To assess the value of feature-tracking cardiac magnetic resonance (FT-CMR) imaging in the quantitative evaluation of acute myocardial infarction (AMI).n=52) and non-STEMI (NSTEMI) (n=48) groups. We compared myocardial strain parameters between the two groups and applied the Pearson’s test to reveal any correlations between the left ventricular myocardial strain parameters and the number of late gadolinium enhancement (LGE) positive segments; we assessed the clinical value of FT-CMR for predicting STEMI using a receiver operating characteristic (ROC) curve.We retrospectively analyzed medical records of patients with acute myocardial infarction (AMI) diagnosed in the Department of Cardiology of Hubei No.3 People’s Hospital of Jianghan University from April 2020 to April 2022, who underwent feature-tracking cardiac magnetic resonance (FT-CMR) examination. Based on the electrocardiogram (ECG) findings, patients were divided into ST-elevation myocardial infarction (STEMI) (p<0.05). The number of LGE-positive segments in patients with AMI negatively correlated with the radial, circumferential and longitudinal strains. The results of the ROC curve analysis showed that radial, circumferential and longitudinal strain values have a diagnostic value for STEMI (p<0.05).The number of LGE-positive segments in the STEMI group was significantly higher than that in the NSTEMI group. The myocardial radial, circumferential and longitudinal strains in the STEMI group were significantly lower than those in the NSTEMI group (FT-CMR, a non-invasive and rapid method for analyzing myocardial strains, has a high diagnostic value for AMI and should be helpful for the prevention and intervention of ventricular remodeling after myocardial infarctions. The main pathological changes in acute myocardial infarction (AMI) are acute myocardial ischemia and necrosis.etc.).Cardiac magnetic resonance (CMR), a non-invasive and radiation-free imaging technology, has become the gold standard for the measurement of cardiac parameters, and feature-tracking cardiac magnetic resonance (FT-CMR) is often used to measure cardiac structures and function  with AMI diagnosed in the Department of Cardiology of Hubei No.3 People’s Hospital of Jianghan University from April 2020 to April 2022 who underwent FT-CMR examinations. Patients were continuously monitored by electrocardiogram to observe changes in heart rate, heart rhythm, blood pressure, and respiration, and venous access was established soon after admission. Drug and reperfusion therapy were performed according to the patients’ conditions. The disease course ranged from three to six years with an average of 4.46 ± 0.68 years. All the patients received coronary angiography and percutaneous coronary intervention, followed by FT-CMR. The median door-to-ECG, artery access and balloon times were 19 minutes, 84 minutes and 118 minutes, respectively. The average age of the patients was 65.88 ± 8.56 years. The mean left ventricular ejection fraction (LVEF) was 42.56 ± 6.98%. According to ECG records, we had 52 patients with STEMI in the STEMI group, and 48 patients without STEMI in the NSTEMI group. We counted 365 LGE-positive segments of which 251 were detected in the STEMI group and 114 in the NSTEMI group.Age≥18 yearsPatients with AMI diagnosed by coronary angiography or CT angiography according to the relevant diagnostic criteria formulated by the Chinese Society of Cardiology of Chinese Medical Association:Patients received FT-CMR examination within one month after AMI onsetPatients with complete and continuous cardiac imaging dataPresence of other heart diseases, such as heart valve disease, congenital heart disease, cardiomyopathy, or severe arrhythmiaSevere metabolic diseases of the lungs, liver or kidneysPresence of autoimmune diseasesPatients complicated with cardiac rupture, ventricular wall tumor, appendage thrombosis, heart failure and cardiogenic shockPatients who have experienced cardiac arrestth of May, 2021)This study was approved by the medical ethics committee of Hubei No.3 People’s Hospital of Jianghan University  with a steady-state free precession (SSFP) cine sequence, 8-Channel cardiac phased coil, and MR compatible ECG gating and respiratory gating board. Scanning methods: 1) We performed axial, coronal and sagittal localization scans with the patient in a supine position. 2) The long axial plane of the left ventricular two-chamber heart and four chamber heart, and the short axial plane of left ventricle were determined on the basis of the standard axial plane. 3) The images were collected to obtain the SSFP film sequence of each section at the end of an expiration.We set the following acquisition parameters setting - turning angle (47.5° ± 2.5), visual field (36.0 cm × 38.0 cm), echo time (1.6 ± 0.1 ms), repetition time (3.2 ± 0.25 ms), and the specified scanning acquisition layer thickness (8 mm). We applied the sensitivity reversion method to measure the two-chamber center, the four-chamber center and the short-axis cavity after 10 to 15 minutes. The imaging parameters considered included the visual field (36.0 cm × 38.0 cm), the repetition time (4.1 -4.2 ms), the echo time fixed (1.6 ms), the specified layer thickness (0.80 cm), the total imaging scanning (8-10 layers), and the set reversal time (300 ms). 4) For the delayed enhancement scan we applied an intravenous injection of gadopentetate dimeglumine , the dose was 0.2 mmol/kg, the injection rate 4.0 mL/s, and the same amount of 0.9% sodium chloride was injected at the same rate. After the intravenous injection of contrast agent for 10 minutes, the scanner set with sensitivity inversion recovery sequence took LGE images of short axis, two chamber heart, four chamber heart and left ventricular inflow and outflow tract.A senior radiologist with a CMR certification blinded to the patient’s condition performed the imaging examination and interpretation of the results. According to the SSFP sequence, the FT-CMR machine generates short axis movies of the two-chamber heart and four-chamber heart and transmits all images to the CVI42 software ; the complete cardiac cycle is thus outlined. The left ventricular ejection fraction (LVEF) and myocardial strain parameters  were obtained using the relative movement and displacement of the left ventricular endocardium and the upper edge of the epicardium. The radial strain, circumferential strain, longitudinal strain, and other indexes are compared in absolute values . Global left ventricular deformation force: for the strain analysis of left ventricular short axis . We diviχ̅±S), we applied independent sample t-tests for comparisons between groups; count data were expressed as numbers (percentages %), and Chi squared tests were used for comparisons between groups. Pearson’s correlation analyses were used to analyze correlations between the strain values of the left ventricular myocardium and the number of LGE-positive segments. The clinical value of myocardial strain parameters in the diagnosis of STEMI was assessed by analyzing the working characteristics of subjects (in ROC curve).We used the SPSS 22.0 software to analyze the data. The measurement data were expressed as mean and standard deviations (p>0.05). However, the number of LGE-positive segments in the STEMI group was significantly higher than that in NSTEMI group (p<0.05) (p<0.05) , 32 (61.54%) males and 20 (38.46%) females; in the NSTEMI group, there were 48 patients , 26 (54.17%) males and 22 (45.83%) females. We found similar numbers of cases, ages, sex ratios, disease courses and LVEFs between the two groups ((p<0.05) . The rad(p<0.05) .p<0.05) (p<0.05)   ROC curv(p<0.05)  and Fig.This study analyzed the diagnostic efficacy of FT-CMR and related post-processing techniques for STEMI in patients with AMI. Our results show that the number of LGE-positive segments of the STEMI group was significantly higher than that of the NSTEMI group, indicating that the infarcted area in patients with STEMI was significantly higher than that of patients with NSTEMI, which is consistent with the findings of Dong et al.Our results show that the radial, circumferential and longitudinal strains of the left ventricular myocardium in patients with STEMI were significantly lower than those in patients with NSTEMI (p<0.001). This suggests that the epicardial myocardial ischemia injury in patients with STEMI is more serious than that in patients with NSTEMI, a finding consistent with the pathological characteristics of STEMI myocardial infarction involving the whole myocardium.26Our study was mainly a retrospective case-control study with a small sample size, without in-depth studies on the impact of FT-CMR on LGE negative sites or the number and location of culprit vessels in patients with STEMI. In addition, we did not assess the impact of baseline data such as age or gender, and we did not analyze the peak strain in each direction during systole. The patients in this study had inevitably taken therapeutic drugs, such as anticoagulants, before we collected the images, and that may have altered the study results. Our survey presented data deviations and our conclusions are subjective. Multi-center RCT studies with large sample sizes are needed to explore and confirm our findings.FT-CMR is a non-invasive and rapid method for analyzing myocardial strain. It has high diagnostic value for AMI and is helpful for the prevention and intervention of ventricular remodeling after myocardial infarctions.JY conceived and designed the study.WZ, XW, XS and YW collected the data and performed the statistical analysis.JY prepared the manuscript and is responsible for the integrity of study.All authors have read and approved the final manuscript.


