Levosimendan improves cardiac function in heart failure populations; however, its exact mechanism is not well defined. We analysed the short-term impact of levosimendan in heart failure patients with ischemic and non-ischemic cardiomyopathy (CMP) using multiparametric cardiac magnetic resonance (CMR). We identified 33 patients with ischemic or non-ischemic CMP who received two consecutive CMR scans prior to and within one week after levosimendan administration. Changes in LV ejection fraction (LVEF) and LV volumes, as well as changes in strain rates, were measured prior to and within one week after levosimendan infusion. LV scarring, based on late gadolinium enhancement (LGE), was correlated to changes in LV size and strain rates. Both LV endiastolic (EDV) and endsystolic volumes (ESV) significantly decreased  after levosimendan administration, with no significant impact on LVEF (p=0.41), cardiac output (p=0.61), and strain rates. Subgroup analyses of ischemic or non-ischemic CMP showed no significant differences between the groups in terms of short-term LV reverse remodeling. The presence and extent of scarring in LGE did not correlate with changes in LV size and strain rates. CMR is able to monitor cardiac effects of levosimendan infusion. Short-term follow-up of a single levosimendan infusion using CMR shows a significant decrease in LV size, but no impact on LVEF or strain measurements. There was no difference between patients with ischemic or non-ischemic CMP. Quantification of LV scarring in CMR is not able to predict changes in LV size and strain rates in response to levosimendan. The inodilator levosimendan is a calcium sensitizer used in patients with acute, decompensated heart failure or in the setting of cardiac surgery for ischemic heart disease or valvular heart disease . In addiCardiac magnetic resonance (CMR) is a well-established tool for the assessment of cardiac function und structure. CMR is considered the gold standard in the assessment of ventricular function and allows for accurate scar quantification based on late gadolinium enhancement (LGE) . The preRecent advances in CMR feature tracking techniques also allow for the evaluation of myocardial deformation. The technique is based on identifying the motion of cardiac structures through the cardiac cycle. From the assessment of these movements, longitudinal and circumferential strain values can be derived that provide information about myocardial fiber function . Here, gTherefore, the aim of this analysis was to evaluate the impact of levosimendan on cardiac function, structure, and deformation, assessed CMR in a heart failure population.All patients who received levosimendan prior to planned heart surgery for valvular and/or coronary artery bypass grafting between March 2010 and February 2018 were identified via the institutional pharmacy records. This cohort was scanned for the presence of two consecutive CMR scans that were obtained during the clinical routine work-up for the evaluation of LV function, size, viability assessment and presence of scarring.Overall, 54 patients were identified who received levosimendan in the analysis period. Seven patients were excluded due to the lack of two consecutive CMR . Another five patients were excluded due to right heart failure based on pulmonary or tricuspid valve insufficiency.All patients were scanned on a 1.5T system . The CMR imaging protocol included steady state free precession (SSFP) imaging in two-, three-, and four-chamber views, using the left ventricular outflow tract and short axis for the evaluation of cardiac function . Phase contrast angiography was performed in patients with aortic insufficiency in slices perpendicular to the ascending aorta at the sinotubular junction. Typical parameters were: TR: 4.8 ms; TE: 2.8 ms; matrix: 320 × 300 mm; flip angle: 12°; temporal resolution: 25 to 55 ms; and velocity window: 2.5 to 4.0 m/s depending on the presence or absence of alaising. LGE was performed in the short axis, with two-, three-, and four-chamber views, 10 to 15 minutes after the injection of 0.15 ml gadobutrol  per kg bodyweight using T1-weighted, phase-sensitive, inversion-recovery (PSIR) sequences . A second CMR scan without LGE was conducted after the administration of levosimendan.For CMR evaluation, LV volumes and function were derived from short axis Cine SSFP, whereas scarring was determined from the LGE images. To quantify both functional and scar parameters, a commercially available post-processing software was used . LV function was derived from short axis Cine SSFP images in diastole and systole according to valid recommendations . PositivForty-two patients were included in the advanced CMR postprocessing analysis . For the assessment of global longitudinal strain (GLS) and global circumferential strain (GCS), long axis and short axis Cine SSFP were analyzed using a recently developed feature-tracking software . During the analysis, another nine patients had to be excluded due to poor image quality/motion artifacts (n=4), lack of LGE (n=1), or incompatibility of the CMR scans with the feature-tracking postprocessing software (n=4).Ultimately, 33 patients were included for analysis. Patient characteristics are listed in Table ICMP, defined by the presence of subendocardial LGE, was present in 17 patients (52%), and valvular disease was observed in 10 patients (30%). In the latter group, three patients presented with severe aortic stenosis, four patients presented with aortic insufficiency, two patients had an isolated mitral valve insufficiency, and one patient presented with a combination of an aortic stenosis and a severe mitral valve insufficiency. A combination of ICMP and valvular disease was observed in six patients . In patients with aortic insufficiency mean phase contrast derived regurgitant fraction was 42.5% .Levosimendan was administered via a 24h lasting infusion (0.1 mcg/kg/min) without the application of a starting bolus under hemodynamic monitoring in an intermittent care setting. Brain natriuretic peptide levels were assessed before and 3 days after the infusion.Three to seven (mean 3.8) days after levosimendan infusion, a second CMR without LGE was performed to evaluate changes in LV size, function, and strain. All analyses were performed by experienced CMR readers , in consensus, strictly according to the recommendations of the society of cardiac magnetic resonance . ConsecuAll statistical analyses were performed using SPSS for Windows . Baseline characteristics are displayed as mean±SD, or median (IQR), and total numbers (%), as appropriate. Normal distributed parameters of LV function, size, and strain parameters were compared using a paired T-test. Non-normally distributed parameters (NT-proBNP) were compared using the paired Wilcoxon test.We stratified patients according to the presence or absence of post-ischemic scarring on LGE, defined by the presence of a subendocardial scar and a scar volume of more than 5% of the LV mass. In this subgroup analysis, not only the absolute values of the LV parameters, but also the delta values of the parameters were compared between the groups using a univariate ANOVA. A subgroup comparison of NT-proBNP was performed using the Kruskal-Wallis test. Furthermore, the potential impact of scar volume on changes in LV function was assessed by a correlating the LV scar volume (%) to the Δ of LV functional parameters using a Pearson correlation.2 to 5.1 ± 2.3l/m2), global longitundinal strain (GLS) (−7.8 ± 4% to − 8.3 ± 4%), global circumferential strain (GCS) (−12.3 ± 5.5% to −12.4 ± 5.6%), and global radial strain (GRS) (16.7 ± 8.9 to 17.6 ± 8.8) also remained unaffected. Results are shown in Table Mean end diastolic volume (EDV), and mean end systolic volumes (ESV) significantly decreased after levosimendan infusion  .Twenty-three patients presented with subendocardial scars (ICMP), and/or a combination of ICMP and valvular disease. Ten patients showed LV dilatation based on valvular disease only, but without any post-ischemic, subendocardial scar. Results of a group comparison of these two patient cohorts is shown in Table Table In this retrospective analysis using multiparametric CMR, we were able to monitor the response to levosimendan infusion in patients with systolic heart failure. In the study cohort, a single dose of levosimendan resulted in significant reduction in LV size, shown by a significant decrease in LVEDV and LVESV Fig . This reLevosimendan for the treatment of acute heart failure has been shown to be safe and efficient compared to placebo and dobutamine , 18. HowIn our cohort, using CMR, treatment response to levosimendan resulted in a significant decrease in LV size after a single infusion over 24 hours. This resulted in only a non-significant change in LV EF. These findings with CMR in our cohort differ from data reported from echocardiograms or studies using pulmonary catheterization , 22, 23.CMR, including LGE for quantification of scar load, has not been applied to response assessment or response prediction after levosimendan administration. In the literature, mostly invasive monitoring using pulmonary artery catheterization or echocardiography has been reported , 20. In The assessment of left ventricular strain parameters and changes in these parameters appear to be valuable predictors of treatment response in various cardiac diseases . The metIn