Cardiovascular complications, including ventricular arrhythmias associated with abnormalities of ventricular repolarization, are the leading cause of morbidity and mortality in patients with acromegaly. Herein, we aimed to investigate ventricular repolarization using Tp–e interval, Tp-e interval/QT, and Tp-e interval/QTc ratios in acromegalic patients compared to healthy subjects.A total of 29 patients  with acromegaly and 30 control subjects  were enrolled in the study. Tp–e and QT interval, corrected QT (QTc), Tp–e/QT, and Tp–e/QTc ratios were calculated from the 12-lead electrocardiogram.Tp-e interval , Tp-e/QT ratio , and Tp-e/QTc ratio  were significantly higher in patients with acromegaly compared to control group. A positive correlation was determined between left atrial volume index (LAVI) and Tp-e interval .The current study is the first to have shown significantly increased Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio were increased in acromegalic patients. These results may be important for screening malignant arrhythmic events in acromegaly. Acromegaly is a rare disorder resulting from excessive growth hormone production (GH) and serum insulin like growth factor-1 (IGF-1) concentrations ,3. CardiVentricular repolarization abnormalities are central elements in arrhythmogenesis. Previous studies showed that ventricular repolarization can be evaluated by QT interval (QT), corrected QT interval (QTc), QT dispersion (QTd), and T wave measurements ,9. The tThe aim of the present study was to assess ventricular repolarization parameters of acromegalic patients using Tp-e interval, Tp-e interval/QT, and Tp-e interval/QTc ratios. To our knowledge, no prior studies have examined previously the association between these parameters and acromegaly.In this study, we enrolled consecutively eligible outpatients of the Endocrinology Department with the diagnosis of acromegaly. A total of 33 acromegalic patients and 30 healthy individuals were enrolled in the study, 4 acromegalic patients were excluded. Patients with renal dysfunction (n = 2), acute or chronic infection, cardiovascular diseases including ischaemic heart disease (n = 1), congestive heart failure, severe valvular heart disease, abnormal serum electrolyte values (n = 1), pregnancy, malignancy, left and right bundle branch block, Mobitz type II, third-degree atrioventricular block, ventricular preexcitation, atrial fibrillation, a permanent pace-maker, severe kidney, liver and lung disease, those taking any class I and III antiarrhythmic medication were excluded from the study. Therefore, 29 patients with acromegaly and 30 gender and age-matched healthy volunteers were included in the study after exclusion criteria were applied.The 12-lead electrocardiogram (ECG) was recorded at a paper speed of 50 mm/s  at rest in the supine position. All of the ECGs were scanned and then Adobe Photoshop software was used for ×400% magnification. ECG measurements of QT and Tp-e intervals were performed by two cardiologists who did not know the patient data. The Tp-e interval was defined as the difference between the peak of the T wave and the end of the T wave. The U wave was excluded from the Tp-e interval. The QT interval was measured from the beginning of the QRS complex to the end of the T wave and Corrected QT (QTc) was calculated with the Bazett formula: cQT = QT√. Measurements of the Tp-e interval were evaluated from precordial leads. The Tp-e/QT ratio was calculated from these measurements. Additionally, twenty-four hour holter recordings were evaluated by using three-channel analog recorders using the ELATEC Holter system.The echocardiographic assessment was analysed by using a Vivid S60N Dimension Cardiovascular Ultrasound System  with a 3.5 MHz transducer in the left lateral decubitus position. Parasternal long and short-axis views and apical views were used as standard imaging windows. The ejection fraction was calculated by using the modified Simpson method. Septal and posterior walls’ thickness, left ventricular (LV) end-systolic and end-diastolic dimensions left atrial diameter were measured from parasternal long-axis view. Tissue Doppler imaging (TDI) was acquired from the lateral and septal walls of the left ventricular basal section. E/A ratio and E/e′ ratios were analysed in the evaluation of LV diastolic function. Left ventricular mass index (LVMI) was calculated by the ratio of calculated LV mass to the body surface. Left ventricular hypertrophy (LVH) was defined as the calculation of LVMI > 115 g/m2 in men and >95 g/m2 in women. Left atrial (LA) volume was assessed by the biplane area-length method from apical 4- and 2-chamber views. LA volume/body surface area was measured for LA volume index (LAVI). All these echocardiographic measurements were performed by experienced investigators according to standards outlined by the American Society of Echocardiography guidelines [Serum GH and IGF-1 levels were measured by using cobas 8000 Modular Analyzer Series . Biochemical measurements including fasting blood glucose, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, serum creatinine, serum electrolytes were evaluated using cobas 8000 Modular Analyzer Series  . Complete blood count (CBC) was calculated by an automated analyzer .All data analyses were performed with SPSS version 22.0 . Categorical variables are expressed as counts and percentages, and continuous variables are presented as mean ± standard deviation or as median and interquartile ranges. Categorical variables were compared by the chi-square test or Fisher’s exact tests as appropriate. Comparisons of parametric values between the 2 groups were compared using independent samples t-test. Comparisons of nonparametric values between the 2 groups were done by Mann-Whitney U test. The goodness of fit of the model was evaluated by the Hosmer-Lemeshow test. Pearson correlation analysis was performed to examine the relationship between Tp−e interval, Tp−e/QT ratio, and Tp−e/QTc and other variations. A 2-sided p-value of < 0.05 was considered statistically significant.The baseline clinical characteristics and laboratory parameters of the patients are shown in The electrocardiographic and echocardiographic findings are given in There were no significant differences between the two groups in the echocardiographic dimensions including the left ventricular ejection fraction, left ventricle end-diastolic diameter and left ventricle end-sistolic diameter (p > 0.05). Acromegalic patients exhibited significantly higher values in interventricular septum , left ventricular posterior wall thickness , LVMI  and left atrial diameter  compared to control group. Similarly, LA volume , LA area  and LAVI  were also significantly higher in patients with acromegaly. TDI demonstrated e’ lateral value  was significantly lower in acromegalic patients. Additionally, no significant difference was observed between E/A and E/e′ values of patients between the groups (p > 0.05).Finally, the Pearson correlation coefficient was performed to estimate the correlation between LAVI and Tp-e interval. We found a significant positive correlation between LAVI and Tp-e interval (r = 0.272, p = 0.039; In this study, we evaluated ventricular repolarization parameters in patients with acromegaly and compared them with healthy control subjects. Our study results indicate that acromegalic patients had longer Tp-e interval, Tp-e/QT, and Tp-e/QTc ratios when compared to healthy subjects. To the best of our knowledge, this study was the first clinical trial focusing on the Tp−e interval, Tp−e/QT, Tp−e/QTc ratios in acromegalic patients.Cardiovascular diseases are one of the most prevalent in acromegalic patients and in 60% of uncontrolled acromegalic patients die from cardiovascular comorbidities ,17. In tVentricular repolarization parameters are related to malignant arrhythmias and have prognostic significance in terms of mortality and sudden cardiac death. Several studies have shown that QT, QTc, QTd, and T wave measurements were clarified as a sign of increased dispersion of ventricular repolarization ,9. Tp-e Malignant ventricular arrhythmias and sudden death can be seen higher in acromegalic patients compared to the general population . The sevThe relationship between diastolic dysfunction and Tp-e interval, Tp-e/QT, and Tp-e/QTc ratios which may be related to cardiomyocyte involvement and increased risk of arrhythmia has been shown in Fabry patients . RegardiThe results of the current study should be assessed with some limitations. First, this study is a single-center and relatively small sample population. Second, this is a cross-sectional study so we could not follow the arrhythmic episodes of patients. Finally, we did not have the data demonstrating at what time point when the Tp-e interval, Tp-e/QT, and Tp-e/QTc ratios started to prolong or change following diagnosis of acromegaly. Future large, prospective and randomized clinical trials are required to assess the clinical applicability of our findings.In conclusion, Tp-e interval, Tp-e/QT, and Tp-e/QTc ratios were increased in patients with acromegaly, which may indicate a higher risk for ventricular arrhythmias in patients with acromegaly. Tp-e interval, Tp-e/QT, and Tp-e/QTc ratios are simple, inexpensive, and noninvasive methods that may be valuable for screening for ventricular repolarization in acromegalic patients.