Cardiac amyloidosis is a serious and progressive infiltrative disease caused by the deposition of amyloid fibrils in the heart. In the last years, a significant increase in the diagnosis rate has been observed owing to a greater awareness of its broad clinical presentation. Cardiac amyloidosis is frequently associated to specific clinical and instrumental features, so called “red flags”, and it appears to occur more commonly in particular clinical settings such as multidistrict orthopedic conditions, aortic valve stenosis, heart failure with preserved or mildly reduced ejection fraction, arrhythmias, plasma cell disorders. Multimodality approach and new developed techniques such PET fluorine tracers or artificial intelligence may contribute to strike up extensive screening programs for an early recognition of the disease. The most frequent forms of CA are light-chain (AL) and transthyretin-related (ATTR) amyloidosis that can be classified in hereditary (ATTRv) or wild-type (ATTRwt) depending on whether a mutation of TTR gene has been identified . Althoug2.2.1.It is common knowledge that in patients with ATTR-CA the deposition of amyloid can be observed in soft tissue structures  in addition to myocardial tissue, leading to carpal tunnel syndrome, lumbar spinal stenosis , 4, or b2.2.It is well known that aortic stenosis (AS) and ATTRwt share the same epidemiological background as their prevalence is particularly high in male octogenarians, but whether this represents a simple epidemiological association, or a causal relationship is still an unanswered question. As previously summarized by Rapezzi et al. , there aATTRwt's prevalence among aortic stenosis cohorts is variable between 4% and 16%, mainly influenced by the mean age of the studies' population and by the diagnostic criteria or imaging exams used for diagnosis . In a veRecently, researchers' efforts have been focused on identifying clinical, biochemical, electrocardiographic, and echocardiographic features that could help clinicians to raise the suspicion of underlying CA in patients affected by AS. Although some instrumental characteristics can be shared by both conditions (particularly LV hypertrophy), the identification of multiple distinctive features (listed in 2.3.n = 5) and they found a prevalence of CA among patients undergoing bone scintigraphy for non-cardiac reasons of 1%, with a higher likelihood in men and increasing prevalence with age (n = 45) of patients, reaching 1.4% among male octogenarians. Of them, 14 patients with a median age of 82 years underwent a comprehensive cardiological evaluation, including ECG, echocardiogram and endomyocardial biopsy in selected cases. Five patients eventually received a diagnosis of ATTRwt, and 1 patient was found to have ATTRv. Despite the small number of definite diagnoses of ATTR-CA, this study highlighted for the first time the possibility of pre-clinical identification of patients affected by ATTR-CA in an unselected population. A subsequent study investigated the prevalence of myocardial tracer uptake in bone scans in an older cohort, finding a higher percentage of unexpected positive scans  (p = 0.022).Studies investigating prevalence of cardiac uptake in individuals undergoing bone scintigraphy for oncologic or rheumatologic reasons provide the most reliable information about the prevalence of CA in the general population. Recently, Aimo et al. performed a systematic meta-analysis of published studies (with age . The larwith age . Authorsars old) . InteresA recent Australian study found a prevalence of 0.43% of cardiac uptake in a heterogeneous cohort of over 3,000 patients who underwent 99mTc-hydroxy-methyl-diphosphonate (HMDP) bone scans for non-cardiologic reasons . Data coIn this study, a positive correlation between positive scans  and septal wall thickness measured by echocardiography was observed, as well as between LV mass and the amount of HMDP uptake (measured by heart to whole body ratio); conversely, the degree of tracer uptake correlated negatively with LVEF, suggesting that higher HMDP uptake is associated with more advanced disease. However, in this population positive HMDP scans were surrogate marker of ATTR-CA, as AL amyloidosis was not systematically excluded, representing a possible confounding variable.2.4.Nowadays, heart failure (HF) represents a considerable public health issue as it affects approximately 5% of the general population aged ≥60 years and HF with preserved ejection fraction (HFpEF) accounts for near the half of HF diagnosis in US . To datep 0.03) on histological screening in LV autopsy specimens, CA has been found to be a common etiology in such patients within several subsequent clinical studies. It should be noted that small quantities of transthyretin amyloid are commonly seen in the autoptic analysis of hearts of elderly patients, but their contribution to the burden of HFpEF is unclear. Indeed, whether the neurohumoral dysregulation and metabolic imbalance seen in HFpEF population can cause a destabilization of wild-type transthyretin molecules or on the other side the cytotoxic and profibrotic effect of the primary deposition of amyloid fibrils can cause the diastolic dysfunction underlying the disease is still an open question. In 2015, Gonzalez-Lopez and colleagues  (n = 217), 62 received a final diagnosis of CA with an estimated prevalence of nearly 29%. In this phase, statistical analyses showed that apical sparing alone or a combination of at least two red flags, had a diagnostic accuracy >70%, providing a guide for physicians in proceeding with further tests for AC when performing echocardiography for any reason. CMR may play a supplementary role in the instrumental evaluation of LV hypertrophy. In fact, in addition to the morphological and functional assessment of myocardial walls, CMR offers tissue characterization by measuring native T1 and native T2  and extra-cellular volume (ECV). Those three measures have been proven in many studies to add both a diagnostic and prognostic value, even in distinguishing AL and ATTR amyloidosis   aimed toloidosis , 43.3.As previously explained, the epidemiology of CA is vertiginously evolving, as if a “Pandora's box” was just opened by international scientific community. per se can disrupt the transmission of electrical impulses along conduction fibers. Also, there is an emerging hypothesis for a cytotoxic role of transthyretin molecule involving the dysregulation of intracellular calcium signaling causing action potential prolongation, in addition to oxidative stress and apoptosis  has been gaining share, although its use on clinical practice is still hypothetical. In a screening setting, PET tracers may have a superior role both on detection of amyloid deposits and differentiation between ATTR and AL. For instance, 18F-Fluorbetaben was first tested by Law et al. in a small group of patients and showed higher standardized uptake values (SUV) in cardiac amyloidosis (both AL and ATTR forms) than hypertensive heart disease . A recenLastly, artificial intelligence (AI) represents a widespread technique whose application in cardiology has been promisingly tested and approved in several contexts . AI desc4.CA is a threatening disease which may be hiding in multiple conditions such as carpal tunnel syndrome, aortic stenosis, heart failure, plasma cell disorders. In those scenarios, detecting the disease may be difficult because some features overlap each other, therefore the application of a multimodality imaging approach along with the awareness and recognition of specific characteristics, so-called “red flags”, are fundamental. Although the cost-effectiveness of a screening strategy in CA has not been scientifically proven yet, this extensive and meticulous approach can be beneficial for various potential reasons: - intercepting a pre-symptomatic phase in which “disease-modifying” therapies may act the most; - recognizing an underlying neoplastic process such as AL amyloidosis; - identifying hereditary CA from probands to siblings; - better understanding (and maybe predicting) the cardiac disturbances of recruited patients; - tailoring supportive cardiac and non-cardiac therapy within the peculiar CA pathophysiology and natural history. On this basis, the efforts of scientific community must continue along the direction of increasing knowledge of the disease.


SDI displayed a significant correlation with 3D auto RV ejection fraction (EF), tricuspid annular plane systolic excursion (TAPSE), fractional area change, and RV longitudinal strain (RVLS)-free wall . Cumulative SLEDAI score also showed a significant correlation with RV EF, TAPSE, FAC, and RVLS-free wall . By multivariate regression analysis, SDI remained an independent predictor of RVLS-free wall  and TAPSE .Studies on the right ventricular dysfunction (RV) in systemic lupus erythematosus (SLE) patients are limited, particularly in the pediatric age group. The study aimed to identify subclinical RV alterations in childhood-onset SLE (c-SLE) using conventional and three-dimensional echocardiography (3DE). Forty SLE pediatric patients and 40 healthy controls were included. Disease activity and chronicity were evaluated by SLE disease activity index (SLEDAI) score and SLE damage index (SDI). Participants underwent detailed RV echocardiographic examination with conventional and 3DE assessment using 3D auto RV software. Patients included 35/40 (87.5%) females with mean age of 15.6 ± 1.7 years. Using conventional pulmonary artery systolic pressure echocardiography-derived measurement, none of the c-SLE patients had pulmonary hypertension. By 3DE, RV end-systolic and end-diastolic volumes (  Conclusion: Subtle right ventricular myocardial dysfunction could be detected in childhood-onset SLE patients, especially via 3D-derived auto RV echocardiographic parameters, despite the absence of evident pulmonary hypertension. These parameters correlate with the SLE disease activity and chronicity scores. Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder associated with chronic inflammation and immune complex deposition in involved organs. Cardiovascular diseases are considered one of SLE patients’ most common causes of morbidity and mortality –3. MoreoThe two-dimensional (2D) approach to the RV via conventional echocardiography (ECHO) is technically challenging compared to the one of the LV. This is because of its complex triangular crescentic shell anatomy. Moreover, the RV location retrosternal forward to the LV add to the challenge of its 2D assessment . Therefo.Three-dimensional echocardiography (3DE) overcomes complex geometry problems, thus enabling a comprehensive assessment of RV chambers, internal volume, and RV ejection fraction (EF) determination. It may be considered an alternative to cardiac magnetic resonance imaging (cMRI) . FurtherAs far as we know, a single study in the adult population has investigated RV function using 3DE parameters in SLE patients . HoweverThe prospective observational case–control study included 40 pediatric patients with SLE and 40 healthy controls. The work was conducted between November 2020 and February 2022 after approval of the institutional research board (IRB) of Mansoura University, Faculty of Medicine, Egypt. Informed consent was obtained from legal guardians for all study participants. The cases were recruited from the SLE outpatient clinic in a single tertiary center, Mansoura University Children’s Hospital, Egypt.2  [Pediatric patients up to 18 years old with SLE having a duration of illness of at least 3 years were included, in addition to age and sex-matched healthy controls for comparison purposes. All included patients diagnosed after fulfilling the American College of Rheumatology (ACR) classification criteria for SLE . In addiformula) .Patients with congenital heart disease, arrhythmia, primary cardiomyopathies, or significant cardiac valve disorders (more than mild stenosis or regurgitation) were excluded. Besides, we excluded patients with acute hemodynamic instability . Additionally, cases with chronic obstructive pulmonary disease, interstitial lung disease, and other restrictive pulmonary abnormalities were