DCM, imaging studies on short-term changes in LV size are lacking and results of long-term studies are somehow divergent. On the one hand, the presence of LGE has been shown to be a negative predictor of LV reverse remodeling in non-ischemic CMP . On the There are several limitations of our study. First, it is a retrospective, single-center cohort study with the focus on imaging parameters. Data on the outcome and/or impact of levosimendan infusion on intermediate and long-term outcome are not available. In addition, the sample size is small and patients were selected non-randomly by a single referring physician, which may have caused a patient selection bias for the analysis. On the other hand by this patient selection was more homogenous than in a multi center setting. Additionally data on hemodynamic changes in case of valvular disease (e.g. changes in regurgitant fraction) are missing as flow measurements have not been implemented in all CMR studies.Multiparametric CMR including strain imaging can be used to monitor effects of levosimendan infusion. In patients with ischemic or non-ischemic CMP, a significant reduction in LV size can be observed after a single dose of levosimendan. This was not accompanied by a significant change in LV deformity parameters evaluated by strain measurements. CMR imaging and quantification of myocardial scarring is not able to predict treatment response to a single dose of levosimendan.F-J shows a patients with ischemic cardiomyopathy and a subendocardial scar in the lateral wall. CMR before and after levosimendan infusion shows no decrease in LV size and no changes in global longitudinal strai


Myeloperoxidase (MPO) secreted by neutrophils is the enzyme that kills bacteria and other pathogens. Acute myocardial infarction (AMI) is usually caused by thrombosis in response to vulnerable plaque rupture. Circulating MPO was found to be associated with increased mortality in AMI patients. However, the relationship between MPO in thrombi and the prognosis of AMI patients remains unknown.MPO expression in thrombi is associated with the prognosis of patients who underwent primary percutaneous coronary intervention (PCI) after AMI.This study included 41 consecutive patients with acute ST‐elevation myocardial infarction, who successfully underwent primary PCI, during which we collected thrombi remaining in the culprit artery using aspiration catheters. These thrombus samples were fixed, and immunohistochemical staining against MPO and heme oxygenase‐1 (HO‐1) was conducted. Enrolled patients were divided into two groups based on the induction of thrombotic MPO, which was quantified using Image J software.p < 0.01). In the MPO group, a reduction in the thrombotic HO‐1 level contributed to the development of adverse LV remodeling. Logistic regression showed that MPO was a considerable risk factor for adverse LV remodeling .We observed that increased MPO was associated with lower left ventricular ejection fraction (LVEF) and worse LV remodeling in AMI patients. Instead, patients with decreased thrombotic MPO induction had a considerable improvement in LVEF 1 month after discharge (54.4 ± 2.0% vs. 61.1 ± 2.3%, MPO expression in thrombi is associated with reduced LVEF and deteriorated LV remodeling in AMI patients, which may be due to HO‐1 suppression in thrombi. Although the trends of cardiac mortality in developed countries have dropped in recent years, AMI is still considered the second killer in adults in China. To date, we already know that the pathological nature of AMI is caused by thrombi that block the coronary arteries. Subsequent ischaemia and hypoxia in the heart lead to symptomatic chest pain and cardiac malfunction if revascularisation is not applied. A previous study revealed that a high thrombus burden in culprit arteries leads to more complications and worse outcomes.2O2) and chloride anion (Cl−) during the neutrophil respiratory burst.Myeloperoxidase (MPO) secreted by inflammatory cells, such as neutrophils, is an enzyme that kills bacteria and other pathogens in the body. It is produced in the granules of neutrophils and is a heme‐binding protein, which acts as a subfamily of peroxidases and produces hypochlorous acid (HOCl) from hydrogen peroxide , diabetes , and dyslipidemia (plasma low‐density lipoprotein cholesterol concentrations >4.3 mM).2.2Patients underwent primary PCI if they had acute STEMI and ischemic symptoms of <12 h, had acute STEMI and ischemic symptoms <12 h, had contraindications to fibrinolytic therapy, or had STEMI and cardiogenic shock. Blood samples were collected before the primary PCI procedure, and circulating MPO levels were detected using an ELISA kit . During PCI, coronary angiography revealed that all enrolled subjects had a high thrombus burden in the culprit arteries. Aspiration thrombectomy was performed as before2.3p < 0.05 was considered statistically significant. Finally, significant variables were entered into a logistic regression equation to test factors that predict LV remodeling (LVEF improvement ≥10%).Statistical analysis was performed using GraphPad Prism 8.0. Individual means of different groups were compared by one‐way analysis of variance, followed by post hoc Newman–Keuls tests. To take uneven variances into account, for comparisons between groups of unequal numbers, Welch's correction for Student's t‐test was used. Paired or unpaired t‐tests and chi‐square tests were used as appropriate. A value of 2.4All enrolled patients took prescribed standard medications  after discharge. We performed follow‐up echocardiography (echo) at 1 month and 3 months to evaluate left ventricular (LV) remodeling. The parameters measured included LV ejection fraction (LVEF), LV diastolic end diameter (LVDED), LV systolic end diameter (LVSED), LV diastolic end volume (LVDEV), and LV systolic end volume (LVSED).3p < 0.05). On the contrary, the CK‐MB level was increased in the MPO+ group . Although not significant, patients in the MPO‐ group were likely to have lower circulating MPO level (709.3 ± 99.7 vs. 1065.0 ± 349.3) and N‐terminal brain‐type natriuretic peptide  and higher incidence of single‐vessel diseases (52.6% vs. 36.4%) than their counterparts. Finally, in‐hospital echo test was performed in both groups. The results showed no differences in LVEF, LVDED, LVSED, LVDEV, or LVSED between the two groups . This improvement in LVEF was caused by a slight increase in LVDEV and a decrease in LVESD. Nevertheless, in the MPO+ group, LVEF remained unchanged 1 month after the procedure and decreased at 3 months of follow‐up . Finally, we entered three parameters, including ischemic time, MPO, and HO‐1, into a logistic regression equation after determining a 10% increase in LVEF as a cardiac improvement. We found that MPO  and HO‐1  were significantly associated with LVEF improvement, defined as a 10% increase in LVEF  failed to achieve significance.Immunostaining revealed a higher level of HO‐1 in thrombi collected from the MPO‐ group than from the MPO+ group Figure . FurtherF Figure . However4To date, we already know that atherosclerosis is an inflammatory disease. Inflammatory cells, such as neutrophils, secrete enzymes that degrade the fibrous cap on top of the atherosclerosis plaque and subsequently make the plaque vulnerable and then ruptured.LV remodeling is commonly observed in patients with AMI.HO‐1 is one of the main protein enzymes that degrade heme in the body.5In this study, the number of enrolled patients was very limited. This is because, according to the European society of Cardiology Guidelines for the management of AMI, thrombotic aspiration is only recommended for patients with high thrombus burden. In our hospital, we did not conduct thrombectomy in every patient who underwent primary PCI, and we therefore strongly considered this work as a pilot study. However, before starting this study, we had carefully performed statistical power calculations using average values and found that the current number of enrolled patients had a 100% statistical power. Further clinical investigation with a larger sample size must provide solid evidence in the future. In addition, follow‐up was completed at 3 months; regardless of our finding that thrombotic MPO played an important role in the development of adverse LV remodeling to some extent, we failed to observe the long‐term effect of thrombotic MPO on cardiovascular death or major cardiac events. A longer follow‐up is currently on‐going, and future data could help us further clarify the true functions of MPO in thrombus.6Our findings strongly support that the inflammation indicated by MPO may suppress HO‐1 levels and worsen the recovery of cardiac functions in patients with AMI. We conclude that the expression of MPO in thrombi is associated with reduced HO‐1 induction and worse LV remodeling in patients with acute STEMI.None.Figure S1MPO and HO‐1 are present in the thrombus collected from patients with AMI Immunochemical staining for MPO and HO‐1 was conducted in all 41 thrombotic samples, and positive staining was detected in all samples. Representative MPO‐positive staining is shown on the left panel (labeled with arrows). Representative HO‐1‐positive staining is shown on the right panel (labeled with arrows). The magnification was 200×. AMI, acute myocardial infarction; HO‐1, heme oxygenase‐1; MPO, myeloperoxidaseClick here for additional data file.