Left bundle branch block (LBBB) has been confirmed to be independently associated with adverse outcomes in dilated cardiomyopathy (DCM). However, prognostic data on nonspecific intraventricular conduction delay (NSIVCD) are still limited and conflicting. We aimed to evaluate the prognosis of DCM with NSIVCD.A total of 548 DCM patients who underwent cardiovascular magnetic resonance imaging (CMR) from January 2016 to December 2017 were consecutively enrolled. The cohort was divided into four groups: 87 with LBBB, 27 with RBBB, 61 with NSIVCD, and 373 without intraventricular conduction delay (IVCD). After a median follow-up of 58 months (interquartile range: 47–65), 123 patients reached the composite endpoints, which included cardiovascular death, heart transplantation, and malignant arrhythmias. The associations between different patterns of IVCD and the outcomes of DCM were analysed by Kaplan‒Meier analysis and Cox proportional hazards regression analysis.Of 548 DCM patients, there were 398 males (72.6%), and the average age was 46 ± 15 years, ranging from 18 to 76 years. In Kaplan‒Meier analysis, patients with NSIVCD and LBBB showed higher event rates than patients without IVCD, while RBBB patients did not. By multivariate Cox regression analysis, LBBB, NSIVCD, NYHA class, left ventricular ejection fraction (LVEF), indexed left ventricular end-diastolic diameter (LVEDDI), percentage of late gadolinium enhancement mass (LGE%), and global longitudinal strain (GLS) were found to be independently associated with the outcomes of DCM.In addition to LBBB, NSIVCD was an unfavourable prognostic marker in patients with DCM, independent of LVEDDI, NYHA class, LVEF, LGE%, and GLS. Dilated cardiomyopathy (DCM) is the most common cause of heart failure and cardiac transplantation worldwide , with a In addition to LBBB, there are two other intraventricular conduction delays (IVCDs) with widened QRS complexes, including right branch bundle block (RBBB) and nonspecific intraventricular conduction delay (NSIVCD). NSIVSD is defined as QRS duration ≥ 110 ms in adults who do not meet the criteria for LBBB or RBBB . The outPrevious studies have shown that patients with DCM with regional fibrosis identified by cardiovascular magnetic resonance (CMR) late gadolinium enhancement (LGE) imaging methods have adverse outcomes –14. As aTherefore, we aimed to analyse DCM in our medical centre to explore whether NSIVCD is an independent prognostic factor, utilizing measurement of cardiac morphology, cardiac function, myocardial fibrosis, and myocardial deformation by CMR.This was a retrospective study approved by the Ethics Committee of Fuwai Hospital. Written informed consent was waived due to the retrospective nature of this study by the Ethics Committee of Fuwai Hospital. The study was performed in accordance with the principles of the Declaration of Helsinki.2; and (4) other cardiomyopathies, such as hypertrophic cardiomyopathy, hypertensive heart disease, active myocarditis, cardiac sarcoidosis, Fabry disease, peripartum cardiomyopathy, alcoholic cardiomyopathy, metabolic cardiomyopathies, and congenital heart diseases.Of 3523 patients admitted or referred to our hospital who underwent CMR on a 3.0 T Philips MRI system from January 2016 to December 2017, 852 newly diagnosed DCM patients (symptoms occurred within 2 months) were consecutively enrolled. The diagnosis of DCM was confirmed on CMR using the World Health Organization/International Society and Federation of Cardiology definition of DCM . The incOf 852 DCM patients who met the inclusion criteria, 3 patients under the age of 18 were excluded; 196 cases of suspected ischaemic heart disease were excluded. Additionally, 38 cases of suspected severe valvular disease and 24 cases of suspected hypertrophic cardiomyopathy, Fabry disease, or peripartum cardiomyopathy were excluded. Then, 591 DCM patients with LVEF < 45% were selected; nine patients were excluded because of low image quality and unmatched cine phases. In addition, 34 (5.8%) patients were lost to follow-up. Finally, a total of 548 DCM patients were enrolled  had LBBB, 27 (4.9%) had RBBB, 61 (11.1%) had NSIVCD, and 373 (68.0%) had no IVCD. Diagnostic criteria for LBBB and RBBB were based on the American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society recommendations [The last follow-up was in December 2021. The median follow-up time was 58 months, ranging from 3 to 71 months (interquartile range: 47–65). The outcomes were composite endpoints, which included sudden cardiac death, heart failure death, heart transplantation, LV assist device installation, malignant ventricular arrhythmias, and appropriate shocks of implantable cardioverter defibrillators (ICD) or cardiac resynchronization therapy defibrillators (CRT-D) during the follow-up. Malignant ventricular arrhythmias included ventricular fibrillation, ventricular flutter, and sustained ventricular tachycardia requiring a cardioverter. All the data were obtained via medical records, clinic visits, and telephone interviews. Suspected outcomes were reviewed by two independent investigators blinded to CMR data.2; and 25–30 phases per cardiac cycle. LGE imaging was performed 10 min after injection of contrast .All patients underwent CMR examination on a 3.0T MRI system . Balanced steady-state free precision (bSSFP) cine was acquired in two-, three-, and four-chamber long-axis and short-axis views. The short-axis cine included eight slices covering the entire LV from the mitral valve ring to the apex. The main imaging parameters were as follows: slice thickness, 8 mm, no gap; repetition time, 3.4 ms; echo time, 1.5 ms; matrix size, 224 × 256; field of view, 320 × 320 mmThe left ventricular end-diastolic diameter index (LVEDDI), left ventricular end-diastolic volume index (LVEDVI), left ventricular end-systolic volume index (LVESVI), LVEF, left atrial diameter (LAD) and left ventricular mass index (LVMI) were measured by software CVI42  and normalized by the body surface area calculated with the Mosteller equation. Left ventricular mass was measured at end-diastole.CMR strain analysis by feature tracking was performed on cine images via CVI42. LV endocardial and epicardial contours were automatically tracked and manually corrected in short-axis slices and three long-axis slices in end-diastolic phases. LV global radial strain (GRS) and global circumferential strain (GCS) were derived from the short-axis cine. LV global longitudinal strain (GLS) was derived from the two-, three-, and four-chamber cine . The results were reported as a percentage of LGE mass (LGE%) to total left ventricular mass. CMR analyses were performed by a radiologist fully blinded to the clinical data.Inter- and intraobserver variabilities for strain values were assessed in a randomly selected subgroup of 20 subjects with positive LGE. One observer measured the data once, and a second observer (blinded to the first observer’s results) measured the data at two time points at least two weeks apart (by Y. Y. and K. Y.).As appropriate, variables are presented as the means ± standard deviations, medians with interquartile ranges, or numbers with percentages. Univariate comparisons were performed by the two-sample independent t test, the Mann‒Whitney U test, one-way ANOVA, and the Pearson chi-square test for normally distributed, nonnormally distributed, and categorical variables, respectively. Kaplan‒Meier survival estimates were performed along with a log-rank test to test the proportional hazards hypothesis of Cox regression.P value < 0.1 on univariate analysis were included in multivariate mode. Multivariate Cox regression was performed to determine independent associations with the outcomes. The results were expressed as adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).Univariate Cox regression was initially used to identify variables associated with the outcome. Candidate variables with a P < 0.05 was considered statistically significant. All analyses were performed by IBM SPSS Statistics (version 26).We analysed latent predictors of outcomes from several perspectives: structure remodelling, LV dysfunction, IVCD patterns, myocardial fibrosis, and LV myocardial global strain. Baseline variables considered clinically relevant to outcomes were entered into univariate Cox regression. Collinearity analysis was performed to obtain more appropriate variables by linear regression, and a variance inflation factor > 10 was considered collinear. Given the number of endpoint events, multivariate models were limited to no more than twelve parameters, allowing for approximately one covariable per 10 events to ensure parsimony of the final model. Inter- and intraobserver variabilities were analysed by the intraclass correlation coefficient (ICC). As shown in Tables P < 0.001). Patients with New York Heart Association (NYHA) functional classes III and IV and higher NT-proBNP or troponin levels were more likely to reach the endpoints as expected. The histories of smoking and alcohol, the medications of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, diuretics, mineralocorticoid receptor antagonists, and digoxin between the positive and negative endpoint groups were not significantly different. Among the cohort of DCM patients divided by IVCD patterns, there were significant differences with regard to smoking and alcohol consumption. The IVCD group had a higher proportion of patients with a family history of DCM and higher NYHA classes. There were no significant differences related to medications except for ACE inhibitors. The positive endpoint group had a higher frequency of NYHA classes III and IV. The detailed baseline characteristics are summarized in Tables There were no significant differences in the sex or age distribution between the positive and negative endpoint groups. Of the 548 patients, 87 15.9%) had a family history of DCM, including 59 (13.9%) in the negative endpoint group and 28 (22.8%) in the positive endpoint group. There was no significant difference in the proportion of family history between the negative and positive endpoint groups. There was a significant difference in prognosis between different patterns of IVCD . Subsequently, we conducted pairwise Kaplan‒Meier analyses of the above four groups. Patients with NSIVCD showed higher event rates than patients without IVCD . Patients with LBBB showed higher event rates than patients without IVCD . There was no statistical significance between the event rates of patients with RBBB and those without IVCD . There was also a difference between LBBB patients and NSIVCD patients .Baseline variables clinically relevant to outcomes such as sex, age, alcohol, smoking, family history of DCM, NYHA functional classes and NT-proBNP, structure remodelling parameters, LVEF, IVCD patterns, LGE%, global strain GRS, GCS, and GLS were entered into univariate Cox regression. Univariate Cox regression analysis showed that LVEDDI, LVESVI, LVEDVI, LAD, LVEF, NYHA functional classes, LGE%, IVCD patterns, and strain variables GRS, GCS, and GLS were all significantly associated with the endpoints. A collinearity analysis was performed among the remodelling variables LVEDVI, LVESVI, and LVEDDI. The variance inflation factors of LVEDVI and LVESVI were both > 10 as shown in Table We finally selected the remodelling variables LVEDDI, LAD, cardiac function variable LVEF, NYHA functional classes, fibrosis variable LGE%, IVCD patterns, and strain variables GLS, GRS, and GCS as covariables to create the final multivariate Cox model. With stepwise analyses, LBBB , NSIVCD , LVEDDI , LGE% , LVEF , and NYHA functional classes  were shown to be independently associated with the endpoints after adjustment for other confounding variables , which may be related to genetic factors, with DCM as high as 20–35% . In addiIn addition to LBBB, NSIVCD was an unfavourable prognostic marker in patients with DCM, independent of LVEDDI, NYHA classes, LVEF, LGE%, and GLS. These data may help clinicians adopt appropriate treatment strategies for DCM patients with NSIVCD. Further studies are needed to explore whether there is left ventricular systolic dyssynchrony in DCM patients with NSIVCD as in those with LBBB.