excluded. Moreover, we did not include patients with impaired kidney function, uncontrolled hypertension, or any other systemic disease well-known to impair cardiac function or cases with inadequate ECHO image quality that interfere with the 3D analysis.Detailed history, including the patient’s age, duration of SLE, and medications were obtained. Blood samples were taken for ESR as an inflammatory marker and autoantibodies assay (antidsDNA) in addition to complete blood count (CBC), complement 3 (C3), urinalysis, and a 24-h urinary protein assessment to incorporate into disease activity score. Current and previously reported disease activity  was documented . The cum2), and surface area (in m2) were assessed at the time of ECHO. Blood pressure (systolic and diastolic) in mmHg and heart rate (beat/minute) were evaluated before starting the ECHO.Body weight (in kg), height (in cm), body mass index  equipped with an X5-1 matrix array transducer (5–1 MHz).2) and LV systolic functions, including fraction shortening (FS) and ejection fraction (EF) in percentage, were measured. Color flow Doppler was assessed across the cardiac valves to estimate the presence and degree of regurgitation across tricuspid and pulmonary valves. Pulsed wave Doppler was performed across cardiac valves, including pulmonary and tricuspid peak velocities, early diastolic flow (E-wave), late diastolic flow (A-wave) velocities in centimeter/second, and the E: A ratio was calculated for tricuspid valve. The pulmonary artery systolic pressure (PASP) was calculated in mmHg as the sum of both the tricuspid regurgitation pressure gradient (using the Bernoulli equation from tricuspid regurgitation peak velocity) and the RA pressure (assumed according to IVC diameter and respiratory-related collapsibility). Pulmonary hypertension (PH) was considered when PASP > 30 mmHg at rest [Conventional ECHO: Standard transthoracic ECHO, including apical four-chamber, three-chamber, two-chamber, parasternal short-axis and long-axis views, as well as M. mode, conventional Doppler, and tissue Doppler evaluation, were performed based on the recommendations of the American Society of Echocardiography . M-mode  at rest .Pulsed-tissue Doppler imaging: Early diastolic (E′ wave), late diastolic (A′ wave), and systolic (S′ wave) velocities were measured at the lateral parts of the tricuspid annulus on the apical four-chamber views by pulsed-wave tissue Doppler , then E/E′ ratio, was calculated. The tissue Doppler-derived-Tei index of RV was calculated using the following formula: IVCT′ + IVRT′/ET′, where isovolumic contraction time (IVCT') from the A′ wave end to S′ wave beginning, while isovolumic relaxation time (IVRT') was calculated as the time from the S′ wave end to E′ wave beginning, and ET is the ejection time from the beginning to the end of S′ wave.Three-dimensional auto RV: A 3DE full-volume ECG-gated dataset at RV-focused apical four-chamber view was acquired using Heart Model Acquisition mode (HM ACQ) at a frame rate of more than 20–25 as recommended by ASE . RV fullThe sample was sized using G*Power 3.1.9.2 software to provide a power of 99% and an alpha error of 0.05. The calculation was based on the mean and standard deviation (SD) of 3D-derived RVEF results of Buonauro et al.  on an adThe 3D auto RV reproducibility was determined through intraobserver and interobserver intraclass correlation coefficient (ICC) evaluation for the 3D auto RV-derived RV EF. In a randomly selected sample of 15 patients, the same observer performed an offline reassessment of 3D-derived RV EF a week later for intraobserver variability determination. In contrast, for interobserver variability, the same patients were examined by another observer blinded to the initial results.t-test or Mann–Whitney U test. If the p-value < 0.05, it will be considered statistically significant. Linear correlations between the variables were evaluated using the Pearson correlation coefficient. Multivariate regression analysis was performed to assess the. Intra- and inter-observer reproducibility was quantified using the intraclass correlation coefficient (ICC).Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS)  version 25. Shapiro–Wilk test was used to test data normality of distribution. Data were presented as mean ± standard deviation (SD) or median whenever appropriate. The chi-square or Fisher’s exact test was used to compare categorical variables. When relevant, continuous variables were compared using the Student’s Between November 2020 and February 2022, 40 pediatric patients with SLE and 40 matched healthy controls were enrolled in the study. The demographic characteristics and clinical data of the study groups are summarized in Table Table The conventional ECHO assessment of the two study groups is presented in Table p = < 0.001, 0.002, respectively).In Table p < 0.001. Auto RV-derived lateral and septal LS were impaired considerably in SLE compared to controls (p < 0.001). Additionally, RV TAPSE and FAC were substantially lower in patients vs. controls .Table p > 0.05 for all). Also, no significant difference was found between those who received or did not receive cyclophosphamide, mycophenolate mofetil, or azathioprine.Regarding SLE patients, no significant difference was found between male and female subjects, patients with and without nephritis, arthritis, serositis, cutaneous, and CNS manifestations , while cumulative SLEDAI score negatively correlated with EF, TAPSE, and FAC . SDI negatively correlated with EF, TAPSE, FAC, and RVLS free wall . However, the duration of illness and anti-ds DNA level was not significantly correlated with the studied echocardiographic parameters. By multivariate regression analysis, SDI remained an independent predictor of RVLS-free wall  and TAPSE .The correlations of the patient’s age, disease activity, and damage indices with RV ECHO parameters are shown in Table Intraobserver variability ICC for 3D-derived RV EF was 0.96, while ICC for interobserver variability of the corresponding parameter was 0.94.There have been noticeable improvements in the survival of c-SLE , 28; howAlthough, the mean heart rate was significantly higher in the patients’ group than in the control group, it was within the average heart rate range for age. None of the included cases could be described with sinus tachycardia diagnosis; therefore, it was not expected to affect cardiac function. Similar findings were reported in a study from Turkey on juvenile SLE . NeverthIn the current study, although tricuspid regurgitation in the c-SLE cases was documented in a higher percentage than in the controls with significantly higher PASP, none of our cases had pulmonary arterial hypertension (PAH). Adrovic et al. reported a consistent finding of increased PASP in SLE cases; nevertheless, they documented only one patient with juvenile SLE (2.6%) with PAH . The LeaCardiovascular implications in SLE are the sequelae of mixed pathophysiologic mechanisms, leading to the development of cardiac manifestations at a younger age than the general population. Endothelial cell dysfunction, disrupted innate immune system, and abnormalities in the adaptive immune system are incriminating factors in SLE-induced cardiac involvement. In addition, other SLE-related factors affect myocardial function, such as lupus nephritis, prolonged corticosteroid use, dyslipidemia, and vitamin D deficiency –40, hencUsing conventional ECHO and tissue Doppler, the RV Tei index was significantly increased in patients compared to controls in the current work. Similarly, a study of RV functions in c-SLE documented higher tissue-Doppler-measured Tie index and s-wave velocity at tricuspid annulus was significantly lower in cases than in the control group . In the Despite the non-significance of conventional LV FS and EF, Gin et al. found a significant decrease in systolic velocity of RV tissue Doppler in adult patients with SLE than in controls, especially in SLE patients with pulmonary hypertension. Additionally, the RV Tie index was higher in the SLE group with a statistically significant result . ConsistWith increasing awareness of the RV’s role and the prognostic value in several cardiac diseases, a comprehensive, accurate evaluation of the RV is essential. Conventional ECHO for assessing RV function has inherent limitations because of the complex RV geometry and because most of these parameters depend on the angle or load. These issues were overcome with 3DE and deformation imaging with speckle-tracking ECHO (STE). Accuracy and reproducibility were proven relative to other reference procedures, such as radionuclide ventriculography and cMRI. However, it was reported that the duration of RV analysis (acquisition and offline reconstruction) with 3-DE is reasonably short, with satisfactory image quality –44.TAPSE is an early-affected myocardial parameter in variable diseases , 46. TAP3D-derived strains, including RVLS-free wall and RVLS-septum, were significantly affected in our c-SLE cases compared to healthy children. 3D RV lateral wall strain was defined as a critical parameter of RV dysfunction associated with SDI in the adult population independently of disease duration . A studyr = 0.74–0.9). In addition, 3DE-determined RV EF was independently associated with cardiac outcomes in patients with diverse backgrounds and offered incremental value over clinical risk factors and the other ECHO parameters for predicting future adverse outcomes [In the current work, 3D-derived RVEF and stroke volume were significantly decreased in c-SLE patients compared to the control group. Consistent results were reported by Buonauro and colleagues in uncomplicated SLE adult patients . Nagata outcomes . Howeveroutcomes , 53. Whioutcomes . Regardloutcomes . Moreoveoutcomes , 56. CorOne of the advantages of the fully automated software for 3D evaluation of RV is allowing for single-beat full-volume analysis with a satisfactory frame rate without stitching, making it easier to analyze patients with arrhythmias or those unable to hold breathing . TherefoNo association was reported in the current work between all ECHO findings and specific clinical features of the diseases. However, Leal et al. reported an association between asymptomatic RV dysfunction, neuropsychiatric manifestations, and antiphospholipid antibodies in 35 children with SLE suggesting a common pathological pathway . In addiThe RV evaluation studies in other pediatric rheumatological disorders are scarce. RV systolic and diastolic functions were reported to be impaired in children with juvenile idiopathic arthritis (JIA) compared to healthy controls but with no correlation of ECHO parameters to clinical manifestations of the disease , consistThe major limitation of the current research was that the study was a single-center experience with a non-blinding technique of the investigator regarding the study aim when analyzing the ECHO loops. Moreover, the inherent known limitation of 3DE is the need for good image quality at transthoracic ECHO full-volume dataset acquisition poses a slight risk of selection bias. Another limitation was the lack of concomitant transcatheter invasive pulmonary artery pressure and resistance measurements. Therefore, a large-scale multi-center study on a significant sample of c-SLE patients with variable ethnic backgrounds is warranted to confirm further the current study results. In addition, more extensive multi-center research might impact recommendations for the c-SLE routine follow-up process to expand to functional cardiac monitoring, including RV myocardial functions. Moreover, studying RV functions in c-SLE using cMRI could be the gold standard in future studies.Subtle right ventricular myocardial dysfunctional alterations could be detected in childhood-onset SLE patients, particularly via 3D auto RV-derived echocardiographic parameters, despite the absence of evident pulmonary hypertension. Furthermore, these parameters strongly correlate with the SLE disease activity and chronicity parameters such as damage index and cumulative SLEDAI score. Therefore, it is reasonable to consider including cardiac functional screening and RV in c-SLE cases.