Metabolic syndrome (MetS) is a cluster of metabolic abnormalities that collectively cause an increased risk of type 2 diabetes mellitus (T2DM) and nonatherosclerotic cardiovascular disease. This study aimed to evaluate the role of myocardial steatosis in T2DM patients with or without MetS, as well as the relationship between subclinical left ventricular (LV) myocardial dysfunction and myocardial steatosis.We recruited 53 T2DM patients and 20 healthy controls underwent cardiac magnetic resonance examination. All T2DM patients were subdivide into two group: MetS group and non-MetS. LV deformation, perfusion parameters and myocardial triglyceride (TG) content were measured and compared among these three groups. Pearson’s and Spearman analysis were performed to investigate the correlation between LV cardiac parameters and myocardial steatosis. The receiver operating characteristic curve (ROC) was performed to illustrate the relationship between myocardial steatosis and LV subclinical myocardial dysfunction.An increase in myocardial TG content was found in the MetS group compared with that in the other groups . Furthermore, reduced LV deformation  and microvascular dysfunction  was found in the MetS group. Myocardial TG content was positively associated with MetS , and it was independently associated with TTM  and LV longitudinal PS . ROC analysis exhibited that myocardial TG content might predict the risk of decreased LV longitudinal myocardial deformation (AUC = 0.74) and perfusion function (AUC = 0.71).Myocardial TG content increased in T2DM patients with concurrent MetS. Myocardial steatosis was positively associated with decreased myocardial deformation and perfusion dysfunction, which may be an indicator for predicting diabetic cardiomyopathy. Current literature outlines that the excessive accumulation of lipid in cardiomyocytes  is bound to facilitate myocardial lipotoxic injury, which, plays an important role in the development of diabetic cardiomyopathy –3. On th1H-MRS) can quantitatively detect triglyceride (TG) content in the myocardium. Therefore, this study aimed to evaluate myocardial steatosis using CMR in T2DM patients with or without concurrent MetS and to investigate the association between left ventricular (LV) subclinical myocardial dysfunction and myocardial steatosis.In recent decades, cardiac magnetic resonance (CMR) imaging has been commonly used in clinical practice, which can provide various characteristics of cardiac structure and myocardial tissue –13. MoreInitially, we prospectively enrolled 92 patients, who were diagnosed with T2DM according to the World Health Organization standards, between June 2017 and May 2019 . ExclusiClinical characteristics, medication, and serum biochemical indexes of all patients and healthy controls were collected. Blood pressure was measured approximately 20 min before CMR examinations when the subject was in a relaxed state. Blood sampling for serum biochemical indexes was performed within 1 week of the CMR scan without changing the subject’s medication regimen.Adhering to the definition of MetS by the International Diabetes Federation (2005), we divided T2DM patients into MetS and non-MetS groups . In this2, matrix size 256 × 166). Regarding first-pass perfusion imaging, gadobenate dimeglumine  was intravenously injected at a dose of 0.2 ml/kg body weight at an injection rate of 2.5–3.0 mL/s, followed by a 20 ml saline flush at a rate of 3.0 ml/s. Consequently, first-pass perfusion images were acquired using an inversion-recovery echo-planar imaging sequence  with three standard short-axis slices , as well as basal slices do not cover the mitral valve level.All subjects were examined using a 3.0-T whole-body scanner  in the supine position. A dedicated two-element cardiac-phased array coil was used for signal detection. Furthermore, a standard ECG-triggering device was used and end-inspiratory breath holding were performed. Following a survey scan, cine images such as long-axis four-chamber views and short-axis two-chamber views were acquired using a steady-state free-precession sequence . Endocardial and epicardial traces were delineated manually by two experienced radiologists in the serial short-axis slices during the end-diastolic and end-systolic phases. LV functional parameters and LV mass were automatically determined. LV remodeling was characterized by the ratio of LV mass to LVEDV (LVMVR). The LV global function index (LVGFI) was calculated using the following formula:1H-MRS), and a region of interest was placed over the blood pool as a means of contrast. In addition to myocardial and blood pooled time-signal intensity curves, semi-quantitative perfusion parameters were obtained such as upslope, maximum signal intensity (MaxSI), and time to maximum signal intensity (TTM).To evaluate LV microvascular perfusion, blood pools as well as endocardial and epicardial traces of the meddle slice of first-pass perfusion images were delineated manually .Statistical analyses were performed with commercially available SPSS . Results are expressed as the mean ± standard deviation. One-way analysis of variance test was performed to evaluate the differences among the following groups: T2DM with MetS, T2DM without MetS and control. Based on Bonferroni’s correction for multigroup comparisons, p-values of < 0.017 were considered as statistically significant. Spearman’s and Pearson’s correlation analysis were conducted to identify the relationship between myocardial steatosis and cardiac deformation. Moreover, multivariable stepwise linear regression analysis was employed to identify the relationship between myocardial TG content and subclinical cardiac dysfunction. Receiver operating characteristic curve (ROC) analysis was conduncted to predict myocardial steatosis to LV subclinical myocardial dysfunction.Of the 53 T2DM patients, 23 were included in the non-MetS  and 30 in the MetS group . Table HbA1c was higher in T2DM patients than in normal controls, and serum TG content was higher in the MetS group than in the control group . In terms of medication, the MetS group were more likely to received treatment for this lipid abnormality. The remaining baseline and metabolic characteristics showed no statistically significant difference among all the three groups.The result of the myocardial TG content are summarized in Table 2 vs. 75.93 ± 14.33 g/m2,p < 0.001) and LVMVR  were higher in the MetS group than in the control group.Regarding LV function and deformation, LVEDV, LVESV and LVGFI  were lower in the MetS group compared to the control group, whereas LV mass    . Furthermore, myocardial TG content was positively associated with LV longitudinal PS , TTM , and negatively associated with upslope  , and the myocardial TG content  was also independently associated with LV longitudinal PS (Model.3: R2 = 0.323)  and diastolic blood pressure  were independently associated with the TTM   T2DM patients with MetS may be more likely to present myocardial steatosis; (2) there was a decreased of LV deformation and microcirculation perfusion in T2DM patients with MetS; and (3) an increased myocardial TG content was associated with the reduce of LV longitudinal deformation and microvascular perfusion, and it might be an appropriate predictor of the myocardium damages.1H-MRS MRS can investigate the cardiac metabolism in vivo, thereby quantitatively detecting metabolites, including fatty acids (FA), creatine etc. Therefore, 1H-MRS can help diagnose myocardial steatosis at an early stage and facilitate the targeted treatment of diabetes mellitus.As a noninvasive technique, The pathological mechanism of diabetic cardiomyopathy is complex and multifactorial. Recent studies have indicated that myocardial lipotoxic injury as a result of lipid oversupply plays an important role in diabetic heart disease , 17. In In addition, we observed that only the MetS group exhibited reduced LV longitudinal and radial PS, which might mean reduction of early myocardial diastolic function. According to the distribution of myocardial fibers, the longitudinal myocardial fibers are predominantly located in the sub-endocardium and are most susceptible to early microvascular ischemia . As the An additional finding in our study was that the T2DM in MetS group exhibited a tendency of concentric LV remodeling and reduced of LVGFI. In contrast, the T2DM patients in non-MetS group did not present similar myocardial structural changes. Concentric LV remodeling is considered to be an early sign of obesity-related cardiac remodeling before LV hypertrophy occurs . It has A pervious study has identified myocardial steatosis may play an important mechanistic role in the development of diastolic dysfunction in women with microvascular dysfunction and no obstructive CAD . In our There are several limitations to our study. First of all, this study was a single center study; hence, an assemble bias may have influenced the acquired results. Second, because we did not perform secondary CMR examinations or other follow-up investigations, our results need to be verified by longitudinal studies on T2DM patients. Hence, it is our principle focus to verify these findings in future follow-up studies.Our study found that even when the cardiac function of patients with T2DM is preserved, the combined MetS may increase the reduction of myocardial deformation and myocardial perfusion, and these changes in myocardial structure are related to the degree of myocardial steatosis. Meanwhile, myocardial triglyceride content might be a useful indicator to predicting diabetic cardiomyopathy. Therefore, it is suggested that we should pay more attention to myocardial steatosis in clinically diabetic patients with metabolic syndrome, and reducing myocardial steatosis may also help prevent the progression of diabetic cardiomyopathy.


