Cancer therapy-related cardiotoxicity is a major cause of cardiovascular morbidity in childhood cancer survivors. The aims of this study were to investigate systolic myocardial function and its association to cardiorespiratory fitness in pediatric childhood cancer survivors.In this sub-study of the international study “Physical Activity and fitness in Childhood Cancer Survivors” (PACCS), echocardiographic measures of left ventricular global longitudinal strain (LV-GLS) and right ventricular longitudinal strain (RV-LS) were measured in 128 childhood cancer survivors aged 9–18 years and in 23 age- and sex-matched controls. Cardiorespiratory fitness was measured as peak oxygen consumption achieved on treadmill and correlated to myocardial function.p = 0.004), however, mainly within normal range. Only 13% of the childhood cancer survivors had reduced LV longitudinal strain z-score. Mean RV-LS was similar in the childhood cancer survivors and the controls, −23.2% (95% CI: −23.7% to −22.6%) vs. −23.3% (95% CI: −24.6% to −22.0%) (p = 0.8). In the childhood cancer survivors, lower myocardial function was associated with lower peak oxygen consumption [correlation coefficient (r) = −0.3 for LV-GLS]. Higher doses of anthracyclines (r = 0.5 for LV-GLS and 0.2 for RV-LS) and increasing time after treatment (r = 0.3 for LV-GLS and 0.2 for RV-LS) were associated with lower myocardial function.Mean LV-GLS was reduced in the childhood cancer survivors compared to the controls, −19.7% [95% confidence interval (CI) −20.1% to −19.3%] vs. −21.3% (95% CI: −22.2% to −20.3%) (Left ventricular function, but not right ventricular function, was reduced in pediatric childhood cancer survivors compared to controls, and a lower left ventricular myocardial function was associated with lower peak oxygen consumption. Furthermore, higher anthracycline doses and increasing time after treatment were associated with lower myocardial function, implying that long-term follow-up is important in this population at risk. Cardiovascular disease is a leading non-cancer contributor to early morbidity and mortality in childhood cancer survivors (CCSs) . In addiCancer treatment includes a variety of chemotherapeutic medication and radiation therapy, associated with dose-dependent cardiovascular toxicity . YoungerDespite the development of modern targeted therapies, anthracycline chemotherapy is used to treat a wide spectrum of childhood cancers . AnthracEchocardiography continues to be the mainstay in the evaluation of myocardial function related to cancer treatment. Compared to traditional measures of myocardial function such as ejection fraction (EF) and fractional shortening, measures of speckle-tracking-derived strain have shown to be more sensitive to changes in left ventricular myocardial function and to provide additional prognostic information , 11. For2) is mainly limited by cardiac output   with maiIn the present sub-study, CCSs from the pediatric cancer outpatient clinic at Oslo University Hospital  and Haukeland University Hospital  were invited to participate. Of the 207 eligible CCSs from the PACCS study, 66 declined the invitation and 13 withdrew after inclusion. No one was excluded due to heart failure, arrhythmia, or too low physical capacity. None of the participants used cardiac medication. A total of 128 CCSs underwent echocardiographic examination, and 126 underwent cardiopulmonary exercise test. Due to capacity challenges regarding echocardiographic imaging, only one center, Haukeland University Hospital, recruited controls, and 50 controls were invited. The participants were examined in the period from February 2019 to February 2021. Due to the ongoing COVID-19 pandemic with several restrictions regarding traveling and entrance to the hospitals, and frequent COVID-quarantine in school children, only 23 controls were included.2) according to the Children’s Oncology Group’s long-term follow-up guidelines version 5.0  . The cumsion 5.0  and Feijsion 5.0  Table 12 accordiThe study was conducted in accordance with the Declaration of Helsinki. The Regional Committee for Medical and Health Research Ethics of the South-East Norway Health Authority approved the study (REC 2018/739). Written and verbal information were given to the participants that were adapted to their age and developmental stage. Written informed consent was obtained from all participants and their parents or legal guardians.All echocardiographic examinations were performed with the Vivid E9 ultrasound system  using a 4Vc-D (1.4–5.2 MHz) transducer for all imaging in Bergen and an equivalent 5Sc (1.5–4.6 MHz) transducer for all imaging in Oslo. Data were stored on external hard drives or Digital Versatile Discs allowing offline analyses with the echocardiographic software, EchoPAC version 204 . The participants were examined at rest in supine position. No sedation was used. All the participants underwent a comprehensive functional echocardiographic examination including grayscale images optimized for two-dimensional (2D) speckle-tracking analysis. Quantification of systolic left ventricular (LV) and right ventricular (RV) function was performed following the recommendations from the European and American Societies of Echocardiography , 26.LV-EF was calculated by the modified Simpson biplane technique. Grayscale images for 2D speckle-tracking analysis were acquired at frame rate (frames/second) to heart rate (beats/minute) ratio of 0.7–0.9. Longitudinal strain curves from standard apical four-, three-, and two-chamber view images, analyzed for 18 sub-segments, were used for LV longitudinal strain assessments. Longitudinal strain curves from an RV-focused four-chamber view image, analyzed for six sub-segments including the interventricular septum, were used for RV longitudinal strain assessments .A single cardiac cycle considered to have the most optimal images was selected for analysis of LV and RV 2D strain , 28. TheIn this paper, LV global longitudinal strain (LV-GLS) is used to describe the average peak systolic longitudinal strain from all three left ventricular apical views, and the term RV-LS is used to describe the peak systolic RV longitudinal strain from an RV-focused four-chamber view, including RV free wall and intraventricular septum. All longitudinal strain values are described as negative percentages, as it describes myocardial shortening of segments relative to the end-diastolic length.z-scores were calculated as proposed by Dallaire et al. . PSI was defined as longitudinal shortening after aortic closure relative to maximal global longitudinal strain:PSI > 0% . For anaPSI > 0% . The terAll analyses were performed by a single experienced cardiologist (BE). Randomly selected study participants (5%) were obtained for inter-rater and intra-rater analyses. Another experienced cardiologist (TO) performed the re-analyses for inter-rater reliability. Both were blinded to the original results during re-analysis. Inter-rater reliability measured by a two-way mixed-effect model for absolute agreement was 0.8 [95% confidence interval (CI): 0.1–1.0] for EF Simpson, 0.9 (95% CI: 0.4–1.0) for LV-GLS, 0.9 (95% CI: 0.6–1.0) for RV-LS, and 0.9 (95% CI: 0.7–1.0) for global LV PSI. Intra-rater reliability measured by a two-way mixed-effect model for absolute agreement was 0.7 (95% CI: −0.3 to 0.9) for EF Simpson, 0.9 (95% CI: 0.5–1.0) for LV-GLS, 0.9 (95% CI: 0.6–1.0) for RV-LS, and 0.9 (95% CI 0.8–1.0) for global LV PSI.2) if two of the following three criteria were fulfilled: respiratory gas exchange ratio ≥1.10, Borg scale ≥17, or VO2 reached a plateau with increasing workload. The result for the CCSs was included in the present study to correlate peak VO2 with measures of myocardial systolic function.Cardiopulmonary exercise test was performed by walking/running on a treadmill  with an incremental ramp protocol until exhaustion. The participant was breathing into a Hans Rudolph two-way breathing mask  connected to an OxyconPro analyzer  using the breath-by-breath method. Borg scale   was usedWeight and standing height were measured with the participants wearing light clothing. Resting blood pressure was measured with an automated oscillometric device  after 5 min of rest in supine position, using the lowest of two measurements.Venous blood samples were collected from the CCSs only, in serum tubes and ethylenediaminetetraacetic acid-containing tubes, for measurements of hemoglobin (Hb) and N-terminal pro-brain natriuretic peptide (NT-proBNP). NT-proBNP values >160 ng/L were defined as above the upper limit in children aged 6–18 years .t-tests , and two-sample Kolmogorov–Smirnov test were applied as appropriate.Descriptive variables and outcome data are presented as means with standard deviation (SD) or 95% CI, or as numbers and percentages. The Kolmogorov–Smirnov test was used to test the normality of the outcome variables, and Levene's test of equality of error variance was used to test the homogeneity of the outcome variables variance across groups. For comparison of descriptive variables and outcome data (without significant confounders) between CCSs and controls, Chi-square test or Fisher’s exact test, independent samples z-score adjusted for echocardiographic transducer difference; longitudinal strain adjusted for transducer difference and BSA; and peak VO2 adjusted for sex, age, and treadmill location.Linear regression analysis was used to identify confounders significantly affecting the analyses. Analyses of covariance (ANCOVA) were used to compare CCSs and controls for height, BSA, and BMI adjusted for sex; blood pressure adjusted for sex and age; EF and LS All comparisons were re-analyzed without outliers, which did not significantly affect the