TM transcatheter mitral valve replacement system  is a therapy for patients with symptomatic mitral valve (MV) disease high risk for conventional MV surgery or challenging anatomy for transcatheter MV repair. With over 1000 Tendyne-TMVR performed worldwide and beneficial periprocedural, 30-day, and 2-year outcomes,The TendynePatients undergoing Tendyne-TMVR should be receiving optimal tolerated guideline-directed medical therapy according to American College of Cardiology Foundation/American Heart Association Heart Failure GuidelinesPreprocedural right heart catheterization should be considered in all patients, particularly those with severe pulmonary hypertension (pulmonary artery systolic pressure [PASP] ≥60 mmHg on echo), moderate/severe right ventricular (RV) dysfunction , and/or signs of right heart congestion . Revascularizing severe coronary disease is recommended. Stress echocardiography should be considered in patients with left ventricular (LV) ejection fraction <30% to assess the presence of contractile reserve.Potential periprocedural complications during Tendyne-TMVR include afterload mismatch (ALMM), LV outflow tract (LVOT) obstruction (LVOTO), and LV collapse. ALMM may occur when acute elimination of MR causes a sudden reduction in LV and/or RV systolic function that is poorly tolerated. The combination of ALMM and LVOTO can be particularly challenging to manage, so it is imperative to identify these patients preprocedurally.With LV dysfunction are patients with LV ejection fraction <40%, dilated LV , cardiac output < 3.0 L/min, or cardiac index (CI) < 2.0. Patients at risk of ALMM and biventricular dysfunction are those with RV dysfunction and/or PASP ≥60 mmHg.2 or less, small LV (end-systolic dimension <3.5 cm), dynamic basal septum, long (>28 mm) unsupported anterior mitral valve leaflet (AMVL), narrow (<6 mm) distance between AMVL and septal edge in systole, narrow (<120°) aortomitral angle, and anterior apical access point .These include patients with preprocedural predicted neo-LVOT values in the range of 250 mmThese include those with small left ventricle (<3.5 cm), basal septal hypertrophy, or ischemia.Frequent communication between Tendyne-TMVR implant and anesthetic teams is vital to minimize periprocedural and postprocedural complications. Surgical, anesthetic, and imaging teams should participate in the team brief to ensure the entire periprocedural team is aware of individualized patient hemodynamic risks, medical management plan, and surgical bailout options. It is important to communicate that the final delivery phase is often associated with hypotension and to discuss in advance the balance between patience vs. immediate corrective actions. Following the team brief, there are 4 “checkpoints” when the patient’s condition should be re-reviewed, paying particular attention to the patient’s hemodynamic data, volume status, laboratory data , changes in medications, and re-review of the medical management plan.Continuous cardiac monitoring throughout the periprocedural period is recommended. A pulmonary arterial catheter permits estimation of right atrial pressure, PASP, cardiac output, and CI. Optimal preprocedural hemodynamics include right atrial pressure-to-pulmonary capillary wedge pressure ratio <0.6 and CI >2. Pigtail catheter insertion in the left ventricle is helpful to assess LVOT pull-back gradient. Transesophageal echocardiography (TEE) should confirm anatomical measurements  to ensure no changes from screening. Temporary pacing should be considered in patients with no permanent system who are at risk of ALMM or LV collapse in whom programming heart rate at 80-100 bpm may compensate for a relatively low stroke volume. The implant team should ascertain the patient’s response to induction of anesthesia, identify hemodynamic changes from baseline, acknowledge current medical support, and re-establish whether the patient is likely to tolerate the procedure if requiring significant levels of inotropic support.Surface transthoracic echo (TTE) identifies the optimal intercostal space for LV apical access identified on preprocedural multislice computerized tomography. Once confirmed, the surgical team may extend the parietal pleural and intercostal muscles to improve apical exposure and minimize rib fracture risk. An Alexis soft-tissue retractor  and mini thoracotomy retractor are used, but it may be necessary to surgically divide a rib in patients with reduced apical visualization. Surgical preparation of the LV apex for apical puncture may be performed using 3-0 SH-1 pledgeted sutures in a U-stitch, Star of David, or classic purse string formation. After optimizing TEE X-plane LV and MV imaging, the echocardiographer should confirm LV apical access point during simultaneous LV apical finger palpation by the surgical implanter . Before transapical puncture, the implant team should communicate with the anesthetist for an update on the patient’s condition and medical support and ensure systolic blood pressure is > 100 mmHg to support device insertion and delivery.Following placement of LV apical pledgeted sutures and administration of heparin to achieve an activated clotting time >300 seconds, a 0.035-inch guidewire is inserted into the left atrium (LA) via the LV, and a Fogarty balloon advanced/retracted over the wire to ensure no entanglement with the mitral subvalvular apparatus. A 34Fr delivery sheath is inserted into the LA using an over-the-wire technique, and the Tendyne-device is introduced through the sheath, partially unsheathed in the LA, aligned with the aortomitral continuity using TEE, and retracted until the device cuff rests on the LA floor. The remainder (80%) of the prosthesis is deployed within the annulus and secured with a braided, high-molecular-weight polyethylene tether attached to an epicardial pad. The patient may become hypotensive until the device is fully expanded, so the patient should be well filled with inotropic support if necessary , noting transient low output usually resolves on complete device deployment and so excessive use of inotropes (LVOTO risk) should be avoided. The surgeon should not lower the delivery sheath trajectory as this results in systolic anterior motion of the AMVL and LVOTO. At the procedure end, the tether tension is adjusted to optimize seating of the prosthesis. The implant team  should be alert to potential ALMM, LVOTO, and LV collapse throughout TMVR deployment and complications managed accordingly.Care should be exercised to prevent hypotension caused by AMVL distortion. Inotropic support should be considered with a low threshold for reducing afterload with mechanical support  or extracorporeal mechanical oxygenation for extreme hemodynamic collapse . PulmonaVolume resuscitation, increasing afterload, and beta-blockade must be considered to avoid tachycardia. Inotropic and chronotropic medications must be avoided when possible, and if hemodynamic instability persists, device repositioning, lateral device rotation to optimize LVOT opening (“off-clocking”), atrialization, or device retrieval must be considered.Volume resuscitation and inotropic support will be required with backup pacing , or mechanical support.It is important to ensure from the anesthetist that the patient is tolerating MR reversal and maintaining adequate systolic blood pressure; from the echocardiographer that the Tendyne device is stable and that transvalvular MR, paravalvular leak, and LVOTO have been excluded; and from the surgical team that there is adequate apical hemostasis. The patient’s blood pressure should be < 130 mmHg to facilitate sheath removal. If the patient is stable, the surgical team should proceed with device decoupling and apical pad placement. Apical bleeding should be repaired before delivery sheath removal (a short period of cardiopulmonary bypass may be required).Postoperative management is key to successful outcomes, and patients should be managed like cardiac surgical patients. A clear and algorithmic handover to intensive care/high-dependency unit/ward is vital for the safe progression of the patient from theater/hybrid lab to hospital discharge. The implant team should detail the Tendyne-TMVR procedure, set hemodynamic goals , and communicate the postoperative medical management plan. A decline in cardiac performance can be subtle in the immediate postoperative period, and vigilance is required. The implant team should be informed of any bleeding or changes in cardiac hemodynamics, and large shifts in the patient’s volume status (including overdiuresis) should be avoided. Early extubation ambulation should be encouraged. Pain management is critical, and intercostal or paravertebral nerve block should be considered with removal of chest tubes once there is no evidence of ongoing drainage. Left pleural effusion is common and may cause delayed respiratory insufficiency; drainage may be required. Pulmonary arterial catheter and arterial lines may be removed after 48 hours, and serial echocardiography used to determine hemodynamics. Close attention should be paid to rhythm changes, and new-onset atrial fibrillation cardioverted expeditiously to avoid decompensation. Pacing may be used to optimize heart rate in patients at risk for ALMM. On transfer to ward-based care, patients should be encouraged to mobilize, sedation medication limited, sleep/wake cycles optimized, and nutritional goals met. Diuretics and neurohormonal medications should be switched to a stable oral regime 48 hours prior to discharge and beta-blockers titrated cautiously. TTE must be performed 72 hours or less before discharge to document LV/RV size and function, mitral valve and LVOT gradients, and any paravalvular leak. Anticoagulation with oral Coumadin/Warfarin may be started as soon as safe (often the first postoperative day) to a target international normalized ratio (INR) 2.5 (discontinue bridging subcutaneous low-molecular-weight heparin when INR ≥2.0). Anticoagulation should be for at least 6 months and lifelong if well tolerated. Antiplatelet therapy should be continued as per standard recommendations. Novel oral anticoagulants are not currently recommended, though this is subject to ongoing review in selected cases.Recommended clinical review with INR check and TTE should be performed 4 weeks postprocedure. Patients should be counseled to contact the medical team if there is any wound infection, pain, breathlessness, palpitations, dizzy spells, and fatigue not resolving with rest between discharge and planned clinical review.We present current best practice recommendations on periprocedural management for Tendyne-TMVR, based on consensus from a relatively small number of experienced centers worldwide. These recommendations may change with technological iterations, increasing clinical experience, and expanded evidence base.The authors have no funding to report.Alison Duncan receives consultancy fees from Abbott Vascular, Edwards Lifesciences, Medtronic, and NeoChord. Gry Dahle receives consultancy fees from Abbott Vascular. Lenard Conradi receives consultancy fees from Abbott Vascular. Nicholas Dumonteil receives consultancy fees from Abbott Vascular, Ancora Heart, Boston Scientific, Edwards Lifesciences, and Medtronic. Nimesh Shah receives consultancy fees from Edwards Lifesciences. Benjamin Sun receives proctoring and consultancy fees from Abbott Vascular. Paul Sorajja receives consultancy fees from Anteris, Abbott Structural, Medtronic, Boston Scientific, WL Gore, TriFlo, and Vdyne. Gorav Ailawadi receives consultancy fees for Abbott, Edwards, Medtronic, Admedus, Gore, and AtriCure. Jason H Rogers receives research funding from Abbott and Boston Scientific and consultancy fees from Abbott, Boston Scientific, and Gore. Brian Bethea receives consultancy fees from Abbott Vascular. John Wang had no conflict to declare.