Two weeks after ISO treatment, the animal showed an apical aneurysm accompanied by reduced radial strain in corresponding segments and impaired global systolic function. DT-MRI revealed a loss of contractile fiber tracts together with a disarray of remaining fibers as corresponding microstructural correlates. This preclinical case report provides valuable insights into pathophysiology and morphologic–functional relations of heart failure following MI using emerging imaging technologies.Although heart failure following myocardial infarction (MI) represents a major health burden, underlying microstructural and functional changes remain incompletely understood. Here, we report on a case of unexpected MI after treatment with the catecholamine isoproterenol in an experimental imaging study in mice using different state-of-the-art imaging modalities. The decline in cardiac function was documented by ultrahigh-frequency echocardiography and speckle-tracking analyses. Myocardial microstructure was studied  Although heart failure following myocardial infarction (MI) represents a major health burden, underlying structural/functional relationships remain incompletely understood , 2. Whil−s).We conducted an experimental imaging study to characterize myocardial microstructure and function in a murine model of circumscribed subendocardial damage whose results have been published previously . BrieflyHistological analyses showed subendocardial fibrosis within basal and midmyocardial sections of the LV . Fibroti3 using DT-MRI at 7 T. By using an ex vivo approach without constraining influences such as motion, strain, and electrocardiogram (ECG) triggering, we aimed for full coverage of the entire LV with the highest possible image resolution and quality. On average, the case showed highly reduced mean diffusivity in the LV when compared to the remaining animals  and supply , the used experimental model may be considered as a preclinical correlate of type 2 MI . Indeed,Apical ballooning is also a key feature of stress cardiomyopathy , a transient acute heart failure syndrome putatively caused by the release of catecholamines in response to sympathetic stimulation . InteresIn conclusion, this preclinical case report provides insights into pathophysiological and morphologic–functional relations of heart failure following MI by combining latest functional analysis and cardiac imaging techniques. The advent of clinical DT-MRI may facilitate simultaneous assessment of morphologic and functional changes under these conditions.All datasets generated for this study are included in the article/The animal study was reviewed and approved by Landesamt für Gesundheit und Soziales (LAGeSo), Berlin, Germany.NB performed data collection and statistical analyses, created the figures, and drafted the manuscript. DL performed data collection/data analysis related to DT-MRI and created individual figure tiles. AT, AF-L, and RK performed data collection. AF-L, LS, and UK conceived and designed the study, critically reviewed, and amended the manuscript. LS and UK acquired funding for the study. All authors have contributed extensively to the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Background: Pulmonary artery banding (PAB) is reported as an innovative strategy for children with end-stage heart failure (ESHF) to bridge to transplantation or recovery. We report our early experience with PAB to evaluate outcomes, indications, and limitations.Materials and Methods: This is a single-center prospective clinical study, including infants and children admitted for ESHF owing to dilated cardiomyopathy (DCM) with preserved right ventricular function after failure of maximal conventional therapy. All patients underwent perioperative anticongestive medical therapy with ACE inhibitor, beta blocker, and spironolactone. Post-operatively, all patients underwent echocardiographic follow-up to assess myocardial recovery.Results: We selected five patients  who underwent PAB at a median age of 8.6 months (range 3.9–42.2 months), with preoperative ejection fraction (EF) <30%. Sternal closure was delayed in all. One patient did not improve after PAB and underwent Berlin Heart implantation after 33 days, followed by heart transplant after 13 months. Four patients were discharged home on full anticongestive therapy. However, 2 months after discharge, one patient experienced severe acute heart failure secondary to pneumonia, which required mechanical circulatory support, and the patient underwent a successful heart transplant after 21 days. The remaining three patients are doing well at home, 22.4, 16.9, and 15.4 months after PAB. They all underwent elective percutaneous de-banding, 18.5, 4.8, and 10.7 months after PAB. EF increased from 17.7 ± 8.5% to 63.3 ± 7.6% (p = 0.03), and they have all been delisted.Conclusion: Use of PAB may be an effective alternative to mechanical support in selected infants for bridging to transplant or recovery. Better results seem to occur in patients aged <12 months. Further experience and research are required to identify responders and non-responders to this approach. Significant advances in end-stage heart failure (ESHF) therapy have been achieved and documented in adult patients in recent years, whereas the mechanisms and therapy of heart failure in children are still unknown , 2. The Long-term mechanical circulatory support (MCS) is currently possible and effective even in neonates and infants with ESHF, thanks to the extracorporeal Berlin Heart EXCOR®, which is the only currently available ventricular assist device (VAD) in patients weighing <10 kg , 8. HoweOn the basis of the hypothesis that ventricle–ventricular interaction can benefit dilated left ventricular failure, Schranz et al.  proposedOn the basis of this background and experiences, since 2015, we have embarked on the “PAB strategy” for treating ESHF in infants. We herein report the early results of our ongoing clinical experience, aiming at outlining indications, outcomes, and limitations.This is a single-center, prospective, clinical study including infants and children with DCM since September 2015. Inclusion criteria were as follows: age <4 years, evidence of left ventricle dysfunction, and preserved right ventricle function; being listed for transplant, as indicated elsewhere (3/kg/h).Before PAB, all patients underwent full congestive heart failure (CHF) medical therapy, as recommended by Schranz et al.  lisinop, furosem2). The right ventricle function was assessed using tricuspid annular peak systolic excursion (TAPSE). All these data were evaluated before and after PAB and at the last available follow-up evaluation.Echocardiographic evaluation was focused on the estimation of left ventricular ejection fraction (LVEF) , mitral and tricuspid valves regurgitation [according to European Society of Cardiology (ESC) recommendations],  and tranAll patients underwent PAB through a midline sternotomy, as described elsewhere , with a SD and median value. Continuous variables were compared by using a t-test for paired data. The null hypothesis was rejected for a p < 0.05.All the analyses were performed using a commercially available package . Quantitative values are presented as mean + 1 Five patients (M/F = 4/1) with a median age of 8.6 months (range 3.9–42.2) underwent PAB for ESHF. Three patients were reporting symptoms like fever, malaise, and upper respiratory tract infection before admission. All patients were negative at autoimmune and inborn metabolic disease screening. Three patients were found to be positive for viral infection . PatholoOn admission, the mean baseline EF was 15.4 ± 6.8%; mitral valve regurgitation was moderate in four and mild in one patient; mean TAPSE value was 11.1 ± 4.1 mm. Last, tricuspid