results.To examine whether the differences in EF, LV-GLS, and RV-LS between the CCSs and controls differed by sex, an interaction term for sex and group affiliation was added.post hoc analyses, respectively), or by multiple comparison analyses (with the Sidak correction) with the same adjustments as described above, as appropriate.Comparisons of descriptive variables and outcome data between subgroups of study participants were done by chi-square test or Fisher`s exact test, Welch's ANOVA or classic one-way ANOVA , age at diagnosis, and time after treatment, and between NT-proBNP and anthracycline dose or peak VO2.The Pearson correlation coefficient (PCC) was used to explore associations between systolic myocardial function and treatment exposure, peak VOp < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS version 26.0 .All tests were two-sided, and p = 0.04), and mean systolic BP was lower in the CCSs compared to the controls, 107 vs. 112 mmHg, respectively (p = 0.03). The CCSs and controls were similar with regard to sex and ethnicity distribution, and estimated means of height, weight, BSA, BMI, and diastolic blood pressure.Characteristics of the 151 study participants, 128 CCSs and 23 controls, are described in 2 (SD 91), while 22% were anthracycline naive and treated with vinca alkaloids and/or platinum derivatives. Six (5%) CCSs underwent radiation therapy involving the chest, all of them had also received chemotherapy. Four (3%) had surgical treatment, but no chemotherapy or radiation therapy .For the CCSs, the mean age at diagnosis was 5.3 years (SD 0.3), and mean time after treatment was 6.6 years (SD 3.6). The most frequent diagnosis in the cancer survivor group was acute leukemia (48%), cerebrospinal neoplasms (13%), and renal tumors (11%). Most participants received multiple chemotherapeutic agents during the treatment period, detailed in Four CCSs had NT-proBNP values >160 ng/L defined as the upper limit in children aged 6–18 years , and meap = 0.01).The CCSs had significantly lower mean EF Simpson compared to the controls . Mean EFp = 0.23).The difference in EF Simpson between CCSs and controls was not significantly greater in female vs. male participants: 2.7% (95% CI: −1.7% to 7.1%)  (p = 0.8)The CCSs had significantly reduced mean LV-GLS compared to the controls, while mean RV-LS did not differ significantly between CCSs and controls . Mean LV= 0.004)  and meanp = 0.74) and 2.1% (95% CI: −0.6% to 4.8%) (p = 0.12), respectively.The difference in LV-GLS and RV-LS between CCSs and controls was not significantly greater in female vs. male participants, −0.3% (95% CI: −2.1% to 1.5%)  for CCSs and 0.9 (95% CI: 0.2 to 1.5) for controls (p = 0.001).None of the controls, but 16 (13%) of the CCSs, had abnormally low LV-LS controls . The meap = 0.004) and 0.2 for RV-LS (p = 0.02). Adjustment for anthracycline dose did not alter the result. We found no significant association between age at diagnosis, NT-proBNP, and the measurements of LV and RV systolic function.Increasing time after treatment was associated with lower LV and RV systolic function with PCC 0.3 for LV-GLS  was found more frequently in the wall segments of CCSs compared to the wall segments of controls .p = 0.003), and in 30% (213 of 700) of all the RV wall segments in the CCSs and 21% (26 of 123) of all RV wall segments in the controls (p = 0.04).Any degree of PSS was found in 41%  of all the LV wall segments in CCSs and in 33% (127 of 384) of all the LV wall segments in the controls (p = 0.4), and mean global RV PSI was 1.8% (95% CI: 1.2%–2.4%) for CCSs and 2.3% (95% CI: 0.7%–3.8%) for controls (p = 0.6).Mean global LV and RV PSI, and PSI in LV walls and regional wall segments were similar in CCSs and controls . Mean glp = 0.03), for LV-GLS was 0.5 (p < 0.01), and for RV-LS was 0.2 (p = 0.04). Correspondingly, NT-proBNP levels were positively associated with anthracycline dose with PCC 0.4 (p < 0.001). There was no significant association between increasing doses of vincristine, cisplatin, or carboplatin and measures of systolic LV or RV function.Exposure to increasing doses of anthracyclines was associated with lower systolic myocardial function. PCC for EF Simpson was −0.2  in CCSs and 48.6 ml/kg/min (95% CI: 44.5–52.6) in the controls (p = 0.01). Correlation analysis adjusted for sex, age, hemoglobin concentration, and transducer difference/treadmill location revealed a significant association between peak VO2 and LV function measured by LV-GLS  (p = 0.002) in the CCSs, but no significant association between peak VO2 and RV-LS or NT-proBNP level in the CCSs.Mean peak VO = 0.01)  and EF S2), medium dose (100–250 mg/m2), or high dose (250–500 mg/m2) of anthracyclines ] compared to the anthracycline naive subgroup [−20.3% (95% CI: −21.1% to −19.4%)], p = 0.003, and the subgroups treated with low dose [−20.3% (95% CI: −20.9% to −19.6%)], p = 0.001, and medium dose of anthracyclines [−19.7% (95% CI: −20.4% to −19.1%)], p = 0.01, as described in p = 0.05, and the subgroup treated with low dose of anthracyclines [52 ng/L (SD 24)], p < 0.03. NT-proBNP was also higher in the subgroup treated with medium dose of anthracyclines [71 ng/L (SD 36)] compared to the subgroup treated with low dose of anthracyclines (p = 0.03). RV-LS, global LV PSI, and global RV PSI were similar in all four CCSs subgroups.Mean LV-GLS, and corresponding LV-LS z-score for LV-LS was lower in all four CCSs subgroups compared to the control group   ( ≤ 0.02) , and mea ≤ 0.03) . RV-LS, z-score. Treatment with higher doses of anthracyclines and increasing time after treatment were associated with lower LV and RV systolic function, and lower LV myocardial function was associated with lower peak oxygen consumption during the cardiopulmonary exercise test.In this multicenter study, we found lower LV, but not RV, systolic function in 128 pediatric CCSs, compared to 23 healthy controls. The systolic LV function in the CCSs was, however, largely within normal range, and only 13% of the CCSs had abnormally low LV strain z-score was <−2 in 13% of the CCSs, similar to the study by Slieker et al., which reported impaired LV longitudinal strain in 8% of 510 pediatric CCSs treated with similar mean anthracycline dose (150 mg/m2) as our study participants  in our study. Kremer et al. , the homogeneity of variance was not violated. Therefore, we consider the risk of type 1 error to be small. There is a risk of selection bias since extensive and physically challenging testing was part of the main study. This may have led to a selection of the fittest CCSs, which could most likely introduce an overestimate of LV or RV function in the CCSs group. EF and strain measurements are known to be afterload dependent with more reduced EF and longitudinal strain with higher blood pressure (2 is mainly limited by the ability of the cardiovascular system to deliver oxygen to the exercising muscles (2 results. Thus, complex mechanisms could have contributed to the association between decreasing myocardial function and decreasing peak oxygen consumption in the CCSs. Regression analyses revealed significant influence of location in the echocardiographic measures and peak VO2 results in the CCSs examined in Oslo vs. those examined in Bergen, which could not be explained by difference in chemotherapy doses, radiation therapy, blood pressure, or other characteristics. There might be technical- or procedure-related differences in exercise test results, as well as differences related to the ultrasound transducers used for echocardiographic imaging at the two centers. To address this issue as well as the single center inclusion of controls, correction for location was added in the statistical analyses.The strengths of this study are the cohort study design and that all echocardiographic imaging was performed by highly trained sonographers with the same ultrasound system, and all offline analyses were made by one cardiologist with the same echocardiographic software. The calculated intra- and inter-rater variabilities were good to excellent . The limpressure . We foun muscles , but oth2. The right ventricular function was similar in CCSs and controls suggesting regional differences regarding the impact of the cardiotoxic treatment on myocardial function. Increasing dose of anthracyclines and increasing time after treatment were, however, associated with lower myocardial function of both the left and right ventricles. This implies that long-term follow-up, including evaluation of myocardial function, and tight control of modifiable cardiovascular risk factors might be indicated for all childhood cancer survivors.Although the myocardial function was largely within normal range, we found reduced left ventricular systolic myocardial function in pediatric CCSs compared to healthy controls even in participants treated with low doses of anthracyclines. Lower left ventricular function was associated with lower peak VO