Cardiac interactions with organs such as the liver or kidneys have been described in different cardiovascular diseases. However, the clinical relevance of hepatorenal dysfunction in chronic thromboembolic pulmonary hypertension (CTEPH) remains unclear. We determined the association of hepatorenal dysfunction (measured using the Model for End-stage Liver Disease Sodium [MELDNa] score) with right heart function and survival in patients with CTEPH.We analyzed all patients with CTEPH in the Giessen Pulmonary Hypertension Registry who had available MELDNa scores and were not taking vitamin K antagonists. The MELDNa score was calculated as MELD score − serum Na − (0.025 * MELD score * (140 − serum Na)) + 140; the MELD score was calculated as 10*(0.957*ln(creatinine)+0.378*ln(bilirubin)+1.12*ln)+6.43.Seventy-two patients were included . MELDNa correlated well with right atrial and ventricular function and pulmonary hemodynamics. Forward regression analysis revealed that hepatorenal dysfunction mainly depends on right atrial strain and tricuspid regurgitation, but not right ventricular systolic dysfunction. Hepatorenal dysfunction predicted mortality at baseline and follow-up . Changes in hepatorenal function also predicted mortality.Hepatorenal dysfunction in CTEPH is primarily associated with venous congestion rather than cardiac forward failure. As a surrogate parameter for hepatorenal dysfunction, MELDNa is a simple method to identify at-risk patients at baseline and follow-up. Owing to the pathophysiological nature of the disease (which is characterized by pulmonary artery obstructions), right ventricular (RV) afterload and wall tension are increased, and the right ventricle seeks to counteract these changes with cardiac remodeling. First, homeometric adaptation according to the Laplace law leads to concentric hypertrophy and increased wall thickness. A further increase in RV afterload can then lead to heterometric adaptation with right heart dilatation, RV insufficiency, and venous congestion .Clinical studies have focused on the right ventricle and its systolic (dys)function –4. HowevThe liver and kidneys are affected by both venous congestion and reduced cardiac output , 9. TherIt is, however, unclear whether the non-invasive assessment of hepatorenal dysfunction is also associated with the severity of PH and whether the MELDNa score is prognostically relevant for patients with CTEPH. Furthermore, the underlying pathomechanism leading to hepatorenal dysfunction in patients with CTEPH is not fully understood. Therefore, the aim of this study was to determine the association of hepatorenal dysfunction (measured using the MELDNa score) with right heart function and survival in patients with CTEPH.2.2.1.All patients with confirmed CTEPH enrolled between June 2013 and January 2021 in the Giessen PH Registry  were incThe study was approved by the Institutional Review Board of the University of Giessen (No. 266/11), and all patients gave their written informed consent.2.2.via a GE Vivid E9 ultrasound unit . Tricuspid annular plane systolic excursion (TAPSE) was measured in M-mode at the lateral tricuspid valve annulus. Right atrial (RA) area was measured at end-systole corresponding to the maximal area. RA pressure (RAP) was estimated from the diameter of the inferior vena cava and its inspiratory collapsibility .2.3.The surrogate parameter for hepatorenal dysfunction used in this paper was the MELDNa score, which adds sodium levels to the original MELD score . The MELIn sensitivity analyses, hepatorenal dysfunction was defined as a MELD excluding INR (MELD-XI) score  above th2.4.Statistical analyses were performed using R version 4.2.1  and SPSS version 29 . All parameters were evaluated based on the Shapiro–Wilk normality test and histograms for normal distribution. When normally distributed, data are presented as the mean (standard deviation) and compared using Student’s t-tests. Otherwise, numbers are presented as median  and compared using Wilcoxon rank tests. The linear association between variables was assessed using Spearman’s rho. Furthermore, we used univariate and multivariate binary regression analyses to investigate the influence of different parameters on hepatorenal dysfunction in patients with CTEPH. In addition, survival analyses were performed using Kaplan–Meier estimators as well as univariate and multivariate Cox regression.3.3.1.In total, 117 patients with CTEPH had available MELD-XI scores , RV end-systolic area , and TAPSE . TR severity  and RA area  were also significantly linked to hepatorenal (dys)function. Left ventricular global longitudinal strain (GLS), however, was not associated with the MELDNa score (p = 0.532).Correlation analyses indicated that the MELDNa score has a linear association with RA and RV function . In partβ-coefficient: − 0.365, p = 0.003) and TR severity , but not RV systolic (dys)function, were strongly related to hepatorenal (dys)function.The parameters most stringently related to the MELDNa score were ascertained by multivariate linear regression analysis using the forward selection technique The following parameters were included: systolic, diastolic, and mean pulmonary arterial pressure, pulmonary vascular resistance, cardiac index, sex, TR severity, TAPSE, RA reservoir strain, RV GLS, RA area, RV diameter, RV end-systolic area, and RAP. Interestingly, the model showed that RA reservoir strain (p < 0.001) than those without hepatorenal dysfunction. Furthermore, RV and RA strain were more severely impaired . No other significant differences between the two groups were detected (The study cohort was then divided into two groups based on the MELDNa score. Patients with a high MELDNa score (above the third quartile [> 11]) were defined as patients with hepatorenal dysfunction. Patients fulfilling this definition of hepatorenal dysfunction had more severely impaired pulmonary hemodynamics  and signdetected .3.3.p = 0.001). Hepatorenal dysfunction remained as an independent predictor of mortality even after adjusting for age, RV systolic function (TAPSE), and TR severity . Further adjustment for direct oral anticoagulant (DOAC) intake did not change the results .Next, Kaplan–Meier analysis was performed to investigate the prognostic relevance of hepatorenal dysfunction in patients with CTEPH . Survivan = 117) stratified by the MELD-XI score (p = 0.003).A sensitivity analysis of the screening population . Consistent with this, univariate Cox regression showed a significantly increased HR per unit increase of MELDNa . Multivariate Cox regression indicated that hepatorenal dysfunction is associated with survival independent of age, RV systolic function (mirrored by TAPSE), and TR severity . Further adjustment for DOAC intake did not change the results .Dividing the study population into the two groups with and without hepatorenal dysfunction as defined above, the analysis showed a similar interdependency of parameters as observed at baseline: Patients with hepatorenal dysfunction (MELDNa score above the third quartile [> 11]) had more severe impairment of pulmonary hemodynamics, higher BNP concentrations, and impaired RA reservoir strain compared with patients without hepatorenal dysfunction . Kaplan–p = 0.001).In the screening population, follow-up data were available in 91 cases . A sensi3.5.n = 27), whilst the second group was defined as having hepatorenal dysfunction at baseline, but a low MELDNa score during the follow-up . The third group included those with a high MELDNa score at baseline and during follow-up as well as patients who developed hepatorenal dysfunction during follow-up .Finally, the cohort was stratified into three groups according to the change in hepatorenal functional status (based on the MELDNa score) from baseline to follow-up . The firIt became evident that the patients with persistent hepatorenal dysfunction or worsening during follow-up had the poorest prognosis , whereas none of the patients with steadily normal hepatorenal function died within 5 years after follow-up. Notably, patients who presented with hepatorenal dysfunction at baseline but improved during follow-up showed higher survival  than those who had persistent dysfunction or worsening.4.via the routine lab data-based MELDNa score) is associated with impairment of pulmonary hemodynamics and survival in patients with CTEPH. Venous congestion due to TR and RA engorgement rather than cardiac forward failure is suggested as major link between hemodynamic abnormalities and loss of hepatorenal function.To the best of our knowledge, this study is the first to show that hepatorenal dysfunction , or re-evaluation of eligibility for surgery (pulmonary endarterectomy). In contrast to other risk scores [such as the 2015 European Society of Cardiology/European Respiratory Society risk stratification , which hThis study is limited by its retrospective design and missing data. In particular, the follow-up analysis is limited owing to missing data, which may have introduced a bias into the results. The use of the MELDNa score (rather than the MELD-XI score) necessitated the exclusion of 39 patients who used vitamin K antagonists (35% of the 111 patients with MELDNa data) from the primary analyses, which may also have been a source of bias. We chose to focus on the MELDNa score for the primary analyses because of the prognostic importance of hyponatremia (particularly severe hyponatremia) in pulmonary arterial hypertension , 42. DOAIn conclusion, our data indicate that hepatorenal dysfunction is associated with RA dysfunction and TR, and is a risk factor for mortality when assessed at baseline and during follow-up in patients with CTEPH . Thus, tThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Local Ethics Committee of Giessen. The patients/participants provided their written informed consent to participate in this study.AY, HG, and KT: study conceptualization. AY, DZ, MR, SS, ZR, NK, FG, WS, HoG, HeG, and KT: study design and data collection, critical revision of the manuscript, approval of manuscript for submission, and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. AY and HG: data analysis. AY, DZ, HG, and KT: drafting of the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by the Excellence Cluster Cardio-Pulmonary System (ECCPS) and the Collaborative Research Center (SFB) 1213—Pulmonary Hypertension and Cor Pulmonale, grant number SFB1213/1, project B08 .AY reports non-financial support from the University of Giessen during the conduct of the study, and personal fees from MSD outside the submitted work. MR reports grants from the German Research Foundation and non-financial support from the University of Giessen during the conduct of the study, and grants from United Therapeutics, grants and personal fees from Bayer, and personal fees from Actelion, Mundipharma, Roche, and OMT outside the submitted work. FG reports no competing interests. WS reports grants from the German Research Foundation and non-financial support from the University of Giessen during the conduct of the study, and personal fees from Pfizer and Bayer Pharma AG outside the submitted work. HAG reports grants from the German Research Foundation and non-financial support from the University of Giessen during the conduct of the study, and personal fees from Bayer, Actelion, Pfizer, Merck, GSK, and Takeda, grants and personal fees from Novartis, Bayer HealthCare, and Encysive/Pfizer, and grants from Aires, the German Research Foundation, Excellence Cluster Cardiopulmonary Research, and the German Ministry for Education and Research outside the submitted work. HG reports grants from the German Research Foundation and non-financial support from the University of Giessen during the conduct of the study, and personal fees from Actelion, AstraZeneca, Bayer, BMS, GSK, Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer, and United Therapeutics outside the submitted work. KT reports grants from the German Research Foundation and non-financial support from the University of Giessen during the conduct of the study, and personal fees from Actelion and Bayer outside the submitted work.