Specific LV contraction processes were demonstrated by evaluating the LS distribution and time-to-peak strain. These evaluations may have potential to estimate the activation sequence in patients with asynchronous LV activation.Evaluation of longitudinal strain (LS) from two-dimensional echocardiography is useful for global and regional left ventricular (LV) dysfunction assessment. We determined whether the LS reflects contraction process in patients with asynchronous LV activation. We studied 144 patients with an ejection fraction ≤ 35%, who had left bundle branch block , right ventricular apical (RVA) pacing (n = 34), LV basal- or mid-lateral pacing (n = 23), and no conduction block . LS distribution maps were constructed using 3 standard apical views. The times from the QRS onset-to-early systolic positive peak (Q-EPpeak) and late systolic negative peak (Q-LNpeak) were measured to determine the beginning and end of contractions in each segment. Negative strain in LBBB initially appeared in the septum and basal-lateral contracted late. In RVA and LV pacing, the contracted area enlarged centrifugally from the pacing site. Narrow-QRS showed few regional differences in strain during the systolic period. The Q-EPpeak and Q-LNpeak exhibited similar sequences characterized by septum to basal-lateral via the apical regions in LBBB, apical to basal regions in RVA pacing, and lateral to a relatively large delayed contracted area between the apical- and basal-septum in LV pacing. Differences in Q-LNpeaks between the apical and basal segments in delayed contracted wall were 107 ± 30 ms in LBBB, 133 ± 46 ms in RVA pacing, and 37 ± 20 ms in LV pacing ( Global longitudinal strain from two-dimensional 2D) echocardiography is considered to be an accurate and sensitive parameter for the assessment of global left ventricular (LV) dysfunction . LongituD echocarAmong the patients who underwent echocardiography in our hospital from January 2016 to September 2022, we selected those with LV ejection fraction (LV-EF) ≤ 35%, and with LBBB or a ventricular pacing device . Patients without a conduction block (Narrow-QRS) were also examined. Patients with an irregular RR interval, or in whom the endocardial border was difficult to visualize using echocardiography were excluded. Patients with previous treatment for myocardial infarction or who had undergone coronary artery bypass surgery were excluded. In patients for whom coronary angiography was performed, cases with significant stenosis  were excluded. After excluding these patients, 144 were enrolled . Of these patients, coronary angiography was performed in 114 patients 79%). Each patient had one echocardiographic study analyzed. The types of QRS were classified into LBBB (n = 42), RVA pacing (n = 34), LV pacing (n = 23), and no conduction block . The criteria for LBBB included a QRS duration ≥ 120 ms, QS or rS in lead V1, broad R waves in leads I, aVL, V5, or V6, and absent Q waves in leads V5 and V6 [%. Each pAll patients underwent echocardiography with a GE Vivid E9 system . Routine digital grey-scale 2D cineloops were obtained from the 3 standard apical views, and optimized for strain analyses (average 52 frames/s). Quantitative analyses were performed using off-line software . Speckle-tracking LS was evaluated by tracing the endocardial and epicardial borders in 3 apical views. Then, 18 LS curves were obtained in a cardiac cycle , we usedEarly and late systolic contraction were determined from each LS curve Fig. . Early sThe early systolic positive peak (EPpeak) was defined as a positive peak appearing after QRS onset . The timDifferences in Q-LNpeaks between the apical and basal segments  were calculated in each division of the LV walls . This was done by subtracting the minimum from the maximum Q-LNpeak in three segments , apical segments, and to the mid and basal lateral (posterior) Fig. .Table 1PIn patients with LBBB, RVA pacing, and LV pacing, the site of early contraction was determined as the center of the negative strain area at the end of QRS Fig. . The sitpost-hoc test. The relationship between the Q-EPpeak and Q-LNpeak was determined using linear regression analysis. A p value < 0.05 was considered statistically significant. Intra- and inter-observer variabilities of time-to-peak LS (Q-EPpeak and Q-LN peak) were assessed in 25 randomly selected patients . Intra-observer variability was assessed by H.H. Inter-observer variability was assessed by H.I. who is blind to the QRS morphology. Variability was expressed as the absolute difference, absolute difference divided by the mean value, and the intra-class correlation coefficient (ICC).The data are presented as a mean ± standard deviation (SD). Categorical parameters were compared using chi-square analysis followed by Fisher’s exact test. Differences between QRS groups in continuous variables were evaluated using ANOVA with the Tukey–Kramer Table Compared to the patients with a Narrow-QRS, patients with LBBB or RVA pacing had a larger number of segments with ESC Table . In patip = 0.04). In the patient with LV pacing, the Q-EPpeak and Q-LNpeak were short around the lateral wall, and prolonged in the septal and anterior-septal walls . The late contraction sites in LV pacing scattered around the mid region.The distribution of early and late contraction sites was relatively similar for LBBB and RVA pacing Fig. . HoweverThe contraction sequence of the entire LV has been investigated using tagged MRI , 16, SPEThe LV contraction process in LBBB is thought to be caused by abnormalities in LV activation , 21. BasThe LV activation sequence in RVA pacing has been reported to differ from that in LBBB , 5. UsinMiranda et al. evaluated the timing of RV activation at the time of LV pacing . ElectriThere are few reports evaluating the beginning of contraction in a segment to estimate the LV activation sequence . EchocarFirst, evaluation using the apical images in 2D echocardiography did not provide information on circumferential directions. There was a large spatial gap, especially in the basal regions, and this might have reduced the number of segments with ESC in LV pacing Table . Three-dEvaluation of the LS distribution during the systolic period and the time-to-peak strain using 2D speckle tracking echocardiography are thought to be useful for identifying the LV contraction process in patients with an asynchronous LV activation sequence. The sites of early contraction and subsequent LV contraction were visualized using bull’s eye LS distribution maps. The time-to-peak strain could be used to determine the intersegmental contraction sequence and late contraction site.