Positional abnormalities per se do not require treatment, but in their place, the accompanying pulmonary pathology in dextroposition patients and pathophysiologic hemodynamic abnormalities resulting from multiple defects in patients with cardiac malposition should be the focus of treatment. At the time of the first presentation, treating the pathophysiologic aberrations caused by the defect complex, whether it is by improving the pulmonary blood flow or restricting it, is the first step. Some patients with simpler or single defects are amenable to surgical or transcatheter therapy and should be treated accordingly. Other associated defects should also be treated appropriately. Biventricular or univentricular repair dependent on the patient’s cardiac structure should be planned. Complications in-between Fontan stages and after conclusion of Fontan surgery may occur and should be promptly diagnosed and addressed accordingly. Several other cardiac abnormalities unrelated to the initially identified heart defects may manifest in adulthood, and they should also be treated. In a previous paper on the “Diagnosis of Dextrocardia with a Pictorial Rendition of Terminology and Diagnosis”, a detailed discussion of the diagnosis of dextrocardia including other cardiac malpositions was presented . In thatAbnormal positions themselves do not require therapy; however, the associated boney and pulmonary abnormalities in dextroposition subjects and hemodynamic anomalies caused by multiple associated defects in patients with cardiac malposition should be treated. The management of dextroposition and dextrocardia, including other cardiac malpositions, will be reviewed separately. Discussion of management of other cardiac malpositions, namely, ectopia cordis and pericardial defects, is not included in this paper.In patients with dextroposition secondary to a thoracic cage boney abnormality, no treatment is necessary because the heart is usually just displaced without any compression of the cardiac chambers. On extremely rare occasions, when obstruction of a given cardiac chamber occurs , treatmePositional abnormalities of the heart themselves do not require any therapy, but, in their place, the accompanying heart defects and the ensuing hemodynamic abnormalities should be treated and are reviewed hereunder. The clinical scenarios and their management options are listed in a tabular form in 3, and managing acidosis secondary to respiratory problems with suction, tracheal cannulation, and assisted ventilation as suitable. In patients with suspected ductal dependent lesions, intravenous prostaglandin E1 (PGE1) infusion [Patients with complex heart defects present with symptomatology early in the newborn period while subjects with simpler and milder heart defects may come to light later in infancy, childhood, and adulthood. Treatment at first presentation of neonates is similar to that utilized for other cyanotic congenital heart defects (CHDs) and is described elsewhere ,8 and ininfusion ,10,11,12Following stabilization of the baby, treatment should focus on the pathophysiologic anomaly (pulmonary oligemia and pulmonary plethora) produced by the associated cardiac defects that many of the cardiac malposition infants have. Pulmonary oligemia should be addressed at presentation to prevent both short-term adverse effects such as hypoxemia, progressive acidosis, and death and long-term consequences, namely, the development of clubbing of fingers and toes, cerebrovascular accidents, relative anemia, severe polycythemia, paradoxical embolism, brain abscess, coagulation abnormalities, hyperuricemia, uric acid nephropathy, and gout. Pulmonary plethora should be tackled to avoid short-term effects, namely, congestive heart failure (CHF) and death as well as long-term consequences, namely, the development of pulmonary hypertension, progressive dilation of the left ventricle, and pulmonary vascular obstructive disease (PVOD). In addition, addressing both pulmonary oligemia and pulmonary plethora in a timely manner is likely to help normal pulmonary alveolar development.1 starts at an initial dosage of 0.05 to 0.1 μg/kg/min, which may be gradually decreased to 0.015 to 0.02 μg/kg/min. Following stabilization of the infant, a more permanent provision of blood flow to the pulmonary circuit should ensue, usually by a modified Blalock–Taussig (BT) anastomosis [In infants with decreased pulmonary blood flow secondary to severe narrowing or atresia of the pulmonary artery or valve and a big VSD or a single ventricle, administration of PGEstomosis ,14,15  with an obstruction to the pulmonary venous return should have immediate surgical correction ,27,28,29Other problems, namely, interatrial obstruction, interventricular obstruction, aortic arch interruption, and aortic coarctation may be seen at presentation or may develop later  and shouSubjects with simpler and single defects such as pulmonary valvar stenosis , atrial After initial palliation, as reviewed above, a methodical review of all the available imaging studies should be performed to assess the feasibility of undertaking biventricular repair ,39,40,41This stage is as described in the “Management at Initial Presentation” segment.This comprises bidirectional Glenn operation ,60,61,62This comprises re-routing the inferior vena caval blood flow to the pulmonary circuit with a non-valved conduit ,49 Figu along wiStage IIIB comprises device closure of the fenestration ; this isAs mentioned above, some of the babies with cardiac malposition, particularly those with isolated dextrocardia and isolated levocardia, are likely to have heterotaxy, and these patients with asplenia/polysplenia syndrome usually have a deficient splenic function. Consequently, such infants are at a greater risk of bacterial infections ,65. ThroIn patients with single ventricles, both the pulmonary and systemic circulations work in parallel in place of the normal in-series circulation. Consequently, a finite equilibrium connecting both circulations should be preserved to ensure an adequate flow into both systemic and pulmonary circuits ,68. In cSeveral complications were reported in subjects who had a Fontan operation. The reported complications were arrhythmias, obstructed Fontan pathways, residual intra-/extracardiac shunts, cyanosis, thromboembolism, transient ischemic attacks, cerebrovascular accidents, collateral vessel formation, congestion of the systemic venous circuit, and protein-losing enteropathy ,74,75,76Adult patients with cardiac malposition, apart from the postintervention problems reviewed in the aforementioned sections, may also develop problems akin to those seen in normal (levocardia) adults. Management of these issues is reviewed in this section.Coronary artery obstruction and myocardial infarction do occur in cardiac malposition patients; the prevalence of coronary problems is generally thought to be comparable to that seen in the general population . It is nSupraventricular arrhythmias also occur in dextrocardia patients, and it is generally thought that the incidence of these arrhythmias is not substantially different from that observed in the normal population (levocardia). Atrial fibrillation/flutter appear to be the most common among these arrhythmias while supraventricular tachycardia (SVT), including atrioventricular reentrant tachycardia (AVRT) and SVT associated with WPW (Wolff–Parkinson–White) syndrome, can also occur. Arrhythmias are usually treated with antiarrhythmic medications and patients without adequate control are subjected to catheter ablation procedures (cryoablation or radiofrequency (RF) ablation). The feasibility of catheter ablation procedures for atrial fibrillation/flutter ,99,100, Subjects with refractory arrhythmias may require the Maze procedure which can also be successfully conducted in dextrocardia patients ,106.Cardiac malposition patients with complete heart block  or sick Some patients with dextrocardia have a higher propensity for sudden cardiac death; such patients may need implantable cardioverter–defibrillators (ICD). While transvenous ICDs are the first-line therapy, transvenous access may be difficult because of congenital venous anomalies or acquired venous obstruction. In such patients, subcutaneous ICDs (S-ICDs)  may be implanted. The reported experience with this form of therapy is encouraging ,116,117.Subjects who have atrial fibrillation/flutter are at risk of developing embolic episodes and, therefore, initial anticoagulation and subsequent occlusion of the left atrial appendage are recommended. While closure of the appendage of the left atrium is challenging in dextrocardia subjects, it can be successfully accomplished ,119,120.Aortic valve (AV) abnormalities causing severe aortic regurgitation or severe stenosis may occur in dextrocardia patients ,125,126.Mitral valve abnormalities producing severe mitral regurgitation have been seen in dextrocardia. Surgical repair  or replaRheumatic fever appears to occur in dextrocardia patients as well, resulting in mitral stenosis. When mitral stenosis is severe, surgical commissurotomy  or balloHypertrophic cardiomyopathy (HCM), while rarely reported in patients with cardiac malposition, has been described ,142,143.Addressing pulmonary pathology in patients with dextroposition as per the guidelines established in standard textbooks is appropriate. In cardiac malposition, treatment of the pathophysiologic abnormality produced by multiple defects at the time of initial presentation by either increasing the pulmonary blood flow or restricting it is first undertaken. Other cardiac defects are also addressed to optimize the care. The feasibility of biventricular repair should be explored, and if that is not feasible, a single ventricular repair option (Fontan) should be offered. Antibiotic prophylaxis and prophylactic Ladd’s procedure are prescribed in heterotaxy patients. Complications following initial palliative procedures and subsequent Fontan surgery may occur, and these should be promptly detected and treated in a timely manner. Adult patients with dextrocardia, in addition to postintervention complications, may develop other disease entities, similar to those seen in the normal population, and these should be treated with either surgical or transcatheter methodology, as deemed appropriate. It is concluded that most of the problems encountered in patients with dextroposition and dextrocardia can be effectively treated with the currently available therapeutic modalities.