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Introduction: The perioperative management of patients with pulmonary hypertension (PH) undergoing cardiac surgery represents one of the most challenging clinical scenarios. This fact mainly depends on the relationship existing between PH and right ventricular failure (RVF). Levosimendan (LS) is an inodilator that might be an effective agent in the treatment of PH and RVF. The aim of this study was to examine the impact of the duration of cardiopulmonary bypass (CPB) on the therapeutic drug monitoring of LS and to evaluate the effect of preemptive administration of LS on perioperative hemodynamic and echocardiographic parameters in cardiac surgical patients with preexisting PH. Materials and Methods: In this study, LS was administered in adult patients undergoing cardiac surgery before CPB in order to prevent exacerbation of preexisting PH and subsequent right ventricular dysfunction. Thirty cardiac surgical patients with preoperatively confirmed PH were randomized to receive either 6 μg/kg or 12 μg/kg of LS after the induction of anesthesia. The plasma concentration of LS was measured after CPB. In this study, a low sample volume was used combined with a simple sample preparation protocol. The plasma sample was extracted by protein precipitation and evaporated; then, the analyte was reconstituted and detected using specific and sensitive bioanalytical liquid chromatography with mass spectrometry (LC-MS/MS) methodology. The clinical, hemodynamic, and echocardiographic parameters were registered and evaluated before and after the administration of the drug. Results: A fast bioanalytical LC-MS/MS methodology (a run time of 5.5 min) was developed for the simultaneous determination of LS and OR-1896, its main metabolite in human plasma. The LC-MS/MS method was linear over a range of 0.1–50 ng/mL for LS and 1–50 ng/mL for its metabolite OR-1896. Measured plasma concentrations of LS were inversely related to the duration of CPB. LS administration before CPB during cardiac surgery was effective in reducing pulmonary artery pressure and improving hemodynamic parameters after CPB, with a more pronounced and durable effect of the drug at the dose of 12 μg/kg. Additionally, administration of LS at a dose of 12 μg/kg in cardiac surgical patients with PH before CPB improved right ventricular function. Conclusion: LS administration decreases pulmonary artery pressure and may improve right ventricular function in patients with PH undergoing cardiac surgery. Pulmonary hypertension (PH) constitutes a significant challenge in the perioperative care of patients presenting for cardiac surgery ,2. This RVF in the perioperative setting is associated with mortality rates ranging up to 22–90%, as well as significant complications, including increased need for inotropic and mechanical circulatory support, prolonged mechanical ventilation, and prolonged length of intensive care unit (ICU) and in-hospital stay ,7.The most frequent type of PH in patients presenting for cardiac surgery is PH secondary to left heart disease ,9. MitraRegardless of the underlying cause, PH may be exacerbated during cardiac surgery due to several causes. The most important causes involved include systemic inflammatory response and pulmonary reperfusion syndrome after cardiopulmonary bypass (CPB) ,14,15, aExacerbation of preexisting PH during cardiac surgery is related to increased right ventricular (RV) afterload and may lead to RVF. The most important consequence of uncontrolled PH is RVF, which in turn is accompanied by decreased pulmonary blood flow, decreased left ventricular (LV) preload, and decreased cardiac output (CO) and arterial blood pressure (BP). The subsequent drop in coronary blood flow further worsens RV function, and consequently, a vicious cycle is established that eventually leads to supra-systemic RV pressures and cardiovascular collapse ,5,6.RVF in the perioperative setting is difficult to diagnose and even more demanding to treat. It typically presents intraoperatively as difficulty in separation from CPB and as LCOS or multi-organ dysfunction in the postoperative period. Currently, there are no established evidence-based guidelines for the perioperative management of RVF in cardiac surgical patients with PH. The principal management goal is to prevent RVF by reducing RV afterload, optimizing preload, and enhancing RV contractility ,23,24.+ channels in vascular smooth muscle cells, causing vasodilation in both arterial and venous smooth muscle cells. The cardioprotective properties of LS are associated with the opening of mitochondrial ATP-dependent K+ channels in the cardiomyocytes, providing protection against ischemia-reperfusion injury, apoptosis, and oxidative stress [In this context, several pharmacologic agents administered intravenously or via inhalation have been used in order to prevent the worsening of PH during cardiac surgery and treat RVF. These agents include prostaglandins, nitric oxide (NO), milrinone, adrenergic agents, and levosimendan (LS) ,26,27. Le stress . LS has e stress .Given the vasodilatory properties of LS, it could distend pulmonary vasculature and vasculature of the venous system, causing a reduction in both RV preload and afterload, while, given the inotropic action of the drug, it could enhance RV contractility ,33. AlthThe aim of the study is to examine the pharmacokinetic and pharmacodynamic properties of LS in patients with PH undergoing cardiac surgery with the use of CPB, evaluate the efficacy of its administration prior to CPB in preventing exacerbation of PH and RVF, and identify the most effective dose of the drug in the perioperative context.In total, 34 patients were screened for enrollment in this study. Of those, 30 patients fulfilled the inclusion criteria and completed the study. Therefore, the sample consisted of 30 patients  with a mean age of 68.9 years (SD 11.0 years). Half of the patients (N = 15) received a dose of 6 μg/kg, and the other half (N = 15) received a dose of 12 μg/kg. Patients’ characteristics were similar in both dose groups . No in-hp = 0.007). Significantly higher values of LS at 20 min and 6 h after CPB were found when CPB duration was shorter compared to when CPB duration was longer , but no statistically significant difference regarding the LVEF change over time was found between patients with plasma levels of LS > than 6.7 ng/mL at 20 min after CPB and patients with plasma levels of LS < than 6.7 ng/mL at 20 min after CPB (p = 0.101). Similarly, TAPSE values increased over time in patients with LS levels > 6.7 ng/mL at 20 min after CPB (p = 0.001). The degree of change of TAPSE differed significantly between the two groups, as indicated by the significant interaction effect of the analysis. Specifically, the increase was significantly greater in patients with LS plasma concentration > 6.7 ng/mL at 20 min after CPB (p = 0.015)  . Length = 0.015) .Finally, no statistical difference regarding the need for vasopressor (norepinephrine) and additional inotropic support (dobutamine or epinephrine) was found between the two groups of patients.According to the results of the present prospective randomized clinical study, LS administered both at a dose of 6 μg/kg or 12 μg/kg after induction of anesthesia and before CPB in cardiac surgical patients with preoperatively confirmed PH is effective in reducing SPAP values after CPB in comparison to baseline values. Although both doses are effective in reducing SPAP, the decrease is greater when LS is administered at a dose of 12 μg/kg. In addition, both doses are effective in increasing CO and CI, but only the administration of LS at a dose of 12 μg/kg is related to enhanced RV function, as shown by increased TAPSE values. No significant difference in the incidence of hypotension and need for vasopressor support was found between the two groups of patients receiving LS at a dose of 6 μg/kg or 12 μg/kg.These findings suggest that the prophylactic use of LS in patients with PH undergoing cardiac surgery might inhibit or reduce the degree of exacerbation of preexisting PH and potentially subsequent RVF after CPB. This fact could be attributed to the vasodilatory and inotropic properties of LS as well as to the anti-inflammatory action of the drug, given that the exacerbation of preexisting PH during cardiac surgery is strongly associated with the systemic inflammatory response induced by extracorporeal circulation.Regarding the pharmacokinetic profile of LS during cardiac surgery, the results of our study indicate that plasma levels of the drug are in inverse proportion with the duration of CPB. OR-1896 was not present in a detectable concentration in the clinical samples analyzed at 20 min, 6, 12, 24, and 80 h after CPB. This finding could indicate that CPB and extracorporeal circulation could severely affect the pharmacokinetic profile of LS. In clinical practice, this fact could translate into a need for adjustment of the dose of LS administered before CPB in patients undergoing cardiac surgery to obtain therapeutical plasma levels of the drug and, thus, clinical effectiveness. The relation between CPB and the pharmacokinetics of LS could represent a potential reason for subtherapeutic plasma levels of LS and altered metabolism of the drug and its active metabolite, OR-1896, after CPB. Consequently, the inverse relationship between the length of CPB and extracorporeal circulation and the pharmacokinetic profile of LS could create confusion concerning the effectiveness of the drug in cardiac surgery and, by extension, be a potential factor explaining the heterogeneous results of clinical trials with LS in the context of cardiac surgery ,35.Plasma concentrations associated with LS efficacy were assessed in an open-label, non-randomized phase II study in patients diagnosed with heart failure (New York Heart Association III-IV), whereby a 24-h continuous infusion of LS at a dose of 0.2 mcg/kg/min produced peak plasma concentrations of 62.6 ng/mL . AccordiLS has been in clinical use for over two decades and has been the subject of considerable evaluation in a vast range of clinical applications. The main indication of LS is the management of acutely decompensated chronic heart failure, and most of the evidence concerns the effect of the drug on the left ventricular performance. Beyond its main indication, LS has been evaluated