A ball valve thrombus is a common entity in rheumatic mitral stenosis where a large clot forms in the left atrial appendage, the clot detaches from the left atrial appendage, swirls in the left atrium in a clockwise manner, obstructs the mitral inflow producing cyclic acute pulmonary edema, and likely causes left ventricular outflow tract obstruction producing transient syncope or embolism to the brain producing dense hemiplegia. Besides rheumatic mitral stenosis, ball valve thrombus has been described in post-mitral valve replacement patients and restrictive cardiomyopathy. Left atrial myxoma sometimes rocks across the mitral valve producing the effect of a ball valve thrombus. Right atrial ball valve thrombus has been described after prolonged parenteral nutrition through a central line in intensive care units and in carcinoma patients with cardiac metastasis. We report an extremely rare case of a ball valve thrombus in an obese individual where dyslipidemia was the sole triggering factor for the formation of a ball valve thrombus in the left atrium. In critical mitral stenosis, due to mitral inflow obstruction, blood flow velocity across the orifice of the left atrial appendage slows down to less than 40 cm/second and blood starts to clot inside the left atrial appendage. Hence, the left atrial appendage becomes a nidus for thrombus formation in critical mitral stenosis. Sometimes a large thrombus forms inside the left atrial appendage, which detaches from the wall of the left atrial appendage, swirls inside the left atrium in a clockwise manner, and obstructs the mitral valve producing acute pulmonary edema known as a ball valve thrombus. This freely moving large clot inside the left atrium is prone to produce massive hemispheric embolization and catastrophic stroke in middle-aged and elderly individuals. Paroxysmal atrial fibrillation in these patients also makes them prone to developing thrombus inside the left atrial appendage, as during atrial fibrillation and fast ventricular rate, the left atrium behaves as a lake where the blood pool remains relatively stagnant producing a thrombus inside the atrium. The most important aspect of a ball valve thrombus is that sometimes it produces acute left ventricular outflow tract obstruction, hemodynamic collapse, and syncope before producing a hemispheric stroke. Post-cardiac surgery, especially post-mitral valve surgery, postoperative coagulopathy besides mechanical mitral valve in position also predisposes to the formation of a ball valve thrombus in the left atrium . The hug2. All serum chemistries were within normal limits except for dyslipidemia with a low-density lipoprotein (LDL) level of 197 mg/dL, total cholesterol of 264 mg/dL, and triglyceride (TG) of 335 mg/dL. A chest X-ray posteroanterior view revealed cephalization suggestive of passive pulmonary venous congestion. His N-terminal pro-brain natriuretic peptide level was 366 ng/mL suggestive of acute heart failure. Bedside echocardiography was done to evaluate the cause of dyspnea which revealed a freely mobile thrombus of 15 mm × 15 mm  was the provoking factor for the formation of a large clot inside the left atrium. Besides rheumatic mitral stenosis, degenerative calcific mitral valve disease, restrictive cardiomyopathy, and post-cardiac surgery hypercoagulable state with a prosthetic mitral valve in situ, isolated obesity with dyslipidemia can also be a predisposing factor for the formation of a ball valve thrombus in the left atrium. Early recognition of such ball valve thrombi with adequate systemic heparinization with anticoagulation can save young patients from a catastrophic large embolic hemispheric stroke.


Pectus excavatum (PE), a congenital deformity of the chest wall, can lead to cardiac compression and related symptoms. PE surgical repair can improve cardiac function. Intraoperative transesophageal echocardiography (TEE) has been successfully employed to assess intraoperative hemodynamic variations in patients undergoing PE repair. FloTrac/Vigileo™ system  (FT/V) is a minimally invasive cardiac output monitoring system. This retrospective study aimed to assess hemodynamic changes in surgical repair of PE using FT/V and concordance with parameters measured by TEE.N=19 patients submitted to PE repair via Ravitch or Nuss technique were enrolled. Intraoperative cardiac assessments simultaneously obtained via TEE and FT/V system were investigated. The agreement between TEE-derived cardiac output (CO-TEE) and FT/V system parameter (COAP) was evaluated. The relationship between COTEE and COAP was analyzed for all data using linear regression analysis. A significant correlation between COAP and COTEE values  was found. Bland-Altman analysis of COAP and COTEE showed a bias of 0.13 L/min and a limit of agreement of − 2.33 to 2.58 L/min, with a percentage error of 48%. Intraoperative measurements by TEE and FT/V both showed a significant increase in CO after surgical correction of PE (p < 0.005).FT/V system compared to TEE in hemodynamic monitoring during PE surgery yielded clinically unacceptable results due to a high percentage error. After surgical correction of PE, CO, measured by TEE and FT/V, significantly improved. Pectus excavatum (PE) is a congenital abnormality characterized by a depression of the anterior chest wall as a result of dorsal deviation of the sternum and of the third to seventh rib or costal cartilage. Pectus excavatum affects approximately 1 in 400 children. Males are afflicted approximately four times more often than females , also caThe cardiopulmonary consequences of these deformities have been widely debated. Specifically, PE is characterized by a reduction of the sterno-vertebral distance and a leftward displacement and rotation of the heart with compression of the right chambers, thus resulting in limitation of diastolic filling and stroke volume , 6. PatiIntraoperative transesophageal echocardiography (TEE) has been successfully employed to assess cardiac function improvements in patients undergoing PE repair –15. TEE FloTrac/Vigileo™ system  (FT/V) is a minimally invasive cardiac output monitoring system useful in a wide variety of medical situations and allows continuous assessment of cardiac output (CO), stroke volume (SV), and stroke volume variation (SVV). At present, no data regarding the use of intraoperative monitoring via fourth-generation FloTrac/Vigileo™ system (FT/V) to assess hemodynamic changes in surgical repair of PE have been reported.The first aim of this study was to compare intraoperative cardiac output (CO) measurements acquired using the FT/V system by arterial pressure waveform (COAP) and CO measured by transesophageal echocardiography (COTEE) during PE surgery repair. Secondary aims were measurements and assessment of CO changes resulting from the surgical repair.This retrospective study, was approved by the Bioethics Committee of Sapienza University of Rome (no. 6181_2020). All patients submitted to PE repair via modified Ravitch or Nuss technique from January to October 2020 were included in the study. Demographic data, medical history, comorbidities, Haller Index (derived from dividing the transverse diameter of the chest by the anterior-posterior diameter on a simple computerized tomography scan) , operatiAs a standard in this institution, patients received an intraoperative cardiac assessment simultaneously with TEE and minimally invasive monitoring via the FT/V system. Written informed consent was obtained from the patients.χ.” This factor corresponds to the vascular tone and is calculated through a multivariate polynomial function including pulse rate, body surface area, aortic compliance, mean arterial pressure, skewness, and kurtosis of the arterial pressure. CO was recorded by FT/V before and after PE surgical correction.Before anesthesia induction, a 20-G cannula was inserted into the radial artery and then connected to the FloTrac pressure transducer that preprocesses and sends a signal to both the cardiovascular monitor  and to the Vigileo monitor. The FT/V algorithm of hemodynamic calculation has been described in detail . This syThe transesophageal probe was inserted after tracheal intubation and the cardiac examination was conducted by an expert operator with an Esaote TM MyLabTM 30 GOLD—CardioVascular  before and after surgical correction of the deformity. The preoperative and postoperative TEE measurements were made in apnea by disconnecting the patient from the ventilator. TEE parameters were analyzed and recorded before and after PE surgical correction: right ventricular outflow tract distal diameter (RVOT), left ventricular outflow tract diameter (LVOT), velocity-time integral (VTI) of left ventricular outflow tract systolic flow. All measurements were made according to the recommendations for echocardiographic quantification published by the American Society of Echocardiography :RVOT: This parameter was measured in midesophageal right ventricular inflow outflow view, transducer angle 20° to 70°. The RVOT diameter was measured 0.5 to 1.0 cm under pulmonary valve at end-diastole and end-systole.LVOT: This parameter was measured in midesophageal left ventricular outflow tract view, transducer angle 120° to 140°, as the diameter of the left ventricular outflow tract 0.5-1 cm under aortic valve in systole.LVOT VTI: Pulsed Doppler TEE was performed using a deep trans-gastric approach in order to obtain a deep long-axis view of the left ventricle and placing the sample volume just under the aortic valve, taking care to obtain a smooth Doppler profile, calculating the velocity time integral of the Doppler signal directed across LVOT.The LVOT area was calculated from the diameter assuming a circular geometry. LVOT VTI was used to estimate SV as it corresponds to the column of blood that moves through the LV outflow tract during each systole. Cardiac output was calculated from the left ventricular outflow tract area, the velocity-time integral of the blood flow profile, and heart rate.Stroke Volume (SV) = LVOT VTI × cross-sectional area of the left ventricular outflow tractCO: SV multiplied by heart rate.t test for paired observation was used to compare the measured values in each patient before and after the surgical correction. P values < 0.05 were considered significant. Data were analyzed using the SPSS v25.0 software .All results were expressed as means ± SD. The relationship between COTEE and COAP was analyzed for all data using linear regression analysis. The agreement between COTEE and COAP values was assessed by Bland-Altman analysis . Bias (mNineteen patients (4 women and 15 men) were included in the study. 