In this review, we discuss the utility of three-dimensional echocardiography as a supplement to two-dimensional imaging to better assess tricuspid valve disease and anatomy to aide in future innovative therapies.Due to the proportionally high mortality rates associated with isolated tricuspid valve surgery, the invasive treatment of such pathology, historically, has been left largely unaddressed. Recently, there has been an appreciation for the mortality and morbidity of tricuspid valve disease, giving rise to the movement towards identifying less invasive, transcatheter approaches for treatment. Due to the technical complexity of these procedures along with the uniqueness and variability of tricuspid valve anatomy, a better appreciation of the tricuspid valve anatomy and pathology is required for pre-procedural planning. While two-dimensional echocardiography serves as the initial non-invasive modality for tricuspid valve evaluation, three-dimensional echocardiography provides a complete  Recently, the morbidity and mortality associated with tricuspid valve (TV) pathology has become more appreciated. Five-year survival is < 30% with moderate to severe tricuspid regurgitation (TR), which is associated with increased mortality independent of factors such as ejection fraction and pulmonary artery systolic pressure –3. Additvia 2D and 3D transesophageal echocardiography (TEE) and determined that the TV has three well delineated leaflets in ∼54% of patients, four leaflets in ∼39% of patients (two posterior leaflets are most frequent), and two leaflets in ∼5% of patients (The TV consists of three leaflets: the anterior leaflet (AL), which is largest and quadrangular, the posterior leaflet (PL), which is smallest and triangular, and the septal leaflet (SL), which is semicircular in shape with scalloped indentations . Hahn, epatients . There apatients  and is 2via 2D echocardiography have been shown to be consistently underestimated in all views compared to 3D echocardiography  geometry , 12. TVAiography , owing tiography . The TVAiography . The lariography . In addiiography , 14–17.The etiology of TV disease can be classified into primary, referring to pathologic changes to the TV leaflets , or secoen face view of the anatomy and function of all three TV prosthetic leaflets, which 2D imaging is mostly unable to accomplish  and “torrential” (3D VCA ≥ 115 mm2), citing that many patients have evidence of regurgitant jets that progress multiple grades beyond the current definition of severe, although these numerical cutoffs have not been validated  area. Obtaining the velocity time integral of the TR jet gitation . A 2D VCgitation . Rather,cificity , 42. In cificity , 43, andcificity , 44. Thecificity . A correcificity . Recentlalidated , 47. ThiTo capture multiple 3D structures in a dataset, volume angle often must be enlarged, except when assessing the TR VC. This causes a reduction in the frame rate, and therefore temporal resolution. Due to this phenomenon, 3D datasets should be acquired from multiple transthoracic transducer positions that best visualize the TV, with focused 3D examinations being used as a complement to 2D imaging , 27. An en face, the septal TV leaflet should be located at the 6 ‘clock position, although recent studies have suggested alternative approaches more anatomically or surgically appropriate (To obtain 3D imaging of the TV, one must begin the exam with the most optimized 2D examination of the TV, often requiring multiple acquisitions from both the left and right parasternal, apical, subcostal transducer approaches. Once visualized, the image is switched to live/real time 3D to ensure the TV is in view. Once confirmed, full-volume mode is applied, which allows focus on the TV without surrounding structures, thus acquiring an image with an increased frame rate resulting in enhanced resolution. When viewing the TV ropriate , 49. Oncropriate . The atrropriate . In patiDespite the benefits of 3D imaging, projecting a 3D image onto a 2D screen can limit accurate assessment of spatial relationships and is less accurate in representing specific tissue characteristics such as tissue calcifications and vegetations . 3D prinMorbidity and mortality associated with TV disease is no longer lost on clinicians. Due to the complex anatomy of the TV and nonplanar geometry of the TVA, assessing severity of TV disease can be difficult with 2D imaging alone. 3DTTE/TEE as a supplement to 2D imaging has been shown to provide quantitative data regarding TV pathology, as well as enhance innovative procedural interventions of the TV. This literature review has further gathered information on the technique and benefits associated with 3D echocardiography.


P < 0.001) was found in the VTI and CO measured at the 3 different locations across both left and right ventricular outflow tracts.This study aims to evaluate the effect of assessing velocity time integral at different locations across ventricular outflow tracts for calculating cardiac output (CO) in neonates. Velocity time integral (VTI) and CO were measured at 3 different locations across right and left ventricular outflow tracts using transthoracic echocardiography in healthy term neonates without any major congenital heart disease. ANOVA with Bonferroni correction was used to determine the differences between the VTI and CO sampled at these three locations. Forty-one neonates met inclusion criteria with mean gestational age of 38.6 ± 1 weeks and mean birth weight of 3155 ± 463 g. The median hours after birth when echocardiography was obtained was 23 h (range 11–68 h after birth). Left CO were 121 ± 30 mL/kg/min, 155 ± 38 mL/kg/min, and 176 ± 36 mL/kg/min measured below the valve, hinges of the valve, and tip of the valve, respectively. Right CO were 197 ± 73 mL/kg/min, 270 ± 83 mL/kg/min, and 329 ± 104 mL/kg/min measured below the valve, hinges of the valve, and tip of the valve, respectively. A statistically significant difference (     Conclusions: There is a significant difference in measurements of VTI and CO depending on the location of Doppler gate sampling across the ventricular outflow tracts. Consistency and precision in Doppler gate location are essential for measuring VTI and calculating CO while assessing changes in hemodynamic status in critically ill infants. In recent years, target neonatal echocardiography (TNE) has been increasingly used in neonatal intensive care units (NICUs) to evaluate the hemodynamic status in critically ill infants, and it provides a quick and non-invasive real-time assessment of cardiac function and cardiac output –4. PriorThere are several ways to measure cardiac output (CO) using echocardiography. One of the techniques commonly used is using pulsed wave Doppler to estimate stroke volume (SV) as cardiac output is the product of stroke volume and heart rate (HR). SV is estimated by obtaining ventricular outflow tract cross-sectional area (CSA) and velocity time integral (VTI) across respective left or right ventricular outflow tracts. VTI, also known as stroke distance, represents the area under the Doppler spectral curve measured across the ventricular outflow tract during one heartbeat or systole . CSA is Accurate assessment of CO is thus dependent on the precise measurement of VTI and CSA as CO can vary if there is a difference in VTI obtained at various locations across the ventricular outflow tracts. The American Society of Echocardiography (ASE) in collaboration with the European Association of Echocardiography (EAE) and the Association for European Pediatric Cardiologists (AEPC) recommended Doppler sampling gate location to be just below the valve level, where cross-sectional area is measured . HoweverIn our institution, it is a routine practice to perform TNE on all neonates admitted to newborn nursery prior to discharge with verbal consent from the parents. TNEs are performed by NICU fellows under direct supervision of a single echocardiographer with more than 30 years of experience in performing echocardiography in neonates. We noted wide variations in CO obtained with these TNE studies, which led us to conduct this quality improvement project to evaluate the effect of assessing VTI at different Doppler sampling gate locations across the ventricular outflow tracts on the CO in neonates.All healthy term neonates born between February and May 2022 at Los Angeles County + University of Southern California (LAC + USC) Medical Center without any congenital heart disease, except for patent ductus arteriosus and patent foramen ovale, were enrolled. Maternal and neonatal demographics were obtained through electronic health record chart review. Routine TNE was performed in all eligible infants by a single experienced clinician with over 30 years of experience in performing echocardiography in neonates.All echocardiography studies were performed using a Philips EPIQ model cardiovascular ultrasound machine with 9 Hz transducer. Angle correction was not used, and measurement was obtained by a single experienced clinician to minimize the interobserver variation of angle of insonation. The left and right ventricular CO were calculated by measuring the ventricular outflow tract CSA and VTI as described below. The CSA of the left or right ventricular outflow tract was determined by measuring the end-systole internal diameter of ventricular outflow tracts at the hinge point of aortic valve or pulmonic valve annulus, respectively . The diaThe left ventricular VTI was measured in apical five-chambers view Fig. , and theAll measurements were analyzed offline using EchoPAC software by a single investigator following standardization of measurement methodology discussed and agreed upon by other co-investigators. Both VTI and CSA were measured as a single measurement.Other relevant echocardiographic data, which can affect cardiac output, was obtained including age in hours afterbirth when echocardiography was performed and presence of patent ductus arteriosus (PDA) or patent foramen ovale (PFO) and their sizes.p-value of < 0.05 was considered statistically significant for ANOVA. Adjusted p-value was < 0.017 with Bonferroni correction.Neonatal characteristics are presented in mean  and median  as appropriate for continuous variables and number (%) for categorical variables. Analysis of variance (ANOVA) with Bonferroni correction was used to determine the mean differences between the VTI and CO sampled at the three locations of the left and right ventricular outflow tracts. STATA 14, College Station, Texas, was used to perform data analysis. A This is a prospective quality improvement project conducted at LAC + USC Medical Center approved by the Institutional Review Board at our institution with a waiver of informed consent from the parents. In our institution, it is a routine practice to obtain TNE on all neonates admitted to newborn nursery prior to discharge. Verbal consent from the parents is obtained prior to performing TNE.Forty-one neonates met inclusion criteria during the study period, and all had TNE performed within 3 days after birth. The mean gestational age at birth was 38.6 ± 1 weeks, and the mean birth weight was 3155 ± 463 g. Demographics and characteristics of the study population are reported in Table p < 0.001) (Table p < 0.001)   Table . There w1) Table . Post hol) Table . Mixed mMeasurement of cardiac output is one of the most important echocardiographic parameters that helps in the evaluation of end-organ perfusion, oxygen delivery, and tissue perfusion in patients with hemodynamic instability . CO is cSeveral prior studies have described CO in healthy term neonates measured non-invasively via transthoracic echocardiography to be approximately 135 to 325 mL/kg/min –10. The 2 versus LVOT diameter of 6.4 mm and CSA of 0.33cm2), contributing to a higher RV CO observed. Abushaban et al. also reported similar results where the CSA of pulmonary valve was greater than CSA of aortic valve in preterm infants less than 35 weeks of gestation [Our study demonstrated that there are significant differences in the measurements of VTI and CO depending on the location of Doppler sampling gate at the ventricular outflow tracts, and this was consistent for both left and right ventricular CO and VTIs. Our results contrast with those reported by Ihlen et al.  and Fishestation .We acknowledge there are several limitations with this quality improvement project. Baseline variations in VTI and CO measured in the echocardiography obtained prior to the start of this project were not evaluated for comparisons to the values measured in this study. All echocardiograms were performed by a single clinician echocardiographer with over 30 years of experience in neonatal echocardiography, which is a real strength of the study, and all echocardiography were read by a single echocardiography-trained neonatologist. However, as a result of a single operator, interobserver differences and generalizability of the results were not studied. Our sample size was relatively small and only consisted of healthy term neonates without any major congenital heart disease. We selected this cohort as our initial study population to avoid confounding variables. Most infants had contamination of left and right ventricular CO from cardiac shunts (PFO and PDA shunts). Furthermore, although this study demonstrated that there are significant variations in VTI and CO estimated non-invasively via transthoracic echocardiography depending on the sampling locations, which location best correlates with the true CO was not compared to the gold standard of invasive CO from catheter study, via direct Fick’s method, or cardiac magnetic resonance imaging. However, there are several studies in both neonates and adults that showed CO measurements obtained via transthoracic echocardiography are consistent with invasively obtained measurements , 20–22.In conclusion, there are significant differences in both left and right ventricle VTIs and CO measured at different locations along the respective ventricular outflow tracts. Therefore, consistency and precision in the Doppler sampling gate location is critical for accurately measuring VTI and CO while assessing changes in hemodynamic status; as changes in CO may be related to the location of Doppler gate sampling rather than changes in hemodynamic status in critically ill newborns. This becomes even more important when intervention is based upon trending of VTI and CO measurements. Following this project, we will establish and implement unit protocol, so consistent methodology is used in obtaining VTI and CO with transthoracic echocardiography to ensure clinical decisions are based on accurate measurement of CO. We recommend performing a larger study to confirm our findings and test these results in the preterm infants and those with hemodynamic instability.


