review will focus on the most modern advances in the field of cardiovascular imaging along with its applications for the prediction of SCA in patients with HF. Modern artificial intelligence applications in cardiovascular imaging will also be discussed. SCA occThis review will discuss the role of multimodality imaging techniques for the prediction of SCA in patients with HF.2Myocardial injury may result in tissue fibrosis, represented by a focal scar, which is often the case after an acute myocardial infarction, or diffuse interstitial, as commonly observed in NIHD. Myocardial fibrosis is a major substrate for ventricular arrhythmias (VA), as it causes electrical dispersion, laying ground for the initiation and maintenance of re-entrant VA .2.1In 1980s, lacking technologies able to measure scar size and characteristics, systolic function estimated with 2D-echocardiography  emerged as an indirect marker of scar burden. The most recent European Society of Cardiology guidelines provide different recommendations for ICD implantation for primary prevention of SCA in patients with ≥1 year of life expectancy according to the HF etiology. In IHD, they provide a Class I recommendation in patients with symptomatic heart failure (NYHA class II or III) and a LVEF≤35% despite ≥3 months of optimal medical therapy (OMT) and a Class II recommendation in asymptomatic patients (NYHA class I) and LVEF≤30% despite ≥3 months of OMT . A class2.2Speckle tracking echocardiography is a modern technique which can accurately quantify the extent and timing of systolic deformation ,20, as s2.3Beyond GLS, speckle tracking echocardiography allows the quantification of mechanical heterogeneity of left ventricular contraction. Mechanical dispersion (MD) is calculated as the standard deviation of the time to peak longitudinal strain in the 16-segments of the left ventricle , as show2.4The assessment of diastolic dysfunction as a predictor of SCA emerged only recently, despite a strong rationale and previous findings from experimental studies ,29. In aLeft atrial strain is a modern technique to assess diastolic dysfunction with increased accuracy across different clinical situations . In a re33.1Late gadolinium enhancement (LGE) assessed with cardiac magnetic resonance (CMR) is an accurate technique for the characterization of myocardial tissue and the detection areas of focal myocardial fibrosis, appearing hyperintense on delayed CMR imaging ,35. Fig.At variance with IHD, in the setting of NIHD LGE is not a constant feature, being identified in 45–77% of affected patients according to different studies ,52. HoweMoreover, recent studies further explored the characterization of scar by postprocessing LGE sequences and its correlation with arrhythmic risk. In 2021, Acosta et al. analyzed the correlation between scar characterization and an arrhythmic endpoint in 217 patients (39.6% with IHD) with a class I indication for CRT. Among these patients, in addition to the presence and the extension of scar, the heterogeneity of scar (expressed as border zone mass/scar mass ratio) and the border zone channel mass were the strongest predictors of the primary composite endpoint of appropriate ICD therapy or SCD, representing the ideal substrate for reentry arrhythmias .An important and still unclear question is whether there is a quantitative relationship between scar extent and cardiac events and whether does exist an optimal threshold of scar extent able to discriminate high-risk patients, thus needing adequate therapeutic interventions. Some studies reported that scar extent is associated with arrhythmic events in both IHD and NIHD ,58,59. IIn the last few years there has been a growing interest in a peculiar distribution pattern of LGE: the so-called ring-like left ventricular scar, defined by the presence of at least three contiguous sub-segments with LGE at the subepicardial or mid-wall layer in the same slice. This pattern has been reported to be a common feature of left dominant arrhythmogenic cardiomyopathy , partial3.2Further advances in CMR imaging techniques allowed the detection of diffuse myocardial fibrosis, by means of myocardial T1-mapping and extracellular volume fraction assessment. Indeed, diffuse myocardial fibrosis results in longer T1 native relaxation times compared with normal myocardium , and in 4Myocardial delayed enhancement (MDE) with computed tomographic (CT) imaging has been demonstrated to accurately display scar tissue as compared with pathological specimens and LGE-CMR ,68. Howe5Nuclear perfusion imaging using Single Photon Emission Computed Tomography (SPECT) with technetium 99 m or positron emission tomography (PET) with rubidium-82, 15O-labeled water or 13N-ammonia are useful techniques to assess the presence of reversible or non-reversible  myocardial perfusion defects. Reversible myocardial perfusion defects at nuclear imaging identify areas of viable tissue with inducible myocardial ischemia. Inducible myocardial ischemia and viable dysfunctional myocardium may create a vulnerable substrate predisposing to VA. In relation to