38 acceptable pairs of measurements of cardiac output were analyzed: a pre-correction and a post-repair measurement for each patient obtained via TEE and FT/V. Preoperative reported electrocardiography alterations were: right bundle branch block in four patients, incomplete right bundle branch block in five patients, right atrial enlargement in one patient, left axis deviation in one patient, right axis deviation in three patients, left posterior fascicular block in two patients and left ventricular hypertrophy in one patient. No patient was affected by valvular disease. Patients received a moderate intravenous fluid administration (5–6 mL/kg/h), and no significant variations in fluid balance were reported.The demographic data are represented in Table R = 0.65, p < 0.001). The Bland-Altman plot displays the limits of agreement between COTEE and COAP  –23. HowePulse contour devices showed to be less dependable compared to Doppler-derived CO because they miss compensating for circulatory modifications in peripheral resistance. FT/V showed greater bias in both low and high systemic vascular resistance (SVR) states compared to thermodilution . DespiteThe estimations made with FT/V showed a considerable bias and a wide range of levels of agreement compared to PAC –28. FormWhen repeated hemodynamic variations occur, like during surgery for PE repair, the k value may be delineated at a time in which vascular peripheral resistance, arterial compliance, or impedance may not be the same as the moment of estimation . The resAlthough FT/V has failed to show that it is comparable to TEE for cardiac monitoring during surgical repair of PE, this tool can be helpful for intraoperative management. The use of this minimally invasive system can allow even less experienced personnel to monitor cardiac changes during PE surgical correction. It was also shown that hemodynamic measures vary significantly and almost instantaneously following surgical decompression, and the FT/V system has the advantage to allow continuous monitoring of these parameters. During PE surgery, major complications can occur. They include bleeding due to possible perforation of the heart and large vessels, bleeding of the chest wall, right ventricular compression, hypotension, and arrhythmias, which can be promptly identified and treated thanks to the aid of continuous hemodynamic monitoring .This study has some limitations. Although thermodilution was not used as a gold standard reference because it would require a PAC, which would represent an additional unjustifiable risk in these patients, CO measured by TEE was previously reported as clinically acceptable and is a well-validated tool in reporting hemodynamic changes in PE repair surgery . In addiIn conclusion, the FT/V system compared to TEE in hemodynamic monitoring during PE surgery was not clinically acceptable due to a high percentage error. Nevertheless, FT/V was able to monitor and detect an intraoperative increase of hemodynamic parameters after correction.


Our aim was to evaluate the short- and medium-term electrocardiographic changes after percutaneous ASD closure with GCO in a pediatric population. Methods: We enrolled 39 patients with isolated ASD submitted to trans-catheter closure from January 2020 to June 2021. ECG was performed before, at 24 h and 6 months after the procedure. P wave dispersion, QTc and QTc dispersion were calculated. ECG Holter was recorded at 6 months after implantation. Results: Patients’ age and body surface area (BSA) were 8.2 ± 4.2 years and 1.0 ± 0.3 m2 respectively. At the baseline, mean P wave dispersion was 40 ± 15 msec and decreased at 24 h (p < 0.002), without any further change at 6 months. At 24 h, PR conduction and QTc dispersion significantly improved (p = 0.018 and p < 0.02 respectively), while the absolute QTc value considerably improved after 6 months. During mid-term follow-up, QTc dispersion remained stable without a significant change in PR conduction. The baseline cardiac frequency was 88.6 ± 12.6 bpm, followed by a slight reduction at 24 h, with a further amelioration at 6 months after the procedure . After device deployment, two patients developed transient, self-limited junctional rhythm. One of them needed a short course of Flecainide for atrial ectopic tachycardia. No tachy/brady-arrhythmias were recorded at the 6-month follow-up. ASD closure resulted in a marked decrease in right heart volumes and diameters at 6 months after percutaneous closure. Conclusions: Percutaneous ASD closure with the GCO device results in significant, sudden improvement of intra-atrial, atrio-ventricular and intraventricular electrical homogeneity. This benefit persists unaltered over a medium-term follow-up. These electrical changes are associated with a documented positive right heart volumetric remodeling at mid-term follow-up.Background and aim: The GORE Ostium secundum atrial septal defect (ASD) is a common congenital heart defect, found in about 1/1000 live births and leads to right chamber volume overload, pulmonary hypertension, systemic embolism, atrial arrhythmias and premature death over a long-term follow-up ,3,4. AtrIn addition, also in other congenital and acquired heart diseases, P wave and QTc dispersion are well-known predictors of arrhythmias and are often considered as prognostic factors of morbidity and mortality.The arrhythmic predictive role of P wave anomalies, that is, P wave duration and its dispersion on a 12-lead ECG, has also been discussed as the crucial determinant in a variety of clinical conditions, especially in paroxysmal atrial fibrillation (PAF) in healthy hearts. ,9. The pAs the P wave conduction time is correlated to atrial arrhythmias, the prolongation of QTc dispersion is connected to the differences in recovery times in the various regional segments of the ventricular myocardium.This correspondence is well associated with the increased risk of ventricular arrhythmias and sudden cardiac death for patients with coronary artery disease, chronic heart failure, diabetes mellitus or PAH ,11,12.The QT dispersion is also an indicator of electrical remodeling after ASD percutaneous closure, which is then linked to positive ventricular geometric change, and consequently, fewer arrhythmic complications ,14.Thus, decrease in P wave and QTc dispersion is supposed to assume a protective role in the development of atrial and/or ventricular arrhythmias ,15,16,17® Cardioform ASD Occluder device  (GCO) has been recently claimed as a significant technical innovation in transcatheter ASD treatment since it combines high softness and anatomic compliance with the potential to close large defects, even in challenging settings [The new GOREsettings ,19,20. TThis multi-center study aims for the first time to investigate the electrocardiographic changes after implantation of this novel device in pediatric and young adult patients.This was a prospective single-arm study performed at the Pediatric Cardiology and GUCH Unit of the Heart Hospital “G. Pasquinucci” of Massa and the Pediatric Cardiology Unit of the University of Padua. The study was approved by our institutional review board, and informed consent was obtained from all patients involved in the study or their parents/guardians. We enrolled pediatric patients (age 5–18 years) with isolated, hemodynamically significant ASD submitted for percutaneous closure between January 2020 and June 2020. The following patients were excluded from the study: (i) patients with sinus venosus or primum type ASD, (ii) patients with inadequate rims, (iii) patients with significant cardiac/extra-cardiac comorbidities. A 12-lead surface ECG was recorded the day before the interventional catheterization, and at 24 h and 6 months after the procedure. In addition, we performed ECG-Holter monitoring at 1 and 6 months after device implantation in order to detect both cardiac rhythm changes and possible brady-or tachyarrhythmias.Patients’ baseline characteristics, clinical history and medication were collected from medical records.The interventional procedure was performed under general