P < .05); GK Angle was negatively correlated with restrictive ventilation parameters in the patients with AS (P < .05). The GK Angle of the patients with AS affects the cardiac structure and diastolic function. The larger the GK Angle is, the smaller the left and right at ventricle diameters are. In addition, GK Angle also affects the left ventricular diastolic function. GK Angle is related to the degree of pulmonary function impairment, and the larger the GK Angle is, the worse the pulmonary function it will be.This paper aims at analyzing the characteristics of cardiopulmonary functions in the patients with ankylosing spondylitis (AS), and exploring the influence of global kyphosis (GK) on cardiopulmonary functions. Clinical data of 46 patients with AS and kyphosis, who had been admitted in our hospital from October 2021 to October 2022, were analyzed retrospectively. According to the to global kyphosis (GK) angle, 23 subjects were divided into Severe Group (GK > 95°), and 23 subjects were divided into in the Moderate Group (80° ≤ GK ≤ 95°). Cardiac structure and cardiopulmonary function parameters were compared between both groups, and the influences of GK Angle on other parameters were analyzed by Pearson or Spearman correlation analysis. The cardiac structure and function measurements in both groups were within the normal range. The pulmonary functions of both groups decreased to different extents. Correlation analysis showed that GK Angle was significantly negatively correlated with the left atrioventricular size  and diastolic function parameters  in the patients with AS ( Its pathological changes are lesions in the attachment of the ligament, joint fibers or bone stiffness, vertebral osteoporosis, muscle stiffness and atrophy, and kyphosis. It leads to structural and functional damages and reduces in quality of life. In the Severe Group, kyphosis leads to muscle fatigue, activity related pain caused by continuous tension of spinal muscles while standing upright, inability to look straight ahead, intraperitoneal complications, and impaired respiratory function.–6 Restricted chest wall movement and abnormal lung parenchyma are the main factors leading to pulmonary dysfunction. AS not only reduces the volume of thoracic cavity due to kyphosis, but also further reduces the volume of thoracic cavity due to rib compression of abdominal cavity caused by kyphosis of thoracolumbar spine, thus affecting pulmonary function. In addition, the inflammatory reaction of AS disease also causes ossification of thoracic joints and mandatory spondylitis, thus reducing thoracic compliance and further damaging pulmonary function. However, whether global kyphosis (GK) angle affects cardiac systolic and diastolic function in the patients with AS and thoracolumbar kyphosis is still uncertain. In this study, the pulmonary function, cardiac structure and functional characteristics of the patients with AS were retrospectively analyzed, and the relationship between GK Angle and the degree of pulmonary function impairment, whether the GK Angle of the patients with AS affects the cardiac structure, diastolic function, and the left ventricular diastolic function were explored after excluding the influence of thoracic malformation and gender.Ankylosing spondylitis (AS) is a chronic disease involving the axial skeleton of the body, and it is a kind of rheumatism characterized by chronic inflammatory changes in large joints, such as sacroiliac joint and hip joint, and spinal arthritis belongs to one of its subtypes, with a prevalence rate of about 2%.°; The clinical data and various auxiliary examination data are complete. Exclusion criteria: The patients with primary rib and thoracic deformities; The patients with congenital heart disease; The patients with a history of cardiothoracic surgery; The patients with a history of spinal trauma or spinal surgery; The patients suffer from bronchial asthma, expansion and other lung diseases, or with a recent history of lung infection.Inclusive criteria: The patients with AS were confirmed; The patients’ main deformity is kyphosis, and the GK angle is ≥ 80°) and 23 patients were divided into Moderate Group (80° ≤ GK angle < 95°). The study was approved by the Medical Ethics Committee of the Hospital (Ethics No.: 2022052301), and all subjects had signed the informed consent.Retrospective analysis was conducted on the patients with AS who had been admitted in *** Hospital from October 2021 to October 2022. In this study, 46 patients who were qualified for the above criteria were selected and included. According to different GK angles, 23 patients were divided into Severe Group (GK angle ≥ 95max), measured value/estimated value of VC-max, measured value/estimated value of total lung capacity (TLC), measured value/estimated value of TLC; Obstructive ventilation function parameters: measured value of forced expiratory volume/forced vital capacity (FEV1/FVC) in the first second, measured value/predicted value of FEV1/FVC; Severity parameters of ventilation function: measured value of forced expiratory volume in the first second (FEV1), measured value/predicted value of FEV1; Small airway function parameters: MMEF75/25 measured value, MMEF75/25 measured value/predicted value, MEF75 measured value, MEF75 measured value/predicted value, MEF50 measured value, MEF50 measured value/predicted value, MEF25 measured value, MEF25 measured value/predicted value; Ventilation function parameters: measured value of carbon monoxide dispersion (DLCO), measured value/estimated value of DLCO.The general data of the patients, such as age, height, weight and arm length, were collected. All patients completed the whole spine X-ray examination in standing position, and the GK angle was measured on the full length anteroposterior and lateral X-ray films using Surgimap software. The Philip7C ultrasonic instrument was used to measure the cardiac structure and cardiopulmonary function parameters: Cardiac structure parameters: left atrial diameter (LAD), left ventricular diameter in end diameter (LVDD), left ventricular diameter in end systolic (LVSD), right atrial diameter, right ventricular diameter (RVD), aortic diameter (AO), main pulmonary artery diameter, inter ventricular septum thickness, left ventricular posterior wall thickness; Left ventricular systolic function parameters: ejection fraction (EF); Left ventricular diastolic function parameters: ratio of early diastolic maximum peak velocity (E peak) to late diastolic maximum peak velocity (A peak)(E/A), ratio of early diastolic velocity (e’) to late diastolic velocity (a’)(e’/a’), ratio of early diastolic maximum peak velocity (E peak) to early diastolic velocity (e’) of mitral septal annulus (E/e’). The automatic pulmonary function tester was used to measure pulmonary function parameters: restrictive ventilation function parameters: measured value of forced vital capacity (FVC), measured value/estimated value of FVC, measured value/estimated value of maximum vital capacity , while GK angle was significantly higher than that of Moderate Group (P < .05). The average age of both groups was also statistically significant (P < .05).See Table P < .05), and the parameters of left ventricular diastolic function E/A, e’/a’ in the Severe Group were significantly lower than that in the Moderate Group (P < .05), while E/e’ was significantly higher than that in the Moderate Group (P < .05). There was no significant difference in the diameter , ventricular wall thickness  and systolic function parameters (EF) between both groups (P > .05).The measured results of cardiac structure of both groups are shown in Table max measured value, TLC measured value, TLC measured value/predicted value) in the Severe Group were significantly lower than those in the Moderate Group (P < .05), and the measured value, FEV1 measured value/predicted value in the Severe Group were significantly lower than those in the Moderate Group (P < .05). The small airway function parameters  and ventilation function indexes  in the Severe Group were significantly lower than those in the Moderate Group (P < .05). There was no significant difference between both groups in obstructive ventilation function parameters  (P > .05).See Table P < .05), and significantly positively correlated with diastolic function parameters (E/e’) (P < .05). GK angle had no correlation with other cardiac structure and function parameters (P > .05). Age was negatively correlated with left atrioventricular size , RVD, and e’/a’ (P < .05), but not with other parameters (P > .05).The correlation analysis results of GK angle, age and cardiac structure and function parameters are shown in Table max measured value, VCmax measured value/predicted value, TLC measured value, TLC measured value/predicted value), ventilation function severity parameters , and ventilation function indicators  (P < .05). There was a significant positive correlation between GK angle and obstructive ventilation function parameters  (P < .05). GK angle had no correlation with other parameters (P > .05). Age was negatively correlated with restrictive ventilation function parameters , ventilation function severity parameters , small airway function parameters , and ventilation function indicators  (P < .05). See Table GK angle of the patients with AS was significantly negatively correlated with restrictive ventilation function parameters  P < .0. There w In this study, the patients with AS were all associated with different degrees of thoracolumbar kyphosis, and