inducible myocardial ischemia, in a retrospective analysis of SPECT imaging in a large cohort of patients with IHD, summed stress score was significantly associated with increased risk of SCA . In a reThe ability of nuclear imaging in the visualization and quantification of underlying pathophysiological processes predisposing to VTs could be particularly useful in NIHD, in which the benefit of implantation of ICD in primary prevention is still debated . The stuIn addition to myocardial ischemia, hibernating myocardium was shown to be vulnerable to VA . The PARmeta-hydroxyephedrine (11C-HED) was shown to be a strong predictor of SCA [The pivotal role of sympathetic imbalance for the development of VA is well-known, especially in the setting of myocardial ischemia . Indeed r of SCA . In the r of SCA , in a por of SCA  showing 6Recent advances in cardiac imaging techniques led to the identification of a great number of imaging parameters associated with increased risk of SCA in patients with HF. It appears time to overcome the limitations posed by echocardiography-based LVEF assessment, and to implement a multimodal-imaging approach, which is key to best predict patients at increased risk of SCA.All authors listed have significantly contributed to the development and the writing of this article.The authors do not have permission to share data.This item belongs to the item group IG000035.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Our study aimed to assess prospectively myocardial fibrosis in asymptomatic DMD-FC compared to a sex-matched control group (CG) with similar age distribution using native T1 relaxation time and ECV quantification were determined in each group. Late gadolinium enhancement (LGE) was assessed in all cases.38 DMD-FC with verified genetic mutation and 22 healthy volunteers were included. Using CMR, native T1 relaxation time was similar for DMD-FC and CG . Likewise, the mean global ECV value was also similar between the groups . The segmental analysis of mean ECV values according to the American Heart Association classification did not show any differences between DMD-FC and CG. There was a non-significant trend towards higher mean ECV values of DMD-FC in the inferior and inferolateral segments of the myocardium .There were 38 DMD-FC (mean age 39.1 ± 8.8 years) and 22 healthy volunteers (mean age 39.9 ± 12.6 years) imagined by CMR. The mean global native T1 relaxation times and the mean global or segmental ECV values. There was a trend towards higher segmental mean ECV values of DMD-FC in the inferior and inferolateral walls of the myocardium.There were no statistically significant differences in the mean global and segmental native TThe online version contains supplementary material available at 10.1186/s13023-023-02899-9. Duchenne (DMD) and Becker (BMD) muscular dystrophies are X-linked recessive disorders caused by mutations in the dystrophin gene. Progressive muscular wasting, weakness, respiratory failure, and cardiovascular diseases are caused by pathogenic variants in DMD patients , 2. It hThe most common form of cardiac involvement in muscular dystrophy is dilated cardiomyopathy , 5, presFemale carriers of Duchenne muscular dystrophy gene mutations  were previously considered non-manifesting . However1 mapping and extracellular volume (ECV) quantification, might be more suitable for detecting diffuse myocardial fibrosis, as already-published studies in DMD/BMD patients have shown [1 relaxation time or elevated ECV values in DMD/BMD-FC [Therefore, other CMR-based methods, such as native Tve shown –18. AlsoD/BMD-FC , 19, 20.1 mapping and ECV quantification by CMR. Prior to now, there had been no direct comparison to CG.This study aims to assess prospectively myocardial fibrosis in asymptomatic DMD-FC compared to a sex-matched control group (CG) with similar age distribution using native TThe demographically similar study population included 38 DMD-FC with verified genetic mutation and 22 healthy volunteers. The most common mutation was the deletion of 45–52 exons. The asymptomatic DMD-FC were defined based on clinical examination, and all completed the prepared questionnaire.2), CMR contraindications, or limited life expectancy.All eligible subjects who fulfilled the inclusion criteria  were enrolled. The volunteers had no pathological findings on CMR, no anamnesis of cardiac disease, and no other pathological tests. Exclusion criteria for both groups included renal insufficiency (estimated glomerular filtration rate < 30 mL/min/1.73 mThe hematocrit was obtained on the same day that CMR was performed. Following the Declaration of Helsinki (2000) of the World Medical Association, the Faculty Hospital St. Anne’s Ethics Committee (reference number 55 V/2016) approved the study.CMR was performed using a 1.5T scanner  according to our standard protocol. It was equipped with 5-element posterior and 32-element anterior phased-array receiver coils allowing for parallel acquisition techniques in the supine position with repeated breath-hold. Functional imaging using balanced turbo field echo (b-TFE) cine sequences included four-chamber, two-chamber, and LV outflow tract long-axis views and a short-axis (SAX) stack. Typical acquisition parameters were: field of view 320 × 280 mm, reconstruction matrix 256, slice thickness 8 mm, acquisition voxel size 1.7 × 1.7 × 8.0 mm, repetition time ≈ 3.2 ms, echo time ≈ 1.6 ms, and SENSE factor 1.7.LGE images in all long-axis views and the SAX view were acquired 10 min after an intravenous bolus of 0.2 mmol/kg of the gadolinium-based contrast agent gadobutrol  using an inversion recovery (IR-TFE) sequence, and, if uncertain, by phase-sensitive inversion recovery TFE (PSIR-TFE). Both two- and three-dimensional acquisitions were performed in mid-diastole. Typical parameters for the IR-TFE sequence were field of view 320 × 320 mm, reconstruction matrix 288, voxel size 1.6 × 1.7 × 10 mm, repetition time ≈ 4.1 ms, echo time ≈ 1.2 ms, and SENSE factor 2.5.1 mapping was performed as described previously [1 (pre-contrast) and a 4(1)3(1)2 scheme for T1 post-gadolinium (15 min after contrast agent administration). MOLLI sequences were acquired at the mid-ventricular level in the SAX plane using typical imaging parameters .Teviously  using a 1 and post-gadolinium T1 maps. They manually contoured the epi- and endocardial walls in the mid-ventricular slice of SAX using 10% of the myocardial wall as border cutting in both the native and the post-gadolinium images. Then, a motion correction algorithm (integrated into cvi42) was applied to register the images, and the software calculated pixel-by-pixel maps from these images. The ECV quantification was calculated according to (1-hematocrit) / for each segment, and the mean global ECV value was the average of the values in those segments [1 values of the myocardium/blood before and after the application of the contrast agent.Two experienced readers  used cvi42  to construct the native Tsegments . The acrWall motion abnormalities were assessed qualitatively  by an experienced cardiologist (RP) with 29 years of experience and a radiologist (VF) with 38 years of experience with CMR. LV functional and morphological parameters were calculated from the SAX stack using the summation-of-disc method following the recommendations on post-processing evaluation from the Society for Cardiovascular Magnetic Resonance (SCMR) .The radiologist (VF) and the cardiologist (RP) employed a semi-quantitative approach to determine the presence of LGE according to the American Heart Association (AHA) 17-segment model  in the IVariables in both groups were compared using the Student’s t-test for unpaired data. The normal distribution was checked by the Kolmogorov-Smirnov test and a visual inspection of histograms; in a case when the Student’s t-test revealed no difference, this meant the Kolmogorov-Smirnov test was also used to check the identity of distributions of quantitative variables in both groups. The data are presented as mean ± standard deviation (SD).1 relaxation time and ECV values to determine the magnitude of the effect that could be identified as statistically significant by the Student’s t-test. The following assumptions were used: α = 0.05; power = 0.8 ; normal distribution; standard deviation corresponding with the actual distribution in the CG. As the nature of our study was explorative, we neither assumed nor performed any multiple testing corrections, which would increase the risk of type II error and decrease the power of the test.The power of the tests was considered for native T1 relaxation time was assessed with the intraclass correlation coefficient , which was determined from eight randomly selected cases analysed by two readers .The interobserver agreement of both native and post-gadolinium global TAll analyses were performed using Statistica  and in R (v4.2.1) with RStudio IDE  software. The value of α = 0.05 was used as a threshold for statistical significance throughout the analyses.38 DMD-FC (mean age 39.1 ± 8.8 years) and 22 healthy volunteers (mean age 39.9 ± 12.6 years) were included. There was no statistically significant difference between the LVEF of DMD-FC (65.7 ± 5.5%) and CG . 5% of asymptomatic DMD-FC of our cohort had small hypokinesia of the apex and the inferolateral wall of LV. Also, 20% of DMD-FC had LGE that was detected on the inferolateral wall (4 DMD-FC) and inferior wall (3 DMD-FC) of LV, while LGE was absent in the CG.1 relaxation time was similar for DMD-FC and CG   for mean global T1 post-gadolinium relaxation times, showing excellent interobserver reliability.The values of ICC were 0.980 (95% CI: 0.921 to 0.995) for mean global native T1 relaxation times or the mean global and segmental ECV values in asymptomatic DMD-FC with normal LVEF compared to sex -matched CG with similar age distribution. Regarding the segmental values, although statistically non-significant, there was a trend towards higher mean ECV values in the inferior and inferolateral segments of the myocardium in DMD-FC in our study. This may be potentially of concern, as similar segments are affected as in DMD patients; however it should be noted