anesthesia by fluoroscopic with trans-esophageal echocardiographic (TEE) guidance. ASD size was assessed by static or dynamic sizing, based on the interventional cardiologist preference. Static sizing was performed by using the Amplatzer Sizing Balloon , which was inflated up to disappearance of the atrial shunt on TEE evaluation (“stop-flow” diameter). Dynamic sizing was accomplished by the pulling technique (“stretched” diameter) using an off-label sizing balloon . Afterwards, the size of the GORE Cardioform ASD occluder device was chosen based on the company indications ,22,23. TECG analysis was blind on the status of the patients and manually performed by one experienced physician. A standard 12-lead electrocardiogram (ECG) was recorded at a rate of 25 mm/s and a calibration of 1 mV/cm for all the patients at the baseline and during follow-up. The P wave, PR interval, QRS amplitude, and QRS and QT dispersion were measured as follows in the C2 or V5 lead:P wave: defined as the interval between the onset (junction of the isoelectric line at the beginning of the P wave deflection) to the offset (junction between the end of the P wave and the isoelectric line) of the P wave.P wave dispersion (P dis = P max − P min) was calculated using these values.PR interval: defined as the interval between the beginning of the P wave and the beginning of the QRS complex.QRS voltage: defined as the amplitude measured from the nadir of the QRS complex to its peak.QRS duration: defined as the maximum QRS duration in any lead from the first to the last sharp vector crossing the isoelectric line.QT interval: defined as the interval between the beginning of the QRS complex and the end of the T wave. QT dispersion was defined as the difference between the maximum and the minimum of the QT intervals. The method for the corrected QT (QTc) interval measurement was performed by using the Bazett’s equation in any of the 12 ECG leads, but preferably in the C2 or V5 lead.We performed echocardiographic studies before and 6 months after the percutaneous procedure. We investigated both atrial and ventricular volumes, right and left ventricular diameters, their wall thickness and their function according to the Transthoracic Echocardiography Guidelines ACC/AHA/ASE 2019 .t-test correlation was used to evaluate the relationships between continuous variables.Statistical analysis was performed using SPSS for Windows v. 27 . Continuous variables were expressed as either mean ± SD or interquartile ranges when appropriate. The normal distribution was verified by using the Kolmogorov–Smirnov test. Categorical variables were presented as either absolute number or percentages. Post hoc analysis was performed with the Least Significant Difference (LSD) test. Student’s The inter-operator and intra-operator variability and the Intra-Class Correlation Coefficient (ICC) were used to evaluate the intra- and inter-observer correlation.p value < 0.05.Statistical significance was defined as 2 , respectively. The stretched ASD diameter was 16.3 ± 4.5 mm (median 16), resulting in QP/QS of 1.7 ± 0.6 (median 1.5) (p = 0.9), with a further significant decrease at 6 months  (p < 0.002) at 24 h from the procedure, without any further change at 6 months  (p = 0.018) and did not significantly change at 6 months  (p = 0.5), but significantly improved at 6 months from the procedure  (p < 0.02) and at 6 months  from the procedure  and 1.0 ± 0.3 mian 1.5) . The GCO= 0,009) . The bas< 0.002) , Table 2 = 0.03) , Table 2rocedure , Table 2p < 0.0001) at 6 months after percutaneous closure associated with a contemporary increase in left atrial volume  and left ventricular diameter . The right ventricular size reduced after six months  and its longitudinal systolic function normalized as well (24.4 ± 4.4 to 22.5 ± 4.5).According to the echocardiographic parameters, ASD closure resulted in a marked right atrial volume decrease . ICCs were between 0.73 and 0.88 about the inter-observer reproducibility.Supra-ventricular arrhythmias affect about 25% of ASD patients of adult age ,25.Over time, several ECG parameters have been proposed as markers of atrial and ventricular electrical vulnerability in ASD patients. Specifically, an increase in P wave dispersion has been correlated to an intra-atrial conduction delay and is potentially predictive of succeeding atrial arrhythmias ,27. The A greater dispersion of the QTc is an important electrophysiological marker that is directly related to greater susceptibility to ventricular arrhythmias and, no less, to sudden cardiac death in cases of several comorbidities ,26,27,28We know from the literature that the RV volume overload may also affect the QTc interval prolongation/dispersion in ASD patients ,30. HoweAccordingly, the change in P wave and QTc dispersion could be an important marker for arrhythmic events, strictly correlated to the potential atrial and ventricular electrical post-procedural remodeling.Despite percutaneous ASD closure having fewer arrhythmic complications in the long-term follow-up compared with surgery , previouHowever, there are scant and conflicting data regarding the short-term atrial electrical remodeling after percutaneous closure of ASD in the pediatric population. Ozylimaz et al.  did not ® Cardioform Occluder device were recently confirmed by the post-marketing results [The efficacy and safety profile of the GORE results ,22,23. R results .This current study demonstrated for the first time a statistically significant reduction in the P wave and QTc dispersion already at 24 h after ASD closure with the GCO device. These favorable changes remained stable during a mid-term follow-up. This improvement of the electrical intracardiac “milieu” could significantly reduce the arrhythmic risk of these patients and potentially prevent the arrhythmic burden recorded early after device implantation ,36,37,38This is the first time ever that a temporal correlation between the electrical and mechanical remodeling has been described in percutaneous ASD closure with GCO device. This result has been also confirmed unaltered during the mid-term follow-up.In addition, we demonstrated that there is not a statistically significant correlation between the size of the ASD, the size of the device and the BSA of patients with P wave dispersion.Finally, the trend of heart rate (HR) showed a significant decrease of the mean HR at 6 months after procedure. We could speculate that this parameter is related to the positive hemodynamic remodeling, without forgetting that external factors (such as childhood irritability) may falsify the absolute value at the moment of registration. In any case, these HR variabilities do not affect the trend of P wave and QTc dispersion, thanks to the application of Bazett’s equation and consequently the nullification of dependence on the cardiac frequency. We could therefore consider the latter parameter as an independent variable.In our series, only one of the patients showed arrhythmias of intracardiac conduction abnormalities during a mid-term follow-up. One patient showed a burst of focal atrial tachycardia early after device implantation that was effectively treated with a short course of Flecainide.This complication could have been due to both the large size of the device and the shortness of the surrounding rims.® Cardioform ASD Occluder in children results in significant, sudden improvement of intra-atrial, atrio-ventricular and intra-ventricular electrical homogeneity These favorable electrical changes persist unaltered over a mid-term follow-up, associated with a documented positive heart volumetric remodeling not hindered by the mechanical impact of the occluding device, and could explain the low rate of cardiac arrhythmias found at the mid-term ambulatory ECG evaluation in this series.Percutaneous closure of hemodynamically significant ASDs with the GOREThese post-procedural electrocardiographic results could therefore be considered as potential positive predictors of good electrical outcome even in the possible long-term follow-up. However, further studies are necessary to confirm potential advantages of this novel, softer device in decreasing the electrical risk of percutaneous ASD closure.This study, aimed to evaluate the short- and mid-term electrical remodeling after ASD closure with this novel device in pediatric patients, has several limitations. Firstly, the sample size is very small, precluding any generalization of these results. However, the clinical and hemodynamic characteristics of these patients were very homogeneous. Indeed, all patients showed large, hemodynamically significant ASD that, in most cases, made them potential candidates for surgical repair. Secondly, no comparison with other commercially available devices, in particular, the most frequently used Amplatzer device, was performed. However, almost all of the scant data reported in the literature were obtained from patients treated with this device, making this comparison unnecessary and redundant, in our view. Although the inter-observer variability was acceptable, manual measurements of ECG parameters remain difficult at 25 mm/s paper speed. Therefore, this setting parameter could represent another study limitation. Further studies are necessary to confirm if increased paper speed or automated interpretation could improve the reliability of data.