their pulmonary functions were damaged to some extent. The larger the kyphosis angle was, the smaller the volume of the thoracic cavity and abdominal cavity would be, and the internal organs would change accordingly. Relevant studies showed that there was a certain correlation between the pulmonary function disorder of the patients with AS with kyphosis and the rotation of the diaphragm in the sagittal plane. According to the basic research, the patients with AS had local pathological changes in the spine and other joints, and pulmonary function decreased, which was related to NF-κB-iNOS-NO signal pathway, oxidation indicators and inflammatory factors were negatively correlated. In addition, the pleura was directly involved in the pathogenesis of AS, affecting the respiratory function. The kyphosis deformity of the patients with AS combined with ossification and fusion of costal vertebra joint, transverse costal process joint, sternoclavicular joint and spinal rigidity changes of different degrees, resulting in limited thoracic movement of patients, which could directly affect the respiratory function of patients. Berdal et al found that the lower the spinal mobility of the patients with AS was, the lower their thoracic mobility would be, and the more significant the damage of FVC% and FEV1% would be, suggesting that AS spinal stiffness could also damage the pulmonary function of patients by reducing thoracic compliance. In this study, the influence of GK angle on pulmonary function was evaluated when other thoracic and spinal deformities were excluded. The results showed that with the increase of kyphosis angle, the patients’ restrictive ventilation function parameters and FEV1 values decreased. The study confirmed that the larger the GK angle was, the worse the pulmonary function was in the patients with AS, and the impairment of restrictive ventilation function was significantly related to the GK angle (correlation coefficient is −0.453 to −0.303), which was consistent with previous studies.,14 Meanwhile, this study confirmed that Cobb angle was not only related to impaired ventilation function, but also an influencing factor of small airway function and diffusion function.Most of the patients with AS and thoracolumbar kyphosis had different degrees of pulmonary function damage, and the disease mechanism was relatively complex. Among them, AS with thoracolumbar kyphosis and rib compression of the abdominal cavity reduced thoracic volume, thus damaging the ventilation function. Common manifestations include conduction block, valve disease, cardiomyopathy, etc. Meanwhile, the high inflammatory state of AS leads to abnormal blood lipid metabolism and increased cardiovascular risk.–19 Whether GK angle is an independent influencing factor of cardiac structure and function in the patients with AS has not been determined. Therefore, this study further studied the influence of GK angle on cardiac structure and function after controlling rib deformity, gender and other influencing factors. The patients with AS could often be combined with cardiovascular and other extraspinal manifestations. The patients with congenital heart disease were excluded from this study. The cardiac structural parameters of all the patients included in the criteria were within the normal range, but the atrioventricular cavity diameter of the Severe Group was smaller than that of the Moderate Group, the difference was statistically significant. Meanwhile, the correlation analysis showed that the GK angle was significantly negatively correlated with the left atrioventricular cavity diameter (LVDD and LVSD), and the correlation coefficients were −0.304 and −0.341, respectively. It confirmed that the size of the GK angle in the patients with AS could have a certain influence on the cardiac structure, which was consistent with the previous research results.,21 The larger the GK angle was, the heavier the degree of spinal kyphosis would be, and the greater the influence on the volume of the thoracic and abdominal cavity would be. The obvious reduction of the volume of the thoracic and abdominal cavity would affect the normal activity space of the heart in the mediastinum, resulting in the smaller cardiac cavity. In this study, left ventricular systolic function parameters  of all patients were normal. Correlation analysis showed that GK angle was not significantly related to EF values, indicating that left ventricular systolic function was not affected by the degree of kyphosis. However, with the constant increase of GK angle, EF values in the Severe Group were in a downward trend compared with the Moderate Group. The study showed that the ratio of E/A and e’/a’ in the Severe Group was lower than that in the Moderate Group, and E/e’ was higher than that in the Moderate Group. The difference was statistically significant. Meanwhile, the correlation analysis showed that GK angle was significantly positively correlated with E/e’, and the correlation coefficient was 0.039, respectively. It confirmed that GK angle could have a certain influence on the left ventricular diastolic function of patients, which was consistent with previous research results.,23 In conclusion, the GK angle in the patients with AS with kyphosis is significantly negatively correlated with the patients’ cardiac functions, mainly considering the reduction of the patients’ chest and abdominal cavity volume, reducing the range of cardiac activity, and ultimately impairing the patients’ diastolic functions.Clinical statistics show that 10% to 30% of the patients with AS have cardiovascular involvement.There were several limitation of the present study, including small sample size, single center study, and 1 year study period. The future study will be performed using large sample size, multi-center study, and long study period in order to decrease the selection bias, information bias and so on.In conclusion, after excluding the influence of thoracic malformation and gender, the GK angle of the whole spine is still the influencing factor of pulmonary function in the patients with AS kyphosis. The larger the GK angle is, the worse the patients’ restrictive ventilation functions would be, small airway function and diffusion function would be. Meanwhile, GK angle also affects the cardiac structure of the patients. The larger the GK angle is, the smaller the left atrioventricular cavity diameter will be, more greatly influencing the left ventricular diastolic function.This study was supported by Spinal Surgery in Beijing Dawang Road Emergency Rescue Hospital. Thank you very much for the cooperation of the patients and their families. I would like to thank the leaders of Beijing Chaoyang Emergency Rescue Hospital and the Ethics Committee for their strong supports.Conceptualization: Yunfei Yang.Data curation: Yunfei Yang.Formal analysis: Lijun Huang, Guofeng Zhao, Jiyuan Xia, Xinqi Tian, Chang Liu, Qingfu Xia.Investigation: Lijun Huang, Guofeng Zhao, Jiyuan Xia, Xinqi Tian, Chang Liu.Methodology: Jiyuan Xia, Xinqi Tian.Visualization: Chang Liu.Writing – original draft: Yunfei Yang.Writing – review & editing: Yunfei Yang, Lijun Huang, Guofeng Zhao, Jiyuan Xia, Xinqi Tian, Chang Liu, Qingfu Xia.


Figure S1). She reported a history of palpitations, chest pain, hot flashes, and feeling more short-tempered lately. Due to significantly elevated high-sensitivity cardiac troponin T (3614 ng/L) and N-terminal prohormone of brain natriuretic peptide (7208 ng/L), coronary artery disease was ruled out by invasive coronary angiography (see Video S1). Echocardiography showed a severely impaired left ventricular ejection fraction (LVEF 15%) with apical akinesia and hypercontractility of the basal segments (see Video S2). Cardiovascular magnetic resonance imaging confirmed the severely impaired ejection fraction (LVEF 29%) and regional wall motion abnormalities . T2 mapping revealed myocardial oedema in the apical two-thirds of the myocardium with corresponding mildly elevated myocardial extracellular volume (C). There was no myocardial infarction or focal fibrosis on late gadolinium enhancement images (D). Free serum metanephrine, normetanephrine, and chromogranin were significantly elevated. A dedicated abdominal magnetic resonance imaging demonstrated a round, well-demarcated tumour of the right adrenal gland (38 × 45 × 46 mm) which corroborated the diagnosis of an adrenal phaeochromocytoma with secondary takotsubo syndrome. Alpha and beta adrenergic blockade were administered prior to laparoscopic right adrenalectomy, and a 50 × 40 × 35 mm measuring tumour was removed (F + G). Histopathology confirmed the diagnosis of a phaeochromocytoma with small nests of basophilic neuroendocrine cells expressing chromogranin A (H). In a follow-up echocardiography 2 weeks post-surgery, LVEF and wall motion abnormalities had completely recovered (see Video S4). This case illustrates the rare (reversible) condition of a secondary takotsubo syndrome due to a phaeochromocytoma-induced catecholamine storm.An otherwise healthy 41-year-old female patient presented with an onset of cardiogenic shock . Electrocardiogram revealed sinus tachycardia without evidence of ischaemia (see European Heart Journal - Cardiovascular Imaging online.Consent: The patient consented to the use of her anonymized health care data for publication as a case report.Data availability: The data underlying this article will be shared on reasonable request to the corresponding author.jead053_Supplementary_DataClick here for additional data file.