regurgitation was trivial or mild in all. No patient required extracorporeal membrane oxygenation (ECMO) support before PAB .There were no intraoperative deaths . After PThe perioperative course was complicated in one patient only (#2), a 3.5-year-old male who was admitted emergently, already intubated, with left atrial massive dilation, which was compressing the left mainstem bronchus. Unlike the other patients, this child underwent PAB and decompressive atrial septostomy on pump. Furthermore, owing to unstable hemodynamic conditions, ECMO support was required for 7 days. Despite weaning off ECMO, his hemodynamic condition remained unstable, with EF <30%, requiring massive inotropic support and mechanical ventilation, Thus, he underwent elective left Berlin Heart EXCOR® implantation 33 days after PAB.When the last patient was excluded, the median ventilation time, ICU, and hospital stay were 9.5 (6–12), 16.3 (10–20), and 39 days (35–54), respectively. All remaining patients were discharged home with full CHF therapy .At a median follow-up of 30.2 months (25.4–55.7), all patients are alive and well. Two patients required HT after PAB. Patient #1 experienced acute pneumonia 3 months after PAB and required hospitalization in another hospital, where he had severe low cardiac output syndrome and required emergent venous arterial (VA) ECMO support. He was listed for transplant, and he underwent Berlin Heart EXCOR implantation. After 7 days of VAD support, he was successfully heart transplanted. He is currently in excellent conditions 48 months after transplantation, with no residual disabilities.Patient #2, as mentioned above, underwent a successful HT after 12 months of uneventful VAD support, is in excellent clinical conditions 40 months after transplantation, and is on immunosuppressant therapy, with healthy neuropsychological development.The remaining three patients had a progressive improvement of symptoms and left ventricular function. Follow-up data are presented in z-score 11.4 ± 2.1) to 7.6 ± 1.8 mm , whereas EF increased to 63.3 ± 7.6%  and trans-pulmonary gradient of 50–55 mmHg. All patients had a gradual decrease in plasma levels of B-type natriuretic peptide (BNP)/pro-BNP, and they have all been ultimately removed from the transplant list, respectively 9, 10, and 12 months after PAB.At the most recent follow-up , these three patients are in Ross class I and thriving well. At the last echocardiography monitoring , left vePopulation-based studies in the United States, Finland, and Australia estimate the incidence of primary cardiomyopathies to be 1/100,000 person-years in children <20 years of age , 12. IdiManagement of ESHF in infants and children is a challenging problem. Children with ESHF who cannot be stabilized with medical therapy can be supported effectively with MCS to unload the failing ventricle and maintain end-organ perfusion, , 17 as bAlthough some innovative centrifugal intrathoracic pumps have been successfully used in teenagers,  owing toDespite the improvement in the medical management of ESHF patients, with the increased use of VAD and decreased frequency of rejection during the first year post-transplant, life after transplant is not easy, with a survival rate of about 90% 1 year after transplant and with overall 25-year survival of 37%,  which maPAB is an old surgical technique described a long time ago as a palliative surgical procedure for CHD with pulmonary overflow. Despite the fact that early repair is currently the gold standard, PAB remains a valid option to balance pulmonary and systemic circulation in several complex CHD .Based on previous experience derived from re-training of the subpulmonary left ventricle before anatomical correction in congenitally corrected transposition of the great arteries (TGA) or before arterial switch for dextro-TGA (D-TGA), –25 PAB hThe first report of such application of PAB was published by the Giessen group in 2007 . The effThe mechanism underlying the improvement of left ventricle function by right ventricle pressure overload induced by PAB is still uncertain. Most researchers believe that PAB causes a leftward shift of the interventricular septum that can reduce left ventricle dimensions, change its shape from spherical to ellipsoid morphology, and finally reduce the mitral valve annular dilatation and consequently mitral regurgitation, with the result of optimizing volume overload. Additionally, the PAB induces a favorable change in the Frank–Starling curve, and the reduction in left ventricle preload and end-diastolic/end-systolic filling pressures may enable a more favorable hemodynamic state and improvement of LVEF. Third, the PAB may determine an increase in right ventricle contractility (Anrep effect) and can stimulate its hypertrophy, matrix remodeling, and regenerative capacity of a young heart . Last buSome of these post-PAB effects have been partially described in a retrospective study based on cardiac MRI analysis presurgery and post-surgery of 15 children with DCM. This paper  showed tImproved left ventricle echocardiographic function and dimensions after PAB have been reported even in the setting of an experimental model of doxorubicin-induced left ventricle DCM . DespiteSince 2015, we have applied the Giessen methodology to treat ESHF in selected infants and children. Our initial experience with PAB for ESHF has resulted in being an effective strategy to avoid or postpone HT in infants with DCM and preserved right ventricular function. Our population, despite small in number, is comparable in terms of age with that reported by the experience of other centers worldwide. We also report comparable data in terms of in-hospital and ICU stay, and mechanical ventilation time after surgery .In four out of five patients, PAB showed to have an immediate effect in supporting left ventricle function, by the acute increase in right ventricle pressure. Mechanical remodeling, such as ventricular septum shift to the left, with a change in the shape of the left ventricle and a decrease in its preload and mitral valve regurgitation, was observed immediately after PAB. Besides, we found a significant and dramatic increase of LVEF and a decrease of LVEDD and blood level of BNP/pro-BNP at follow-up in those three patients who did not require a transplant.It is of note that those patients, who initially responded positively to PAB (4/5 patients), presented a very different and complex clinical post-operative course. Two patients (1 and 4) experienced acute heart failure during pneumonia. Whereas patient #1 (DCM in non-compaction cardiomyopathy), owing to distance from our center, was urgently admitted to another hospital and underwent MCS and HT, patient #4 (chronic myocarditis) was treated successfully in our hospital with the intravenous infusion of inotropic medications. A similar clinical problem occurred in patient #3 (acute myocarditis), who presented a late acute deterioration of cardiac function, without any infectious cause, and required hospitalization with infusion of inotropic agents. On the contrary, patient #5 (acute myocarditis) has had an uneventful post-operative course and could be discharged to his country of origin.We suggest that a very close clinical and therapeutic follow-up  is necessary for the first months after PAB, to avoid acute left ventricle deterioration due to common pediatric problems . The reason for this is uncertain, but we speculate that it is due to the slow regeneration process of cardiomyocytes, which requires time for a satisfactory myocardial recovery.It is of note that patient #2 did not benefit at all of the PAB, and despite changed intracardiac mechanics (showed by daily TTE monitoring), the clinical condition and cardiac function did not improve. Unlike the other patients, he was the only patient older than 1 year of life (3.5 years) and had an extremely compromised hemodynamic state on admission in our center (sedated and intubated after a cardiogenic shock). Also, he was the only one who presented with a very dilated left atrium compressing the main left stem bronchus and causing air entrapment and lung damage. Owing to this, he underwent PAB with associated atrial septectomy and ECMO support. Despite weaning from ECMO, there was no improvement in cardiac function, and he finally underwent VAD support and HT. Because the presence of a dilated left atrium may be the evidence of a long-lasting myocardial dysfunction before the onset of symptoms, we speculate that this particular patient might have acute myocarditis on an undetected idiopathic DCM. Thus, the long-lasting myocardial damage may have prevented a positive effect of PAB.On the other hand, this failure might be due to a reduced regenerative myocardial capacity, which is known to correlate negatively