Calcimimetic therapy with etelcalcetide (ETEL) has been shown to attenuate the advancement of left ventricular (LV) hypertrophy in hemodialysis patients measured by cardiac magnetic resonance (CMR). The aim of the study was to evaluate whether this effect is accompanied by alterations in LV function and myocardial composition.This was a post-hoc analysis of a randomized-controlled trial of ETEL versus Alfacalcidol (ALFA) in 62 hemodialysis patients. LV function was assessed using LV ejection fraction (LVEF) and LV global longitudinal strain (GLS) on feature-tracking (FT) CMR. Myocardial tissue characteristics were analyzed using parametric T1 and T2 mapping.Of the total study cohort (n = 62), 48 subjects completed both CMR scans with sufficient quality for FT analysis. In the one-year follow-up, LV GLS deteriorated in the ALFA group, whereas the ETEL group remained stable . We did not observe a difference in the change of LVEF between the two groups (p = 0.513). The impact of ETEL treatment on LV GLS over time remained significant after additional adjustment for the change in LV mass during the study period. ETEL treatment did not significantly affect other CMR parameters. There were no changes in myocardial composition between treatment groups .In patients undergoing hemodialysis, treatment with ETEL was protective against deterioration of LV longitudinal function, as evaluated through FT CMR, when compared to the control therapy of ALFA. This effect was not mediated by the change in LV mass.Trial registration URL: https://clinicaltrials.gov/ct2/show/NCT03182699. Unique identifier: NCT03182699.The online version contains supplementary material available at 10.1186/s12968-023-00975-4. Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular morbidity and mortality , 2. It rWe previously demonstrated, in a randomized controlled trial of hemodialysis patients with secondary hyperparathyroidism that treatment with the calcimimetic etelcalcetide (ETEL) could inhibit the progression of LV mass index compared to active vitamin D therapy with alfacalcidol (ALFA) and that this was associated with the drug-induced suppression of fibroblast growth factor 23 (FGF23) . DecliniCurrently, there is little data available regarding the impact of calcimimetics on cardiac function and fibrosis in humans , 16. In Based on our previous findings indicating the inhibition of LV hypertrophy (LVH) progression with ETEL, we have developed the hypothesis that this intervention may also lead to alterations in LV function and fibrosis.Cardiac magnetic resonance (CMR) was used to measure cardiac function, including GLS through feature-tracking (FT), as well as to examine myocardial tissue characteristics using parametric mapping techniques –20.This randomized, controlled, single-blinded study ETECAR-HD  involved a cohort of 62 patients undergoing maintenance hemodialysis who had secondary hyperparathyroidism (i.e. PTH levels ≥ 300 ng/l) and pre-existing LVH, defined as a septum thickness of a minimum of 12mm in the screening echocardiography . PatientEnrollment for the trial was conducted at two dialysis centers located in Vienna, Austria. Participants were deemed eligible only if they exhibited stable volume status.Further information regarding the study design, as well as the entire list of inclusion and exclusion criteria, have been previously reported , 24. AppPatients were randomized to receive either intravenous ETEL or ALFA medication for a period of one year. The treatment initiation involved a dosage of 5 mg or 1μg three times per week after hemodialysis, which was adjusted every four weeks to achieve a target PTH-value of 100-300ng/l while considering of calcium and phosphate levels (2.08–2.55 mmol/l and ≤ 2.5 mmol/l respectively). To avoid confounding of the treatment effect by volume overload, body composition monitoring was conducted. It was performed during the screening phase, followed by regular measurements every two months throughout the duration of the trial . In caseThe objective of this analysis was to investigate whether the use of ETL compared to ALFA medication was linked to alterations in systolic dysfunction and cardiac fibrosis, in addition to the previously reported effect on the progression of LVH .All CMR examinations were performed on a mid-week non-dialysis day, using a 1.5 Tesla scanner  at baseline and after one year of treatment. For evaluation of cardiac mass, steady-state free precession imaging was acquired in two-, three-, and four-chamber views and short axis slices. Short axis was covered by eleven slices (slice thickness: 0.6.0 mm) with a distance factor of 58%. Repetition time (TR) was 52.2 ms and echo time (TE) was 1.21 ms.T1-mapping was performed using an electrocardiographically triggered modified Look Locker inversion recovery (MOLLI) sequence based on a 53 prototyFor T2 -mapping a T2 prepared sequence with balanced steady-state free precession readout was used  . T2 mappTo quantify LV function and mass, feature tracking, as well as mapping parameters commercially available cardiac postprocessing software was used . LV mass index was obtained by normalizing LV mass to body surface area . T1 and Feature tracking parameters were analysed using standard two-, three-, and four chamber cine views for global longitudinal strain and atrial strain parameters, as well as short axis cine for global radial and global circumferential strain parameters. For the assessment of global longitudinal strain (GLS) and global circumferential strain (GCS), long axis and short axis cine SSFP were analysed using a feature-tracking software . Long axis cine images in standard standard two-, three, and four chamber view as well as short axis slices were semiautomatically contoured at the endocardium in systole and diastole and were afterwards manually corrected before data extraction see Fig. . The lon®, measurement in real time, coefficient of variation = 3.7%). Intact FGF23 levels were measured using a chemiluminescent immunoassay . These measurements were conducted at nine different timepoints throughout the trial.Laboratory measurements were performed from blood samples collected at the beginning of dialysis sessions by the central laboratory of the Medical University of Vienna. N-terminal pro-brain natriuretic peptide (NT pro BNP) levels were assessed using an electro-chemiluminescent immunoassay  and multivariate linear regression models. In addition to the crude analysis, we adjusted the model for baseline LV GLS, male sex, LV mass change, and—in an exploratory step—FGF23 change.marginsplot command in Stata.Visual assessment of longitudinal data, stratified by treatment group, were displayed using the We used Stata 15.1  for all analyses and set the level of significance to an alpha of 0.05 unless stated otherwise.A total of 62 patients were recruited for the study and randomly assigned to receive either ETEL (n = 32) or ALFA (n = 30) therapy. Ten patients, five in each group, discontinued their participation in the trial. Reasons for drop-out were renal transplantation or discontinuation of hemodialysis due to renal recovery (n = 7); and death (n = 3). Patients who underwent renal transplantation during the trial were scheduled for a second CMR once they reached a clinically stable condition, which was after 1.8 months on average (between one to four months) after surgery.No study medication was administered during this period. These patients received treatment for a duration of an average of 6.3 months (between three to nine months) prior to undergoing renal transplantation. The patient who discontinued hemodialysis was under study medication for 3.5 months before dropping out. He underwent his second CMR one year after his first and therefore did not receive study medication for 8.5 months. Due to the fact that patients who dropped out of the study but still underwent both baseline and follow-up CMR imaging had received study medication for approximately half of the originally planned study duration, and considering the average time gap between dropping out and the second CMR, the decision was made to use the per-protocol dataset. Out of the initial 62 patients, the remaining 52 individuals received the study medication for the entire duration of 12 months and underwent the second CMR immediately upon completion of the treatment.Four patients were excluded due to insufficient imaging quality for accurate strain assessment. Among the excluded patients, three individuals experienced artifacts caused by arrhythmia  while the fourth patient exhibited breathing motion artifacts on short axis images. Consequently, the cohort for the study consisted of 48 patients, Fig. Patient characteristics at baseline are reported in Table Figure At the initial CMR, patients presented with preserved LVEF 51 ± 9%) and longitudinal function as measured by LV GLS (− 21 ± 5%; see Fig.  ± 9% andThe change in each CMR parameter is listed in Table We observed no differences in other conventional or advanced CMR parameters Table . The adjIn an exploratory step, we found that drug treatment remained significantly associated with a mean change in LV GLS when adjusted for LV mass index change and an FGF23 change (Table T2 relaxation times increased as a function of dialysis duration in both treatment groups (Additional file In this trial, we demonstrated that ETEL, in comparison to ALFA treatment, prevented the decline of LV longitudinal function, as evaluated using FT-CMR, in hemodialysis patients over a one-year period. Our findings revealed no difference in myocardial tissue characteristics, as observed through T1- and T2-mapping, between the treatment groups.There was no significant difference in LVEF between the groups at one-year follow up. Despite the high prevalence of cardiovascular events and progressive symptoms of HF, the majority of patients with CKD exhibit preserved EF –32. AlthIt is worth noting that our patients initially presented with mean LV GLS and EF values that fell within the normal range , 41. PatThe translation of the observed prevention of LV longitudinal function decline into clinical outcomes remains uncertain. The EVOLVE study, the largest trial investigating the impact of calcimimetic treatment in hemodialysis patients, did not demonstrate a significant difference in the primary composite outcome of time until death or the occurrence of the first nonfatal cardiovascular event . The intAlthough previous studies have demonstrated a correlation between impaired LV GLS and elevated plasma levels of NT-proBNP, our study observed a similar increase in both treatment groups . This fiIndividuals with kidney disease exhibit a notable presence of interstitial myocardial fibrosis, which intensifies with the duration of dialysis treatment. This fibrosis is associated with cardiac hypertrophy, resulting in ventricular stiffness and subsequent impairment of both systolic and diastolic function. Additionally, it contributes to a heightened risk of arrhythmias , 52. In One significant limitation of this trial was the small sample size, which was initially determined to detect an effect of the study medication on a different parameter, specifically LV mass. Additional limitations of this study include the relatively short duration of follow-up, which may not capture long-term changes in myocardial remodeling that develop over the course of years, as well as the absence of data on hard cardiovascular outcomes. In line with the EVOLVE study protocol, patients with significantly impaired LV systolic function were excluded from the trial, which represents an additional limitation in this analysis . MoreoveOne of the major strengths of our trial was its prospective design with randomization, ensuring a robust and reliable study methodology. As described in our previous publication, thorough assessments of blood pressure and fluid volume status were conducted to minimize potential confounding factors related to volume and pressure overload on myocardial remodeling and function . AlthougIn summary, our findings indicate a trend towards the preservation of LV longitudinal function with ETEL medication compared to ALFA in hemodialysis patients, although no significant difference was observed in LVEF. These findings suggest that LV GLS may be a more sensitive parameter for the diagnosis of LV dysfunction and for monitoring treatment in this patient population, providing additional support for its potential clinical utility. Given that this analysis was a secondary investigation, the hypothesis regarding LV longitudinal function necessitates further validation in a larger cohort.Additional file 1: Table S1. Association between length of dialysis and baseline CMR parameters. Table S2. Mean change of advanced CMR parameters during study period. Intention-to-treat dataset with follow-up CMR. Figure S1. T2-mapping.