that the magnitude of those differences is much smaller than of those observed between DMD patients and CG, as is evident in various cited studies [There were no statistically significant differences in the mean global and segmental native T studies , 16 incl studies , which c1 mapping and ECV quantification in DMD/BMD-FC [Cardiac involvement, such as cardiomyopathy and the presence of LGE in typical localization, was recently described in DMD-FC , 12. To D/BMD-FC , 19, 20,The first of the studies describes diffuse myocardial fibrosis assessed by ECV quantification in DMD/BMD-FC of gene mutations for muscular dystrophies . AnalyseThe second one  also rep1 relaxation time in DMD/BMD-FC compared to non-carriers and CG [1 relaxation time. While our study had sufficient power to reveal the differences in global native T1 relaxation time with a size comparable to [1 relaxation time found in this study.The last study compared the DMD-FC to non-carrier female relatives and CG and found higher native Ts and CG ; howeverrable to  and empl1 mapping and ECV quantification in a much larger cohort of DMD-FC, and with regards to CG. Moreover, we focused on the assessment of more than just the presence of LGE in the typical location or the described mildly elevated value of ECV or global native T1 relaxation time. This is the first study that compares global and segmental native T1 and ECV values between DMD-FC and CG in a case/control design.The main contribution of our study compared to the mentioned studies , 19, 20 1 mapping and ECV quantification allow for the measurement of diffuse fibrosis that foregoes the mentioned LGE. These methods are also useful in detecting myocardial inflammation or any alteration of the extracellular space [LGE can aid in detecting the extent and the location of myocardial fibrosis. Additionally LGE can uncover incipient heart disease by its presence , 24. Whear space , 25.1 mapping and quantified ECV in DMD patients [1 relaxation time compared to CG, there was no difference between LGE negative DMD patients and CG [1 relaxation time compared to CG [Contrary to DMD-FC, many more studies have assessed native Tpatients , 26, 27.ed to CG .1 relaxation time and ECV values in DMD patients. ECV quantification was regardless the ability to differentiate LGE negative DMD patients and CG [These results align with other authors who detected increased native Ts and CG .1 mapping and ECV quantification can identify the differences and regional abnormalities on the inferolateral wall of the LV between DMD patients and CG with or without LGE [1 relaxation time and reduced LVEF was reported in LGE positive DMD patients, evidencing a relationship between native T1 relaxation time and LV function [Both native Thout LGE , 30–33. function .1 relaxation times and mean global and segmental ECV values were similar to sex- matched CG with similar age distribution. Furthermore, 20% of our DMD-FC cohort had LGE on the inferolateral wall of LV, which is typical localization for the extracellular volume expansion described in DMD patients [Based on our previous studies, all global LV strains and tissue Doppler parameters in asymptomatic DMD-FC were decreased compared to CG , 35. Despatients , 37.1 relaxation time and ECV quantification in symptomatic DMD patients are already known, our DMD-FC cohort did not have any cardiac symptoms.While the differences in native T1 mapping [1 relaxation time and mean global ECV values. Future research is essential to validate the whole process’s reproducibility.This work has some limitations. Some of them are related to the general limitations of native T mapping , 38. It 1 relaxation times and mean global and segmental ECV values in asymptomatic DMD-FC with normal LVEF were similar to CG, as there was no statistically significant difference in any of the CMR-assessed parameters. Although non-significant, there was a trend towards higher mean ECV values of DMD-FC in inferior and inferolateral segments of the myocardium, which should be subjected to prospective assessment.The mean global and segmental native TBelow is the link to the electronic supplementary material.Supplementary Material 1


Mitral regurgitation (MR) burdens the left and right ventricles with a volume or pressure overload that leads to a series of compensatory adaptations that eventually lead to ventricular dysfunction, and it is well known that in rheumatic heart disease (RHD) that the inflammatory process not only occurs in the valve but also involves the myocardial and pericardial layers. However, whether the inflammatory process in rheumatic MR is associated with ventricular function besides hemodynamic changes is not yet established.Evaluate whether rheumatic etiology is associated with ventricular dysfunction in patients with chronic MR.The study population comprised patients aged 18 years or older included in the registry who had echocardiography performed at the National Cardiovascular Center Harapan Kita in Indonesia during the study period with isolated primary MR due to rheumatic etiology and degenerative process with