with patients' age . CurrentOn the basis of these data, we postulate that the potential for cardiomyocyte recovery and hyperplasia/repopulation may be the most significant in infancy, as elsewhere stated . Most paIn our experience, the PAB procedure presents some crucial advantages. First of all, it is a simple surgical procedure, which does not require cardiopulmonary bypass, and can be tolerated hemodynamically by the patients as long as continuous echocardiographic monitoring is assured. Furthermore, there is the possibility to modulate PAB tightness both in the immediate post-operative period (by delayed chest closure) and by graded percutaneous balloon dilation of the band in the follow-up (when PAB is too narrow with high gradient trans-PAB and tricuspid regurgitation increases owing to right ventricle dilation). In fact, in our series, the last three patients underwent percutaneous balloon de-banding to preserve the right ventricle function. Third, when compared with VAD surgery, PAB is easier and less invasive. It does not require left ventricle apicectomy (for the VAD inflow cannula), which may jeopardize the left ventricle function recovery, as suggested by some studies focused on muscle layer contractility and the pivotal role of the left ventricle apex . Last, aIn our experience, in four patients, the gradual clinical improvement and functional left ventricle recovery offered a chance for discharge home. Most importantly, three among five reached complete LVEF normalization , averageOur study cannot clarify if PAB-induced cardiac remodeling was only a modality of transient support of the ventricular function in a framework of myocarditis that would have undergone a spontaneous resolution, or if it had a pathophysiological role  in the cardiomyopathy complete recovery. However, it certainly avoided that four among five patients would undergo a more invasive approach in the acute phase .We conclude that PAB strategy has provided these children a possibility of complete remission without damaging irreversibly the cardiac structures or great vessels and an option to have a healthy life expectancy after recovery, without the drawbacks of life-lasting immunosuppressive therapy.The significant limitations are the small number of patients and the short follow-up time, which prevents long-term cardiac function assessment.The introduction of PAB may represent a paradigmatic change in managing pediatric ESHF. In our experience, PAB resulted in an effective and affordable procedure with acceptable risk and convincing medium-term outcomes. We believe this strategy can be a valid option in selected infants and children with ESHF, as an alternative strategy to MCS for bridging to transplant or, hopefully, cardiac recovery. In our series, better results occurred in patients aged <12 months, probably owing to a preserved myocardial regenerative potential. However, the early post-operative period can be extremely challenging, and serious complications may be caused by transient diseases typical of infancy. Thus, the PAB strategy requires strict clinical follow-up and frequent hospital admissions and evaluations. Further experience and research are required to differentiate between “responder” and “non-responder” patients to this innovative heart failure therapy.The datasets generated for this study are available on request to the corresponding author.The studies involving human participants were reviewed and approved by University hospital of Padua. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.All authors listed have made a substantial, direct and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


QT dispersion (QTd) is related to regional variations in myocardial repolarization. Our study aims to assess the value of QTd in prediction of myocardial ischemia and its severity during stress imaging.We enrolled one hundred patients having stable coronary artery disease (CAD) and fulfilling the “Appropriateness criteria for cardiac radionuclide imaging” (MPI). They were divided into group I including patients with MPI-detected ischemia (50 patients) and group II including patients with normal perfusion scan (50 patients). We excluded unstable CAD and all other causes affecting QTd. During isotope scan, ECGs were taken and QTd was calculated at rest and at maximum heart rate.P = 0.000). QTd difference, the difference between QTd at rest and stress, was calculated. QTd difference was significantly lower in normal than in ischemic group (P = 0.003). There was a significant positive correlation between QTd difference and defect size (P = 0.04).QTd was significantly higher in the ischemic group both at rest and exercise (QTd increases in ischemia and the QTd difference (between rest and stress) correlates positively with severity of ischemia.QTd and QTd difference could be used to improve the accuracy of stress imaging test. Different methods have been introduced and used for diagnosing CAD and investigating the need for revascularization such as the exercise tolerance test (ETT) and imaging techniques, e.g., SPECT (single-photon emission computed tomography).Although the results obtained by SPECT can provide important and reliable information about patients’ prognosis, this method also has some disadvantages including exposure to ionizing radiation and controversial reports about its degree of accuracy .In 1990, Day CP et al.  coined tClinical and experimental data have shown that QT interval prolongation measured from the standard 12-lead ECG is a risk factor for ventricular arrhythmia and sudden death in patients with and those without previous acute myocardial infarction (AMI). The Rotterdam QT project  showed tSome researchers have suggested to use QT interval (QTI) changes in response to exercise-induced ischemia instead of ST-segment changes in order to increase the diagnostic accuracy of ECG. The underlying reason for using QTI for diagnosing ischemia is that exercise-induced ischemia causes heterogeneity in the ventricular repolarization. QT dispersion (QTd) is one of the QTI parameters used more frequently than the other parameters .We aim to investigate the correlation between QTd, during rest and maximum exercise ECG, and the severity and extent of myocardial ischemia detected by myocardial perfusion imaging technique.Patients referred to our center  between July 2018 to December 2018 were enrolled.Case—control study.We included patients having symptoms suggesting chronic coronary syndrome (CCS) and subjected to a clinically indicated myocardial perfusion imaging for the evaluation of the coronary arteries. All included patients have fulfilled the “Appropriateness criteria for cardiac radionuclide imaging.”Patients with (1) previously known congenital heart disease, (2) unstable angina, (3) severe valvular heart disease, (4) chronic renal failure on regular hemodialysis, (5) inter- or intraventricular conduction disturbance (IVCD) in the ECGs including RBBB and LBBB, (6) non-sinus rhythm including atrial fibrillation or implantable pacemaker rhythm, (7) patients taking medications that affect QT interval .All patients were subjected to complete history taking with special emphasis on age, sex, and risk factors  in addition to general and local cardiac examination.All patients underwent the following investigations: 12-lead ECG, transthoracic echocardiography, treadmill exercise stress ECG, and SPECT imaging.During isotope scan, ECGs were serially taken in different stages; therefore, ECGs taken at the beginning of the scan were used to calculate QTd at rest and those taken at the time of maximum heart rate for calculating QTd under stress.For QT dispersion (QTd) calculation, the difference between the minimum and the maximum QT interval on the 12 lead ECG was used if at least eight leads were suitable for analysis . The ECGA simultaneous 12 lead ECG, taken on the day of the stress study of MPI, was used for QT measurements. The QT interval was taken as the interval from the onset of the QRS complex to the end of the T wave, defined as the intersection of the isoelectric line and the T wave. In the presence of a U wave, the end of the QT interval was taken to be the nadir between the T and U wave peaks. No extrasystolic or post extrasystolic QT intervals were included. The maximum QT interval was corrected for heart rate using the Hodges formula (QTc = QT + 0.00175(HR – 60)).QTd difference, which is the difference between QTd at rest and at exercise (stress), was also calculated.All scans were performed using SPECT (Gamma camera Siemens Symbia-E series). The studies were performed according to established guidelines and institutional protocols at the time of the scan. In order to calculate the number of segments involved in ischemic damage, we used the conventional 17-segment