with conflicting results in various perioperative settings, including coronary artery bypass graft surgery (CABG) and valve surgery in patients with low ejection fraction ,38,39, hAlthough the present literature is not extensive, the existing data suggest that LS potentially has a beneficial role in treating PH and associated RVF resulting from various etiologies, including pulmonary arterial hypertension, left heart disease, and congenital heart disease . HoweverOur findings are in agreement with the existing data and support that LS could have a favorable role in preventing the worsening of PH during cardiac surgery and superimposed RVF. In clinical practice, given the high risk of RVF faced by cardiac surgical patients with preexisting PH, administration of LS prior to CPB, in association if necessary with vasopressors, could be protective against exacerbation of PH and subsequent RVF during weaning and after CPB. According to our findings, LS should be administered at a dose of 12 μg/kg to impact RV contractility positively. Alternatively, LS plasma levels above 6.7 ng/mL should be achieved for this goal.This study has a few limitations, in addition to the small sample size. Patients with PH due to valvular disease may demonstrate a decrease in pulmonary artery pressure after surgical correction of valvular pathology due to the release of left-sided obstruction, independently of pharmacological treatment. However, in our study, the persistence of a moderate level of pulmonary hypertension in both groups was documented after surgery. The residual pulmonary hypertension was due either to morphologic changes in the pulmonary vasculature and/or increased pulmonary vasculature reactivity due to systemic inflammatory response. Moreover, the study was designed to compare the effectiveness of different doses of the same drug that, according to the existing literature, are favorable in treating PH. Nevertheless, the absence of a control group receiving a placebo or another drug  represents a limitation. An additional limitation is that the echocardiographic assessment of right ventricular function was performed only using TAPSE. Combining more than one echocardiographic method of right ventricular function assessment would allow us to better evaluate right ventricular performance and distinguish normal from abnormal function. Furthermore, the follow-up period was relatively short, including the intraoperative period and the first two hours of the postoperative period in the ICU. It would definitely be interesting to extend the follow-up period of hemodynamic and echocardiographic data over the first 24 h postoperatively. However, the comparison of hemodynamic measurements involving intubated patients in mechanical ventilation with hemodynamic data involving spontaneous ventilating patients would not be possible. Finally, regarding LC-MS/MS methodology, the method was partially validated based on EMA guidelines for the quantification of drugs in biological fluids . The LC-MS/MS method for the quantification of LS and OR-1896 in human blood plasma was investigated for specificity, linearity, accuracy, and precision. The linearity in the range of 0.1–50 ng/mL for LS and 1–50 ng/mL for OR-1896 was determined over multiple runs with R values typically > 0.999. Specificity was evaluated by monitoring the presence of LS, OR-1896, and IS in blank pooled plasma. No interfering peaks were detected in blank samples. Matrix effect, recovery, and stability studies were beyond the scope of this pilot clinical protocol and will be further investigated in future studies.0 676 OF 006/B’ CYCLE -23/3/20), and informed consent was obtained from each patient before the operation. The study was prospectively registered on clinicaltrials.org before patient enrollment under the number NCT04599816.This prospective, randomized, single-center, and interventional study was approved by the Hospital’s (Onassis Cardiac Surgery Center) Ethics Committee (NThe study population consisted of 30 patients with severe PH due to left heart disease undergoing elective cardiac surgery. Patients were considered to have severe PH if pulmonary artery systolic pressure (SPAP) was greater than 55 mmHg or mean pulmonary arterial pressure (MPAP) was greater than 25 mmHg, as estimated by preoperative transthoracic or transesophageal echocardiography (TEE) or right heart catheterization. The inclusion criteria were adult patients with PH undergoing elective cardiac surgery with the use of extracorporeal circulation. The exclusion criteria were left ventricular ejection fraction (LVEF) < 30%, severe renal failure and hepatic failure, acute or chronic thromboembolic disease, and chronic obstructive pulmonary disease (COPD).Patients were randomly assigned into two treatment groups: Group A, receiving LS at a dose of 6 μg/kg, and Group B, receiving LS at a dose of 12 μg/kg. Randomization was performed using a computer-generated random code. The allocation code was concealed in an envelope that was opened by the nurses participating in the study who were also in charge of preparing the medication.Premedication, monitoring, anesthesia, and mechanical ventilation were standardized. Apart from standard monitoring for cardiac anesthesia, a pulmonary artery catheter (Swan-Ganz) and TEE were used in all patients. The presence of PH was confirmed by the Swan-Ganz catheter after anesthetic induction, and a comprehensive TEE exam was performed in all patients.2 35–40 mmHg)—blood transfusion practice aimed at maintaining hemoglobin concentration between 9 and 10 g/dL.Anesthetic induction in all patients was performed with intravenous doses of midazolam 0.05 mg/kg, fentanyl 2 μg/kg, and rocuronium bromide 1 mg/kg. For maintenance, all patients received sevoflurane at an end-tidal concentration of 0.5% to 2% and intravenous maintenance doses of midazolam and fentanyl every hour, aiming for bispectral index (BIS) values of 40 to 50. Protective ventilation  was used in all patients maintaining normocapnia (PCO2) = 0.007184 × Height(cm)0.725× Weight(kg)0.425.All perioperative hemodynamics parameters and TTE findings were evaluated by a Swan-Ganz catheter  and a Vivid 3 echocardiography device . Variables measured or calculated included heart rate (HR), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), mean arterial pressure (MAP), SPAP, diastolic pulmonary artery pressure (DPAP), MPAP, mean pulmonary to mean systemic pressure ratio (MPAP/MAP), central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP), stroke volume (SV), CO and cardiac index (CI), systemic vascular resistance (SVR), systemic vascular resistance index (SVRI), pulmonary vascular resistance (PVR), pulmonary vascular resistance index (PVRI), tricuspid annular plane systolic excursion (TAPSE) and LVEF. CO was assessed using the thermodilution technique with three injections of room temperature 5% dextrose 10 mL, and PCWP was measured at end-expiration. CO, SV, SVR, and PVR were indexed to body surface area BSA, calculated using the Du Bois formula  by the addition of epinephrine, 0.01–0.1 μg/kg/min.Hemodynamics were treated according to the following protocol during and after surgery: (1) CVP or PCWP to keep values between 10 to 12 mmHg and 16 to 20 mmHg, respectively, with fluid administration, (2) MAP of 60 to 90 mmHg with norepinephrine 0.05 μg/kg/min increased incrementally by 0.02 μg/kg/min until the MAP was 60 mmHg, (3) if CI < 2 L/min/mIntraoperative echocardiographic evaluation was performed by two anesthesiologists and reviewed by an experienced cardiologist. TAPSE was measured in the four-chamber view as the distance between the end-diastolic and end-systolic position of the outer port of the tricuspid annulus. LVEF was calculated using the modified Simson method .2 > 90% at FiO2 of 0.5 by facemask, stable hemodynamics, chest tube drainage <50 mL/h, urine output >0.5 mL/kg/h, and no intravenous inotropic or vasopressor therapy.Patients were weaned from mechanical ventilation when rewarmed and hemodynamically stable and within normal arterial blood gas values. Patients were discharged from the ICU when the following criteria were met: SpOAfter induction of anesthesia and confirmation of PH presence, LS diluted in 100 mL (Dextrose 5% Water) was administered with a continuous infusion for 20 min. LS administration was discontinued in the event of an anaphylactic reaction, refractory hypotension , or intractable arrhythmias, and the patient was excluded from the protocol and further analysis.Before and after the administration of LS, the already determined intraoperative hemodynamic and transesophageal echocardiographic parameters were evaluated by monitoring with the Swan-Ganz catheter and TEE and recorded in our database. Hemodynamic measurements and transesophageal echocardiographic evaluation were performed after induction of anesthesia, 20 min after discontinuation of CPB, at the end of the surgery, and two hours after ICU admission.Blood plasma concentrations of LS were measured at 20 min after discontinuation of CPB and correlated with hemodynamic and TEE parameters evaluated at this point in time. Moreover, the blood plasma concentration of LS was measured at 6, 12, 24, and 80 h after CPB weaning. At the same time points, the blood plasma concentration of OR-1896 was also measured. Blood plasma concentration of LS and OR-1896 was measured using a bioanalytical methodology of liquid chromatography coupled with mass spectrometry (LC-MS/MS). Blood samples (3 mL) for the determination of plasma concentrations of LS and its metabolite OR-1896 were centrifuged within 10 min of sampling. The plasma was separated and transferred into two polypropylene tubes, frozen immediately, and kept at −70 °C until analysis.LS  and OR-1896  were purchased from MedChemtronica AB . Warfarin used as an internal standard (IS) was obtained from Riedel-de Häen . Human plasma pooled gender was purchased by Sera Laboratories International Ltd., trading as BioIVT . Ammonium acetate (LC-MS grade), formic acid , acetonitrile , methanol , water (LC-MS grade) and dimethylsulfoxide  were purchased from Fisher Scientific .m/z 279 → 227 and m/z 279 → 64 were monitored. For OR-1896, the transitions m/z 244 → 201 and m/z 244 → 159 were monitored. For the IS, the transition m/z 307 → 161 was monitored. An indicative MRM chromatogram depicting LS, OR-1896, and IS in concentrations of 0.5 ng/mL, 5 ng/mL, and 1 ng/mL, respectively, is provided in For the quantification of LS in human blood plasma, an LC-MS/MS bioanalytical methodology was developed. Chromatographic separation of LS, OR-1896, and warfarin was carried out using a Synergi Fusion-Reversed Phase column   with an injection volume of 10 μL at a flow rate of 0.30 mL/min. The optimal LC conditions were as follows: mobile phase A: 10% ACN, 90% water, 2 mM ammonium acetate, 0.1% FA, and mobile phase B: 90% ACN, 10% water, 2 mM ammonium acetate, 0.1% FA. The analyte of interest could be achieved following a gradient elution program within a chromatographic time at 5.60 min: starting from 0% phase B (0.00–0.50 min) to 60% phase B (0.50–1.00 min), 60% phase B (1.00–3.60 min) and from 60% to 0% phase B (3.60–5.60). A SCIEX QTRAP 5500+  was operated in negative ionization mode using the multiple