at least moderate regurgitation.The current study included 1,130 patients with significant isolated degenerative MR and 276 patients with rheumatic MR. Patients with rheumatic MR were younger and had a higher prevalence of atrial fibrillation and pulmonary hypertension, worse left ventricle (LV) ejection fraction and tricuspid annular plane systolic excursion (TAPSE) value, and larger left atrium (LA) dimension compared to patients with degenerative mitral regurgitation (MR). Gender, age, LV end-systolic diameter, rheumatic etiology, and TAPSE were independently associated with more impaired LV ejection fraction. Whereas low LV ejection fraction, LV end-systolic diameter, and tricuspid peak velocity (TR) peak velocity >3.4 m/s were independently associated with more reduced right ventricle (RV) systolic function .Rheumatic etiology was independently associated with more impaired left ventricular function; however, rheumatic etiology was not associated with reduced right ventricular systolic function in a patient with significant chronic MR. Rheumatic heart disease (RHD) and its complications are significant health care problems in middle- and low-income countries because of very high prevalence and its tendency to affect patients at a productive age. According to the data published by the Global Burden of Disease (GBD) in 2015, at least 33.4 million people worldwide suffer from RHD [34MR burdens the left ventricle with a volume load that leads to a series of left ventricular (LV) compensatory adaptations and adjustments that vary considerably during the prolonged clinical course of MR. The early compensatory changes with the utilization of the Frank-Starling mechanism are gradually replaced by a chronic remodeling process with enlargement of the LV chamber 7. EventuIn acute rheumatic fever (ARF), which is a precursor to RHD, the inflammatory process not only occurs in the valve but also involves the myocardial and even pericardial layers. Hence, the inflammatory process in ARF is also often referred to as pancarditis . MyocardHowever, the association of this inflammatory rheumatic process and ventricular dysfunction in chronic MR have not been reported. Establishing this association is very important because this process was persistent even after mitral valve surgery. Therefore, the purpose of this study is to evaluate whether rheumatic etiology is associated with LV and RV systolic dysfunction in a patient with chronic MR.This study is a part of valve registry at the National Cardiovascular Center Harapan Kita (NCCHK). In brief, our valve registry was a retrospective, single-center, hospital-based registry of patients aged 18 years or older with valvular heart disease between January 2016 and June 2019 (42 months). The echocardiography result serves as the starting point for a subject to be admitted to the registry. If the report shows the presence of moderate or severe valve lesions, the patient is admitted to the registry, and detailed demographic and clinical characteristics are retrieved from their medical records and the hospital information system. The purpose of the registry is to provide information and describe characteristics of valvular heart disease in our hospital that served as national referral for cardiovascular disease.In this study, patients with moderate or severe rheumatic MR were selected from the valve registry. As a comparison group, subjects with moderate to severe degenerative MR were also selected from the registry. Patients with concomitant structural lesions such as moderate or severe MS, aortic regurgitation or stenosis and pulmonary regurgitation or stenosis, congenital heart disease, or other structural heart diseases were excluded from the study. These abnormalities may also cause ventricular dysfunction that may confound interpretation of the study. Patients with moderate to severe tricuspid regurgitation were not excluded in this study. Hence, we systematically included patients with “isolated” significant MR in both groups. The purpose of selecting patients who also had degenerative MR was to include rheumatic etiology as one of the independent variables.NCCHK is a national referral hospital for cardiovascular disease in Jakarta, the capital city of Indonesia, and an academic hospital for the Faculty of Medicine, University of Indonesia.Echocardiography was performed by sonographers, fellows, and residents and was reviewed by echocardiography consultants, echocardiography fellows, cardiology residents, and sonographers. All reports were reviewed by echocardiography consultants. In this study, echocardiography parameters were directly taken from the reports. Cutoff values for cardiac chamber dimension and left and RV contractility is based on American Society of Echocardiography (ASE) and European Association of Cardiovascular Imaging (EACVI) Recommendations for Cardiac Chamber Quantification by Echocardiography , while d14RHD was diagnosed using World Heart Federation (WHF) criteria, while degenerative MR was diagnosed using the definition from ASE 18. Left Severity of MR was assessed