categorization. The summed ischemic score was also determined based on Cedars-Cinai calculations which show the total severity of ischemia and the number of damaged segments. The severity of ischemia in each segment was also determined based on the same calculations between zero to 4 . True myocardial perfusion defect was described with reference to (1) the defect size or extent , (2) severity of perfusion defect , (3) extent of reversibility , and (4) localization (based on 17 segment model and coronary artery territory if possible).Data were analyzed using computer software called R language (R-studio Version 0.99.484—© 2009-2015) to investigate the correlation between QTd and the scan results as well as to compare QTd values of different groups.Ninety-six males and 4 females participated in our study  were divided into two groups depending on the perfusion scan results. Group I was the case group  who had MPI-detected myocardial ischemia of different severity. Of patients suffering from myocardial ischemia, 23, 14, and 6 patients had mild, moderate, and severe ischemia respectively. While the remaining 7 patients had scarred myocardium. Whereas group II included patients with normal perfusion scan   QTds at rest for patients with normal myocardium and those with myocardial ischemia detected by MPI were 15.7 (± 5.2) ms and 34.24 (± 13.91) ms [P = 0.0033] indicating statistical significant value , was compared between normal and ischemic groups. We found that the mean ± SD QTd was significantly lower in patients with normal perfusion scan (−5.82 ± 12.2 ms) than in those with abnormal myocardial scan (4.12 ± 19.08 ms) [r = 0.279, p = 0.049).Table When adding QTd difference to its result, the sensitivity, specificity, and accuracy of exercise stress ECG test was improved Tables  and 5.TN = 47 patients only had > 0 change in QT-dispersion “exercise/rest” difference.Table Figure In our study, we examined the correlation between QTd and the severity and extent of myocardial ischemia detected by myocardial perfusion imaging. Our findings suggest that QTd values both at rest and had a significant relationship with the extent and severity of myocardial ischemia and rises with the increase in the severity and extent of ischemia.A significant increase in QTd value using dipyridamole upon the induction of abnormal ventricular wall motion was previously reported which means that ischemia could change QTd value .Okishige et al.  demonstrSome researchers have not considered QTd as a standard criterion for assessing the homogeneity of ventricular repolarization. They stated that not only the accuracy of the standards relating to the dispersion but also the existence of a direct correlation between homogeneity of ventricular repolarization and QTd is in question .In contrast, other researchers believe that QTd is a reliable measure for investigating abnormalities of myocardial repolarization and is able to predict severe arrhythmias after myocardial infarction and also mortality because of cardiovascular diseases . This coWe compared the QTd value in patients who suffered from ischemia with normal people based on myocardial scanning and found that this parameter was identical in both groups at rest but significantly increased with the induction of stress in the ischemic group compared with the normal one.Intra-group difference also exists so that the QTd value rises significantly with the increase in the severity of ischemia.It was previously shown that, in patients without chest pain or ST segment depression during stress induction, QTd calculation immediately after stress induction can be very useful for diagnosing CAD .Moreover, QTd increases to more than 60 ms under stress, with 70% sensitivity and 95% specificity that can be useful in the diagnosis of CAD .The patients with CAD have longer corrected QT (QTc) intervals at peak heart rates during exercise. This finding provides insufficient evidence to support routine incorporation of QTc at peak heart rates into exercise test interpretation .Teragawa and his colleagues also observed that stress induction using ATP infusion was associated with increased QTd only in patients with ischemia (ischemia and ischemia with scar), whereas in normal patients or those who suffered from scars, ischemia as the result of ATP infusion caused reduced QTd. They stated that in the normal group, ATP infusion may simultaneously cause a significant reduction of the maximum and minimum QT segment duration. QTd at baseline and during ATP infusion correlated with the ATP-SPECT imaging pattern. Therefore, the induction of ischemia was associated with an increase in QTd in the group with ischemic injuries, and a decrease in QTd in the group without ischemic injuries .Randomized clinical trials (RCTs) have shown that the addition of coronary CT angiography , 17 or fIn recent ESC 2019 Guidelines for the diagnosis and management of chronic coronary syndromes (CCS), exercise ECG alone has been downgraded as an alternative to diagnose obstructive CAD if imaging tests are not available  , 22.Regarding diagnosis of IHD, our study shows that the sensitivity and specificity of stress ECG test for detecting ischemia are 61% and 90% respectively. We noticed that addition of QTd values to the results of stress ECG improves the sensitivity to 72% with an irrelevant effect on the specificity (91%).We found a strong relation between the QTd difference and the defect size in MPS in the ischemic group. The increase in the defect size is associated with increase in QTd difference.Takase and colleagues also observed that QTd at rest in patients with simultaneous reversible and irreversible injuries and those with only irreversible injury was significantly higher than the normal group and the group with reversible injury. However, QTd under stress increased in the group with reversible injury but decreased in other groups .It should be noted that the correlation between QTd and ischemic parameters in the scan is much lower at rest than under stress. As mentioned, such QTd increase under stress might be because of the increase in the heterogeneity of ventricular repolarization caused by the incorrect reaction of the ischemic myocardium to catecholamine or the abnormal flow of calcium ions , 25.The findings of Schmidt and his colleagues  are not Masaki and his colleagues also stated that not QTd, but QT peak dispersion (QTpd) can be useful in detecting stress-induced myocardial ischemia .In our study, we tested an index called QTd difference that actually shows the difference between QTd at rest and under stress. The comparison of this index between the normal and ischemic groups indicates that its value increases significantly in patients with myocardial ischemia. Since QT difference gives a resultant of the two values of stress and rest QTd, this can possibly be a more appropriate index for diagnosis of myocardial ischemia and the homogeneity rate of repolarization of ventricular cells . SchmidtWe found also that the cut-off for QTd in the diagnosis and prediction of the ischemia equaled 9 ms. We could conclude that under exercise-induced stress, patients who had negative stress ECG test for exercise-induced myocardial ischemia but their QTd value was more than (9 ms), those patients most probably had abnormal perfusion scan results.The most eminent results of our study are those concerning with QTd difference and stress. When adding QTd difference to its result, the sensitivity, specificity, and accuracy of exercise stress ECG test was improved.Considering the different results obtained from our research regarding the QTd value and based on the findings of this study, we can conclude that QTd can be clinically useful in identifying ventricular ischemic myocardial events.Further studies are needed to determine diagnostic capabilities of QT dispersion, including its sensitivity and specificity which are currently under investigation to detect the extent that the QTd could be clinically useful in identifying ventricular ischemic myocardial injuries.QTd increases in ischemia and the QTd difference (between rest and stress) correlates positively with the severity of ischemia. QTd and QTd difference could be used to improve the accuracy of stress ECG treadmill test.Patients who had negative stress ECG test for exercise induced myocardial ischemia with QTd difference value more than (9 ms) most probably have abnormal perfusion scan results. So, the QTd can be clinically useful in identifying ventricular ischemic myocardial events.QTd represents a simple, quick, cheap, and resourceful tool to assist in study interpretation, clinical management, and therapy guidance.Relative small number of sample size.The study was conducted in a single center.Most of the involved subjects were males.