In dilated cardiomyopathy (DCM), where the heart muscle becomes stretched and thin, heart failure (HF) occurs, and the cardiomyocytes suffer from an energetic inefficiency caused by an abnormal cardiac metabolism. Although underappreciated as a potential therapeutic target, the optimal metabolic milieu of a failing heart is still largely unknown and subject to debate. Because glucose naturally has a lower P/O ratio (the ATP yield per oxygen atom), the previous studies using this strategy to increase glucose oxidation have produced some intriguing findings. In reality, the vast majority of small-scale pilot trials using trimetazidine, ranolazine, perhexiline, and etomoxir have demonstrated enhanced left ventricular (LV) function and, in some circumstances, myocardial energetics in chronic ischemic and non-ischemic HF with a reduced ejection fraction (EF). However, for unidentified reasons, none of these drugs has ever been tested in a clinical trial of sufficient size. Other pilot studies came to the conclusion that because the heart in severe dilated cardiomyopathy appears to be metabolically flexible and not limited by oxygen, the current rationale for increasing glucose oxidation as a therapeutic target is contradicted and increasing fatty acid oxidation is supported. As a result, treating metabolic dysfunction in HF may benefit from raising ketone body levels. Interestingly, treatment with sodium-glucose cotransporter-2 inhibitors (SGLT2i) improves cardiac function and outcomes in HF patients with or without type 2 diabetes mellitus (T2DM) through a variety of pleiotropic effects, such as elevated ketone body levels. The improvement in overall cardiac function seen in patients receiving SGLT2i could be explained by this increase, which appears to be a reflection of an adaptive process that optimizes cardiac energy metabolism. This review aims to identify the best metabolic therapeutic approach for DCM patients, to examine the drugs that directly affect cardiac metabolism, and to outline all the potential ancillary metabolic effects of the guideline-directed medical therapy. In addition, a special focus is placed on SGLT2i, which were first studied and prescribed to diabetic patients before being successfully incorporated into the pharmacological arsenal for HF patients. Dilated cardiomyopathy (DCM) is a primary myocardial disorder characterized by enlarged ventricles with a contractile deficit that leads to reduced ventricular function in the absence of volume or to pressure overload, congenital heart disease (CHD), or significant coronary artery disease (CAD) . GeneticDCM is a recognized cause of systolic heart failure (HF), a condition in which the impaired cardiac pump is unable to fulfil the energetic demand of the body in terms of nutrients and oxygen supply. HF has been defined as the cardiovascular epidemic of the 21st century , with anMultiple factors, such as hemodynamics, neurohormones, and genetics, participate in progressive heart failure remodeling . The effIn the last decades, there has been a growing interest in the cardiac metabolism; the aim has been to find new potential disease biomarkers and therapeutic targets to improve the HF prognosis .A healthy adult heart produces adenosine triphosphate (ATP) by metabolizing different types of fuels , primarily via oxygen-dependent mitochondrial oxidative phosphorylation and the electron transport chain and, to a lesser extent, the anaerobic glycolytic pathway . Between+ accumulation in the cytoplasm as glycolysis is uncoupled from the oxidation of pyruvate and lactate [The failing heart is considered to be an “engine out of fuel” . A reduc lactate ,23. More lactate , despite lactate ,26. Furt lactate .Changes in substrate utilization in the failing heart have also been observed relative to glucose metabolism, ketone bodies, and long-chain amino acids . More meIn addition, in systolic heart failure, metabolic changes can occur regardless of weight status. However, the specific metabolic changes seen in obese, normal-weight, and underweight individuals may vary. There may be an increased reliance on fatty acid oxidation as a source of energy for the heart in obese people with heart failure. This can lead to an impaired glucose metabolism and decreased myocardial glucose uptake and oxidation. In addition, metabolic dysregulation in the heart may be exacerbated by insulin resistance and inflammation, which are frequently associated with obesity. As previously mentioned, heart failure can cause metabolic changes, such as an increase in glycolysis as a source of myocardial energy, even in healthy people. In heart failure, the oxidative metabolism is less efficient; so, this metabolic switch is made to make up for it. Heart failure patients who are underweight may experience metabolic changes that are comparable to those seen in people of normal weight. There may still be a shift toward more glycolysis . ImplemeRecently, the use of various “omics” technologies, such as metabolomics, has offered a new chance to enhance our understanding of the mechanisms involved in this disease and to find new biomarkers for the prognosis and diagnosis of DCM . A recenFurthermore, Zhao et al., in a study conducted on patients’ plasma, showed that both DCM and ischemic cardiomyopathy (ICM) patients have a unique metabolomics profile compared to that of healthy controls, with some common metabolic changes . AdditioA better knowledge of cardiac metabolic adaptations in HF would certainly serve as a starting point from which to highlight new therapeutic targets, for old and new drugs, to exploit in different phenotypes and disease stages ; Table 1Without affecting their detrimental chronotropic and inotropic effects, betablockers have the ability to directly alter myocardial energetics . By reduThe hormone system known as RAAS controls blood pressure and fluid balance. Angiotensin I (AT I) conversion to angiotensin II (AT II) is blocked by RAAS inhibitors, and the AT II receptors at the end of the route are also blocked. Due to its direct ability to cause and sustain ventricular dysfunction through a variety of pathways, AT II is a key participant in the regulation of cardiac energy metabolism . It affeAfter a median follow-up of 27 months, the PARADIGM-HF study demonstrated that sacubitril/valsartan, the first member of a new class of medications known as ARNI, reduced the morbidity and mortality of patients with HF and reduced EF compared with the ACE inhibitor enalapril . SacubitAldosterone has negative effects that are mediated via the mineralocorticoid receptor; these effects are blocked by MRAs such as spironolactone and eplerenone. MRAs are therefore effective in treating hypertension, especially resistant hypertension, and in lowering the risk of morbidity and death in HF patients through this pharmacological activity. The “off-target effects” of spironolactone have also been shown to have negative effects on lipid and glucose homeostasis . The bloLoop diuretics, such as furosemide, primarily affect the kidneys to increase urine production. However, they may also have an indirect effect on the heart’s metabolism. Hypomagnesemia and hypokalemia can be brought on by loop diuretics. Arrhythmias are more likely to occur in people with these two conditions, which can impair cardiac function by interfering with normal electrical signaling. Additionally, hypocalcemia, which may affect cardiac contractility, can be brought on by these medications. Last but not least, loop diuretics can contribute to all of the metabolic changes associated with RAAS activation (as previously described) by stimulating the RAAS through volume depletion and decreased blood pressure .Although the ideal metabolic environment for a failing heart remains highly debated and poorly understood, it may be a good target for future treatments. With the use of medications such as trimetazidine, ranolazine, perhexiline, and etomoxir, the previous research has concentrated on boosting glucose oxidation, which, in comparison to FFA oxidation, has a higher P/O ratio. These medications have been shown to enhance myocardial energetics and LV function in patients with chronic ischemic and non-ischemic HF and low EF. For unknown reasons, these medications have not, however, ever undergone extensive clinical studies .The failing heart in severe non-ischemic cardiomyopathy, on the other hand, may be metabolically adaptive and not oxygen-restricted, according to some preliminary investigations. This challenges the conventional wisdom that the optimal therapeutic goal is to increase glucose oxidation; instead, it supports the alternative position that increasing fatty acid oxidation is a wise course of action .Trimetazidine is an anti-ischemic medication that, as a result of the inhibition of mitochondrial long-chain 3-ketoacyl CoA thiolase, directly reduces cardiac fatty acid oxidation. This leads to a better coupling of glucose oxidation with glycolysis, which could account for its antianginal effect .It has been demonstrated that this drug also maintains the intracellular levels of high-energy phosphate in the myocardium, improving the ratio of phosphocreatine to ATP by a net 33%. Previous research has revealed that this ratio, which is utilized as a measure of cardiac energetics, is decreased in the failing human myocardium . In a trAdditionally, it has been shown that trimetazidine has a positive impact on the vascular endothelium, as well as glucose metabolism in T2DM patients with ischemic cardiomyopathy, by decreasing endothelin-1 release and increasing insulin-induced glucose oxidation and cyclic guanosine monophosphate (cGMP) release from skeletal muscle cells . TrimetaIn fact, a multicenter retrospective cohort analysis on 669 HF patients revealed that the addition of trimetazidine to standard medical care improved HF hospitalizations and survival . In addiFinally, a recent study has shown that a new molecule called ninerefaxstat considerably improves myocardial energetics, lowers myocardial steatosis, and improves diastolic function in individuals with T2DM and obesity . This suA piperazine-derived substance called ranolazine selectively inhibits the late sodium current in cardiomyocytes. Ischemia, HF, and other pathological circumstances can increase channel activity, which, in turn, causes a reduction in systolic force generation and an increase in diastolic force generation, as well as an increase in oxygen consumption .By lowering sodium influx, ranolazine