using a multiparametric integrated approach as recommended , including vena contracta width and, when feasible, effective regurgitant orifice area and regurgitant volume calculated according to the proximal isovelocity surface area (PISA) method . Moderat2 test or Fisher’s exact test, as appropriate.Continuous variables are expressed as mean ± standard deviation and categorical variables as frequency (percentage). Normality was established using the Shapiro-Wilk test. Continuous variables were compared between the rheumatic and degenerative MR groups using the Student’s t-test or the Mann-Whitney U test, as appropriate, whereas categorical variables were compared using the xP value <0.25. A P value of <0.05 was considered statistically significant. When analyzing the LVEF as the dependent variable, TAPSE was included as an independent variable, whereas when analyzing the TAPSE as the dependent variable, LVEF was included as an independent variable. Statistical analysis was performed with SPSS version 24 .There are two dependent categorical variables in this study: (1) LV systolic function that is represented by LVEF (LVEF is reduced if less than 60%), and (2) RV systolic function that is represented by TAPSE that will be analyzed separately (TAPSE is reduced if less than 17 mm). The association between clinical and echocardiographic parameters with these dependent variables was evaluated using the logistic regression analysis, including as independent variables clinical and echocardiographic parameters associated in the univariable analysis with a In total, 1,130 patients with significant isolated degenerative MR and 276 patients with rheumatic MR were included in the current study. Baseline demographic characteristics, clinical, and echocardiographic characteristics are presented in This is the first study that provides information on the association of the rheumatic process to the left and right ventricular systolic function in the patient with significant chronic MR. Patients with degenerative MR were included in this study as a comparison group to describe the association between the rheumatic process and reduced ventricular function independent from hemodynamic factors. We found that rheumatic etiology was independently associated with more impaired LV systolic function but not with RV systolic function. These findings suggest that besides the chronic volume overload of the left ventricle, there is another mechanism that worsens the LV function in patients with rheumatic MR. The intrinsic myocardial process in RHD may play a role in the mechanism of this impaired LV contractility .The involvement of the myocardium in RHD has been well established in previous studies. Myocardial involvement is confirmed by the finding of Aschoff nodules in the myocardium and the cardiac valve tissue . AschoffInterestingly, the association between these mechanisms and the impaired LV systolic function is not yet established. Williams et al. questioning the significance of myocarditis in children with acute rheumatic carditis . Their sIn this study, the difference of RV systolic function is not statistically significant between rheumatic and degenerative MR. Also, in multivariate analysis, we found that rheumatic etiology was not associated with more impaired RV systolic function. The explanation of this finding is unclear due to the lack of studies addressing this issue. A study by Pande et al. showed evidence of apoptosis in the RV of patients with rheumatic MS that occurred early during rheumatic valve disease, even with low RV systolic pressure . However34The current study gives new insight that there is an intrinsic process in patients with chronic rheumatic MR that significantly worsens LV systolic function in addition to volume overload . This prAlthough the present study is the first to identify the association between rheumatic etiology and the impaired LV and RV systolic function in patients with significant chronic MR, there are several limitations. First, the retrospective single-center nature of our study may constitute a major limitation. However, we believe that this should be considered a pilot study to enhance further research, including a larger subject, on this topic. Furthermore, we exclude coronary artery disease CAD as the possible mechanism of LV systolic dysfunction based only on clinical evidence and resting echo. Also, no data regarding the duration of MR was available. Duration of volume overload due to MR may impact the LV function. Finally, we only use LVEF and TAPSE as parameters for left and right ventricular function, respectively. However, both LVEF and TAPSE were established parameters of ventricular function and are widely used and have prognostic impact. Studies showed that myocardial deformation imaging of LV and RV were good parameters to identify subtle LV and RV dysfunction in RHD .Rheumatic etiology was independently associated with more impaired LV systolic function represented by LVEF; however it was not associated with reduced RV systolic function in patients with significant chronic MR.