N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a potential biomarker for monitoring the status of heart failure. However, the optimal monitoring interval of NT-proBNP is unknown. This study sought to investigate the minimal informative monitoring interval of NT-proBNP in patients with stable chronic heart failure.This retrospective cohort study included patients who were admitted due to heart failure and subsequently followed with serial NT-proBNP measurements in a tertiary hospital. We analyzed NT-proBNP measured between six months after discharge and the earliest timepoint of: an alteration of medication regimen, readmission due to worsening of heart failure, or all-cause death. To distinguish progression of the disease from biological variability and measurement error, the signal-to-noise ratio method was applied with a random-effects model.In the 368 patients included, NT-proBNP was measured for a median 6 times. In the random-effects model, signal (progression of disease) exceeded noise  at 7.9 months , while noise corresponded to a 61% increase from baseline. In stratified analysis using the AHEAD risk score, the minimal informative monitoring interval shortened as the risk score increased .In patients with stable chronic heart failure, the minimal informative monitoring interval of NT-proBNP measurement was 7.9 months in the current population, which varied with underlying risks. The optimal monitoring interval could be lengthened for patients at lower risks. Biochemical markers, including natriuretic peptides such as N-terminal pro-B-type natriuretic peptide (NT-proBNP), are widely used in the clinical management of heart failure. The serum level of NT-proBNP can reliably be used as a diagnostic tool and a prognostic predictor throughout the wide spectrum of acute and chronic heart failure –5. MoreoSeveral studies have reported that serum NT-proBNP was measured routinely every 3 months upon follow-up visits in clinical management of chronic heart failure , 12. NevA single-center retrospective open-cohort study was conducted to identify the true progression and intra-individual variability, as well as to investigate a minimal informative interval of NT-proBNP measurement in patients with stable chronic heart failure. The present study was approved by the institutional research board of St. Luke’s International University (NO. 18-R070). All patients provided informed consent under an opt-out policy.Consecutive adult patients (aged 20 or more) who had been hospitalized at St. Luke’s International Hospital  with a diagnosis of heart failure from January 2003 to December 2017 were assessed for enrollment in the present study. The diagnosis of heart failure was based on Framingham criteria ) or the mean (standard deviation [SD]) as appropriate. Categorical variables are presented as number (percentage). Statistical analysis and model fitting were performed and visualized using R 3.5.2 with the R packages of “dplyr”, “lme4”, “performance”, “ggplot2”, and “forestplot” .Yit in Table In order to distinguish true progression of NT-proBNP from intra-individual variability, we applied the signal-to-noise ratio method with a random-effects linear regression model –22. The From the model above, we calculated between-individual variability  caused by different rates of increase as the variance of the random slope over time multiplied by time, and intra-individual variability (defined as noise) as the variance of the random residual. Equations in detail are shown in Table Stratified analysis was performed according to age, gender, body mass index, left ventricular ejection fraction, renal function, presence of a history of multiple admissions due to heart failure, and the AHEAD risk score . The AHEAD risk score comprises atrial fibrillation, hemoglobin < 13.0 g/dL in male or < 12.0 g/dL in female, elderly (> 70 years), abnormal renal function (creatinine > 1.47 mg/dL), and diabetes mellitus, with one point for each item .Each subgroup was fitted to the model described above in order to calculate the signal, noise, and minimal informative monitoring interval.Online Supplemental Fig. Between January 2003 and December 2017, 1715 adult patients were admitted due to heart failure. Of those patients, 368 patients without end-stage renal disease had 3 or more NT-proBNP measurements during the analytic period , and the median left ventricular ejection fraction was 43.7% (IQR: 29.0–60.7). The patient baseline characteristics are summarized in Table The median age of included patients was 75.5 years (IQR: 63.0–83.0), of whom 57% were male and 13% had a history of admission due to heart failure before the index admission. The median eGFR was 58.6 mL/min/1.73 m2 of 0.87 ) than in the lower ejection fraction subgroup (2.61 ×10−1 ng2/L2 [95%CI: 2.36 ×10−1 to 2.93 ×10−1]). This was inconsistent with the results from 2 previous studies, which suggested that variability in NT-proBNP was not influenced by the left ventricular ejection fraction [The minimal informative monitoring interval shortened along with the accumulation of risk represented by an increase of the AHEAD score. The present results indicate the need for tailored monitoring intervals for NT-proBNP levels in stable heart failure patients based on underlying risks. The difference in minimal informative intervals between patients with higher and lower ejection fractions was driven by a significantly smaller noise in the higher ejection fraction subgroup  changes linearly in patients with a stable status of chronic heart failure. The linearity of its change remains to be further investigated.Utilizing a statistical method taking into consideration the biological variability and measurement error of the NT-proBNP level, we determined that the overall minimal informative interval for monitoring NT-proBNP levels was 7.9 months (95%CI: 5.1–9.6) in the current population, while the intra-individual variability corresponded to a 61% increase from baseline. Of note, the minimal informative monitoring interval was shorter in patients with a worse predicted prognosis. These results emphasize the limitation of frequent measurement of NT-proBNP, the importance of detecting signs of heart failure exacerbation other than NT-proBNP, as well as the necessity of individualization in planning follow-up visits according to different risk profiles.Additional file 1: Supplemental Table 1. Estimates of the random-effects model for the overall stable heart failure population. Supplemental Fig. 1. Schematic of analytic period and follow-up NT-proBNP measurements.