prevents calcium overload and the ensuing rise in wall tension. This would seem to be its primary antianginal mechanism . The benCarnitine-palmitoyltransferase (CPT-I), an enzyme involved in the absorption of mitochondrial fatty acids, is inhibited by perhexiline. Its inhibition increases glucose oxidation while decreasing fatty acid oxidation . In patiEtomoxir inhibits CPT-I, which has comparable effects on glucose metabolism to perhexiline. Additionally, etomoxir may directly activate PPAR (peroxisome proliferator activated receptor) alpha, which would upregulate a number of beta-oxidation-related enzymes . In two Furthermore, etomoxir added to standard therapy improved LV EF, central hemodynamics at rest and during exercise, and clinical status in a small pilot study with ten patients with HF (one patient had ischemic heart disease and nine had dilated idiopathic cardiomyopathy) .Despite these findings, etomoxir has a limited therapeutic application since it may lead to heart hypertrophy  and becaAdditionally, the elevated liver transaminase levels of four patients caused the ERGO study, which was intended to verify the effectiveness of 80 mg of etomoxir/day, to be discontinued early .A key cofactor of fatty acid metabolism, L-carnitine, which is a modified amino acid that resembles a vitamin, controls the intramitochondrial acyl-coenzyme A/coenzyme A ratio. Although its primary function is to support FFA metabolism, there is some evidence from in vitro studies that it can also improve glucose metabolism. A minor improvement in heart energetics and function with L-carnitine supplementation has been supported by a number of research studies in both human and animal tests . DespiteThe reduction in reactive oxygen species caused by xanthine oxidase inhibition  may alsoIt has been demonstrated that coenzyme Q, commonly known as ubiquinone, improves mitochondrial respiration , endotheOvercoming the failing heart’s insulin resistance state is another possible strategy for increasing metabolic efficiency. In various circumstances, the direct pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA) has been shown to improve glucose oxidation. Pre-clinical research on HF animal models revealed that DCA therapy could increase contractile reserve and stop the HF rat from decompensating ,102. AddBranched-chain amino acids (BCAAs) provide an additional energy source for the failing heart. Both the plasma and the heart contained higher concentrations of BCAAs and their metabolites in HF rat models ,105. In Last, but not least, lactate is a normal fuel for the heart and can be converted into pyruvate by the enzyme lactate dehydrogenase (LDH) and fed into the tricarboxylic acid (TCA) cycle, which in turn produces ATP . AlthougAs outlined above, targeting cardiac metabolism by decreasing fatty acid oxidation and promoting glucose oxidation appears to be an interesting approach to the treatment of chronic HF. Several drugs have been investigated in small-scale studies, but large clinical trials are needed to confirm the efficacy of these agents as a part of chronic HF treatment.More recently, a new interest in ketone body metabolism has arisen as their modulation may be of potential benefit to HF patients.Under normal conditions, ketones represent a minimal part of all substrates utilized by the myocardium for energy production. These compounds, however, become critical during periods of stress and fasting since their utilization allows the preservation of glycogen stores. The myocardium is the highest ketone body consumer per unit mass. Ketone body oxidation is also more efficient than fatty acid oxidation in terms of ATP synthesis per molecule of oxygen used ,112. In In hypertrophied and early-stage failing rat hearts, a reduced capacity to oxidize fatty acids and a shift to ketone oxidation as an alternative metabolic fuel have been observed . SimilarA case control study involving patients with chronic dilated non-ischemic cardiomyopathy showed increased amounts of beta-hydroxybutyryl CoA and decreased amounts of myocardial beta-hydroxybutyrate in myocardial tissue, suggesting an increased ketone body metabolism in this setting .Additional studies have shown that circulating ketone bodies in subjects with chronic HF increase proportionally to the intensity of their symptoms, the level of congestion in the venous circulatory system, and the magnitude of neurohormonal and cytokine involvement, as well as the increasing deterioration of left ventricular function ,116. In These results clearly indicate that chronic HF determines a ketosis-prone state . Indeed,It is also known that exhaled breath acetone is increased in HF patients with reduced EF and is associated with higher mortality or heart transplantation .Interestingly, higher serum levels of beta-hydroxybutyrate seem to relate to disease progression and adverse prognosis in arrhythmogenic cardiomyopathy patients, supporting the hypothesis that an enhanced ketone body metabolism may be a standard myocardium response to injuries .According to another study, the cardiomyocytes’ specific loss of succinyl-CoA:3-oxoacid CoA transferase, which is involved in ketone body oxidation, is associated with significantly increased left ventricular volume and a decreased ejection fraction as a response to pressure overload . OverallIn this context, the concept of the therapeutic modulation of ketone metabolism as a potential new target in HF treatment is emerging ,123,124.There is a bidirectional link between diabetes mellitus (DM) and HF. Longstanding diabetes causes changes in myocardial metabolism, abnormal calcium signaling, and inflammatory pathways, resulting in structural and functional changes in the myocardium and leading to the development of diabetic cardiomyopathy and the progression of HF ,126. ConDuring the last decade, cardiovascular outcome trials have investigated several classes of new glucose-lowering agents, including SGLT2i, which, apart from showing evidence of cardiovascular safety, have also been shown to exert beneficial effects on the cardiovascular outcome ,128. MosSGLT2i increase urinary glucose excretion by suppressing the activity of SGLT2 protein in the nephron proximal convoluted tubule, lowering the maximal renal transport capacity for glucose reabsorption and, consequently, the threshold for glycosuria . The ens2 and albuminuria were randomly given canagliflozin or a placebo. Canagliflozin substantially reduced the risk of end-stage kidney disease and renal or cardiovascular death [Numerous studies suggest a nephroprotective effect of long-term therapy with SGLT2i. In the CREDENCE trial, 4401 T2DM patients with an estimated glomerular filtration rate (eGFR) from 30 to 90 mL/min/1.73 mar death . Of notear death ,142. As The mechanisms underlying the nephron protection of SGLT2i are not fully understood. In diabetic patients, glomerular hyperfiltration is an important mechanism of nephropathy. SGLT2i, by activating the tubulo-glomerular feedback, cause vasoconstriction of the afferent arteriole, resulting in a reduction in intraglomerular pressure and, consequently, glomerular hyperfiltration . ReductiOf note, ACE-I and angiotensin receptor blockers (ARBs) cause efferent arteriolar vasodilatation and, when used in combination with SGLT2i, will likely co-impact on intraglomerular pressure and may account for the initial drop in eGFR observed in patients, which is followed by a plateau over time .So far, the mechanisms underlying the protective cardiovascular effects of SGLT2i in patients with and without T2DM are not completely understood, and several hypotheses have been proposed. SGLT2i may modulate many of the important underlying cellular mechanisms that have been documented to contribute to cardiac pathologies, such as hypertrophy, HF, diastolic dysfunction, and arrhythmias . Large cSeveral mechanisms other than improved glycemic control and changes in renal tubular function have been proposed to explain the cardiovascular benefits of SGLT2i. First, the hemodynamic effects of SGLT2i optimize the ventricular loading conditions . SGLT2 iImproved blood pressure control is documented in numerous studies. Zelniker et al. observed a reduction of 4–6 mmHg in systolic and 1–2 mmHg in diastolic blood pressure with the use of SGLT2i . CompareSGLT2i-associated cardiovascular benefits also depend on improved cardiac metabolism and bioenergy ,138. LikTaken together, SGLT2i reverse the profound nutrient, metabolic, and cellular signaling abnormalities seen in HF, thereby restoring the myocardium to a molecular and cellular phenotype that resembles that of a healthy adult heart.The cardiac metabolism is a complex system of interconnected pathways that work together to improve the function of the heart. Due to a lack of substrate and post-transcriptional enzyme modification, this ideal system tends to become out of sync in failing hearts, and particularly in DCM. This causes some pathways to be enhanced while others are diminished, which results in less efficient energy production. A negative change impacting the advanced stages of HF is a deficit in mitochondrial capacities, particularly in oxidative capacities.To decrease or even stop HF metabolic derangement, a number of treatment approaches have been suggested, including increasing ketone body oxidation, increasing glucose oxidation and boosting insulin sensitivity, changing fatty acid oxidation, and increasing BCAA oxidation. Many compounds disappointed expectations when tested on HF patients; they displayed inconsistent findings in terms of heart functions or survival outcomes, despite the pre-clinical investigations starting with promising results. It remains to be determined and researched in additional studies whether these unfavorable results are attributable to a poor sample selection  or to many and diverse mechanisms that have not yet been fully clarified. The most successful strategy so far appears to include changing how the failing heart uses its substrates while also utilizing a number of pharmacological medications. The majority of the current research findings are consistent with the idea that an effective supplementary treatment for individuals with HF could involve switching the energy substrate preference away from fatty acid metabolism and toward enhanced myocardial glucose consumption. Nevertheless, further extensive multicenter randomized studies are required before the precise role of metabolic treatment in HF can be determined.