Editorial on the Research TopicCardiac outflow tract development and diseasesConotruncal anomalies are the group of congenital heart defects involving malformations of the outflow tract (conus arteriosus) and the great vessels (truncus arteriosus) that have abnormal ventriculo-arterial relationships. Conotruncal (or outflow tract) defects are among the most common congenital heart diseases found at birth, and are the leading cause of mortality and morbidity in the first year of life. Tetralogy of Fallot (ToF), transposition of the great arteries (TGA), double outlet right ventricle (DORV), truncus arteriosus (TA), interrupted aortic arch (IAA) and anatomically corrected transpositions are some of the most common conotruncal anomalies.A detailed understanding of the embryogenesis is key to understand the conotruncal anomalies. The role of neural crest and second heart field derivatives has been established during outflow tract development. Thus, defective neural crest or second heart field deployment results in a spectrum of conotruncal anomalies ranging from outflow tract alignment to septation defects .This research topic focuses on recent advances in understanding the pathogenesis, diagnosis, treatment, and outcome of the most common conotruncal malformations. This collection includes four original articles that provide a global and detailed overview of some of the key concepts and recent advances related to these entities. The authors of the collection provide an in-depth review of some of the most important malformations included in this group of defects.Bell-cheddar et al. have prepared an interesting review of DORV providing a general overview including history, description of key morphologic features and anatomical classifications and, a thorough description of the different surgical options. In their review, the authors highlight the importance of a meticulous morphologic assessment prior to deciding the best-suited surgical technique. Particularly important are those anatomical features related to ventricular alignment, ventricular size and coronary anatomy. A detailed list of the most commonly expected surgical complications as well as a practical approach on pre- and post-surgical management is also provided. Overall, Bell-cheddar et al. have done a beautiful job addressing a complex group of CHD in a very organized and practical approach. Moreover, the excellent iconography supporting this manuscript will help readers to engage and better understand the anatomical classifications and different surgical options.DORV was first described in the mid-sixties. This term does not encompass a single congenital heart defect but rather a wide range of phenotypes , 3. Due Harvey et al. extend this knowledge by investigating possible mutations in genes related to myocyte contraction and ventricular septum development in non-syndromic ToF patients. Using one of the largest series of patients who have undergone exome analysis to study de novo variants, their analysis revealed a significant enrichment of variants in pathways involved in aortic and ventricular development, including a specific enrichment in patients with ToF. They also show the importance of chromatin remodeling genes in cardiac development and report overlap with genes involved in autism spectrum disorders and neurodevelopmental disorders.ToF is the most common cyanotic congenital heart disease . As withOne of the emerging fields in pediatric cardiology is prenatal diagnosis. The identification of cardiac malformations during fetal life has led to an improved survival and perinatal management, as well as increased knowledge and acceptance of the condition by families.Gomez et al. addresses the role of some cord blood biomarkers in two of the main conotruncal entities, D-TGA and ToF, studying their correlation with fetal echocardiography and perinatal outcome. The authors reported increased levels of transforming growth factor β1  is a common form of left ventricular outflow tract obstruction that can lead to aortic valve damage. It has a broad spectrum of disease, ranging from a small fibrous ridge on the sub-valvular ventricular septum to a narrow fibromuscular tunnel . The maiIn their cohort, survival rates were 90.8% at 10 years and 88.7% at 20 and 30 years. Main risk factors for mortality were age less than 1 year at the time of surgery, pre-existing Shone's complex condition, mitral stenosis and concomitant surgery on the mitral valve.The incidence of reoperation for SAS was 21.6% at 10 years and 28.2% at later stages.No difference in reoperation was detected regarding the surgical approach. The authors conclude that while most patients have a favorable long-term outcome, the recurrence rate of SAS after surgical repair is not negligible.In conclusion, the manuscripts included in this collection will certainly help to better understanding the conotruncal anomalies, a complex group of CHD with a wide spectrum of morphological types as well as clinical presentations. Early identifications of critical morphological features and the use of new prognostic tools might play an important role in overall postnatal management. Moreover, expanding our current knowledge on genetics and whole exome sequence might provide new insights in the diagnosis and parental counseling. Finally, innovation and development of new surgical approaches and minimally invasive techniques tailored to specific diseases will help to path the way of this complex group of heart anomalies.


At our institution, we occasionally see pregnant patients in the later stages of pregnancy who present with severe pulmonary arterial hypertension caused by congenital heart disease. The physiological changes in pregnancy may worsen the cardiovascular status leading to heart failure which is associated with a high incidence of morbidity and mortality. A scheduled caesarean section in such patients ensures delivery in a controlled environment, avoiding prolonged labour, which is detrimental. Perioperative complications that may worsen pulmonary arterial hypertension should be prevented. The perioperative management, in particular, the anaesthesia technique used and the clinical outcome of this population, is discussed through five interesting cases. Despite a multidisciplinary team and intensive care management, two patients with existing cor pulmonale, one of whom received general and the other central neural blockade anaesthesia, succumbed to their illness immediately after lower segment caesarean section. The management of severe pulmonary arterial hypertension in pregnant patients remains a multidisciplinary challenge among participating physicians. Thorough perioperative preparation encompassing monitoring, medical therapy, timing and mode of delivery, and risk consultation is vital in avoiding circumstances that could exacerbate pulmonary arterial hypertension, with physicians readily equipped to promptly detect and manage any untoward event. Pulmonary arterial hypertension (PAH) is defined as mean pulmonary artery pressure (mPAP) greater than 25 mmHg, with pulmonary capillary wedge pressure, left atrial pressure or left ventricular end-diastolic pressure, less than or equal to 15 mmHg . On manyCase 1A 34-year-old gravida 2 para 1 (G2P1) woman, who had undergone a surgical repair of the atrial septal defect (ASD) when she was a child but was not on cardiology follow-up, was referred to our centre at 36 weeks of gestation with symptoms of heart failure. Upon admission, she appeared breathless with moderate activity but was comfortable at rest, indicating New York Heart Association (NYHA) Class III. She was immediately transferred to the intensive care unit (ICU) for close observation and treatment. Transthoracic echocardiography showed severe tricuspid regurgitation (TR) with a mPAP of 40 mmHg  pulmonary hypertension includes patients with mPAP more than 20 mmHg . All fivPregnancy-related cardiovascular changes which include an increase in blood volume and cardiac output, reduction in systemic vascular resistance, physiological anaemia and hypercoagulability, may camouflage the symptoms and signs of PAH and delay the diagnosis and therapy worsening the prognosis . Venous Patients with PAH should be managed by a multidisciplinary team comprising an obstetrician, cardiologist, anaesthesiologist, intensivist, and neonatologist . RegularElective admission for treatment optimization up to delivery may be necessary . PatientThe recommendations regarding the optimum mode of delivery, anaesthesia and analgesia, the extent of heart monitoring, and peripartum management remain controversial. Regardless of the delivery mode, it is imperative that PAH needs to be well-controlled. Prolonged labour with a consequent increase in cardiac output and venous return can be detrimental . NitrousBoth regional and general anaesthesia require caution to minimize vasodilatation and exacerbation of the compromised cardiovascular status. Epidural or combined spinal epidural (CSE) anaesthesia is well tolerated ,3. Low-dIn conclusion, the management of severe pulmonary arterial hypertension (PAH) in pregnant patients remains a multidisciplinary challenge among participating physicians. Thorough perioperative preparation encompassing monitoring, medical therapy, timing and mode of delivery as well as risk consultation is vital. Perioperative management is focused on avoiding all circumstances that could exacerbate PAH, with physicians readily equipped to promptly detect and manage any untoward event.