reaction mode (MRM) with a dwell time of 50 msec per transition. High-performance liquid chromatography (HPLC) was performed using an Exion LC AB Sciex, a temperature-controlled column compartment, and an autosampler coupled with a SCIEX QTRAP 5500+ mass spectrometer. The electrospray ionization source conditions were set as follows: electrospray voltage of −4500 V for negative mode, source temperature of 550 °C, curtain gas of 20, ion source gas 1 and gas 2 of 50 psi and 45 psi, respectively. For LS, the transitions v/v) ACN/water. Then, mixed calibration standard solutions of LS and OR-1896 were prepared using 1:1 (v/v) ACN/water as diluent: LS  and OR-1896 . A separate set of superstock solutions of LS and OR-1896 were used to prepare QC stock solutions at  for LS and  for OR-1896. Then, mixed QC solutions were prepared using 1:1 (v/v) ACN/water as diluent: LS  and OR-1896 .Individual superstocks of LS and OR-1896 were prepared in a concentration of 2 mg/mL and 1 mg/mL, respectively, dissolved in DMSO. A stock of 1 mg/mL of IS in MeOH. From these superstocks, subsequent stock solutions for LS , OR-1896  and IS (1 ng/mL) were prepared in 1:1  and OR-1896 (1–50 ng/mL) in plasma and QC samples were prepared by spiking 50 μL of plasma with 50 μL of calibration standard solutions or QC solutions of analytes followed by 50 μL of IS. The extraction of analytes from human plasma was performed by protein precipitation using 400 μL cold acetonitrile. Samples were then vortexed and centrifuged for 10 min at 13,000 rpm. The supernatant was collected and evaporated using a Centrivap vacuum concentrator of Labconco . Dried samples were resuspended in 400 μL mobile phase A and vortexed. Then, samples were transferred into a 96-well plate for LC-MS/MS analysis using 10 μL as injection volume. All plasma samples received from patients were thawed at room temperature for the analysis. At first, samples were screened for the presence of the IS, as Warfarin is a commonly used anticoagulant agent. When samples were screened as free of IS, they were extracted and analyzed as described above. The LC-MS/MS method for the quantification of LS and OR-1896 in human blood plasma was investigated for specificity, linearity, accuracy, and precision. Data for accuracy and precision of the developed LC-MS method for the quantification of LS and OR-1896 in human plasma are provided in The power analysis was conducted for a single, two-group between-subjects factor and a single within-subjects factor assessed over four time points. For this design, 30 participants (15/study group) achieves a power of 0.85 for the between-subjects main effect at an effect size of 0.45, a power of 0.90 for the within-subjects main effect at an effect size of 0.25, and a power of 0.90 for the interaction effect at an effect size of 0.25.t-tests and Mann–Whitney tests were used for the comparison of continuous variables between the two groups. For the comparison of proportions, the chi-square and Fisher’s exact tests were used. Repeated measurements analysis of variance (ANOVA) was used to evaluate the changes observed in all patients’ indexes among the different groups over the follow-up period. All reported p values are two-tailed. Statistical significance was set at p < 0.05, and analyses were conducted using SPSS statistical software (version 22.0).Quantitative variables were expressed as mean (standard deviation) or median (interquartile range). Qualitative variables were expressed as absolute and relative frequencies. Student’s In conclusion, according to the results of the present randomized study performed on a small group of patients, the prophylactic administration of LS at a single bolus dose of 12 μg/kg before CPB was effective in reducing pulmonary artery pressure and improving right ventricular performance in patients with preexisting PH undergoing cardiac surgery. Moreover, this study demonstrated that the plasma concentration of LS administered prior to CPB is inversely related to the duration of CPB. More research is needed in order to elucidate the relationship between extracorporeal circulation used in cardiac surgery and the pharmacokinetics of LS and extrapolate knowledge concerning the appropriate dose of the drug that should be used in the context of cardiac surgery. Undoubtedly, larger and well-designed studies are necessary to validate LS’s clinical efficacy and pharmaceutical role in the perioperative anesthetic management of this important group of cardiac surgical patients.


Cardiorenal syndrome (CRS) results from complex interaction between heart and kidneys, inducing simultaneous acute or chronic dysfunction of these organs. Although its incidence rate is increasing with higher mortality in patients, effective clinical treatment drugs are currently not available. The literature suggests that renin-angiotensin-aldosterone system (RAAS) and diuretic natriuretic peptide (NP) system run through CRS. Drugs only targeting the RAAS and NPs systems are not effective. Sacubitril/valsartan contains two agents  that can regulate RAAS and NPs simultaneously. In the 2017 American College of Cardiology/American Heart Association/American Heart Failure (HF) ssociation (ACC/AHA/HFSA) guideline, sacubitril/valsartan was recommended as standard therapy for HF patients. The latest research shows that Combined levosimendan and Sacubitril/Valsartan markets are protected the heart and kidney against cardiovascular syndrome in rat. However, fewer studies have reported its therapeutic efficacy in CRS treatment, and their results are inconclusive. Therefore, based on RAAS and NPs as CRS biomarkers, this paper summarizes possible pathophysiological mechanisms and preliminary clinical application effects of sacubitril/valsartan in the prevention and treatment of CRS. This will provide a pharmacological justification for expanding sacubitril/valsartan use to the treatment of CRS. In 2008, Claudio The angiotensin receptor Recombinant Neprilysin (NEP) inhibitor sacubitril/valsartan consists of the angiotensin receptor blocker (ARB) valsartan and the NEP inhibitor (NEPI) prodrug sacubitril in a 1:1 ratio . PARADIGCRS is a disease that causes renal dysfunction through multiple pathophysiological mechanisms . SeveralCardiorenal dysfunction is characterized by fluid imbalance, particularly volume overload. Fluid homeostasis is largely regulated by the kidneys for normal heart function . PatientChronic kidney disease (CKD) and HF involve chronic inflammatory mechanism, with several pro-inflammatory biomarkers, including tumor necrosis factor-α (TNF-α), initiating spreading inflammatory cascades. In addition, TNF-α-related weak apoptosis inducers (TWEAK), interleukin-1 (IL-1) family members and interleukin-6 (IL-6) are closely associated with HF and CKD. Cell death and fibrosis are linked to these biomarkers in cardiac and renal tissue .Oxidative stress in CRS is triggered by ischemic injury, venous congestion, and inflammation. This oxidative stress is exacerbated by over-activated RAAS in patients with HF and CKD . AccordiIt is reported that the NPS system also plays an important role in the occurrence and development of CRS . SacubitSVR, systemic vascular resistance; ROS, reactive oxygen species; DIC, disseminated intravascular coagulation; SNS, sympathetic nervous system; RAAS, renin-angiotensin-aldosterone system; NPs, natriuretic peptides.“Sacubitril/Valsartan” is a salt complex of sacubitril and valsartan in a 1:1 ratio. This compound inhibits RAAS and activates the NPs system. Research has established the role of RAAS in heart and kidney disease pathophysiology . Recent Atrial type NPs (ANPs), brain type NPs (BNPs), and C type NPs (CNPs) are the most common NPs . CardiacRAAS regulates cardiovascular, renal, and adrenal functions, improving fluid, electrolyte, and arterial pressure homeostasis . The claThe concentration of Ang II in the circulation, offsetting the positive effects of NPs . Accordiin vivo. Sacubitril/valsartan inhibits the binding of Ang II to its receptor by binding NEPI and ARB. Therefore, the combination is designed provide cardiorenal protection , ion channels, and phosphodiesterases (PDEs). Although NP clearance receptors (NPRCs) lack guanylyl cyclase activity, they can mediate NP endocytosis. At the same time, together with the inhibited RAAS system, it reduced inflammation and vasodilation pressure, improved fibrosis, and promoted diuresis and sodium excretion.An estimated glomerular filtration rate (EGFR) is used to measure renal function and hemodynamic changes. HF and CKD share many risk factors. Therefore, CKD is likely to be more prevalent in HF patients. About half of patients with HF also have CKD, increasing their risk of death and morbidity . StudiesIn a study of the effect of sacubitril/valsartan on the decline of EGFR, 8399 HF patients with decreased LVEF were treated with sacubitril/valsartan or enalapril. Compared with enalapril, sacubitril/valsartan treatment showed an improvement in EGFR levels and heart function , suggestSacubitril/valsartan slows down the decline of EGFR consistently across time points. Causland et al. found that sacubitril/valsartan reduced the risk of renal events and slowed the decline of EGFR in HF patients with HFPEF . In theiSacubitril/valsartan slows down the decline of EGFR, with the most benefitting age being under 65. Spannella et al. observed and analyzed 54 consecutive HF outpatients with a decrease in LVEF and clinical indications for sacubitril and valsartan. During the follow-up period, the systolic blood pressure (BP) decreased, whereas the left ventricular ejection fraction (LVEF) only increased slightly. In addition, renal function improved after 12 months compared with the historical control group, with subjects younger than 65 years old and those with CKD benefitting the most .Sacubitril/valsartan has been included in HF prevention and treatment guidelines is an effective and safe pharmacological therapy for use. In Chang et al.‘s study, 466 HF with reduced LVEF (HFrEF) patients received sacubitril/valsartan treatment (group A) and 466 patients received standard HF treatment without ARNI (group B) in HF referral center. Sacubitril/valsartan appeared to be effective treatment for HFrEF patients, including those with late renal function impairment caused by CRS .Cardiac markers not only indicate cardiac function, but also renal function. Acute heart failure (AHF) is closely associated with changes in renal function . In about 30%–50% of patients hospitalized with AHF, renal function declines or improves during their hospital stay . ClinicaPresently, there is no standard therapeutic drug for CRS due to its complex pathogenesis. The first angiotensin receptor NEP inhibitor to be approved is sacubitril/valsartan, which is composed of two drugs, the ARB valsartan and the NEP inhibitor prodrug sacubitril. Both NPs and RAAS can be inhibited by sacubitril/valsartan in the heart and kidneys. Considering the complex pathogenesis of CRS, sacubitril/valsartan exerts protective effects in various ways. Animal experiments and clinical studies have demonstrated that sacubitril/valsartan can reduce the risk of cardiovascular disease and delay deterioration in renal function in people with CRS . Related