Myocardial scar is directly related to the response to CRT after implantation. The extent of myocardial scar can be detected not only by cardiac magnetic resonance but also by two electrocardiographic scores: fragmented QRS (fQRS) and Selvester score (SSc). The aim of our study is to compare the role of baseline SSc and fQRS in predicting response to CRT in a cohort of heart failure patients with true left bundle branch block (LBBB). As a secondary endpoint, we assessed the association of both scores with overall and cardiac mortality, heart failure hospitalizations, ventricular arrhythmias requiring ICD intervention, and major adverse cardiovascular event (MACE).  We evaluated fQRS and SSc of 178 consecutive HF patients with severe systolic dysfunction (LVEF ≤ 35%), NYHA class II-III despite optimal medical treatment, and true-LBBB. Response to CRT was defined as the improvement of LVEF of at least 10% or as the reduction of LVESV of at least 15% at a 6-month follow-up. Each endpoint was related to fQRS and SSc. p=0.003), while the presence of fQRS at baseline ECG was not . No correlation was found between SSc and overall mortality, cardiac death, ventricular arrhythmias, hospitalizations due to heart failure, or for MACE. Similar results were observed between fQRS and all secondary endpoints.  SSc ≥7 was significantly associated with the absence of echocardiographic response to CRT (OR: 0.327; 95% C.I. 0.155–0.689;  In HF patients with true-LBBB and LVEF ≤35% eligible for CRT, myocardial scar assessed by calculating the SSc on preimplant ECG is an independent predictor of nonresponse after multiple adjustments. Neither SSc nor fQRS is associated with overall and cardiac death, ventricular arrhythmias, or hospitalization for heart failure at a 24-month follow-up. Cardiac resynchronization therapy (CRT) is an important nonpharmacological therapy in end-stage heart failure. It is effective in improving symptoms, reversing ventricular remodeling, and reducing mortality. Although several patients meet the inclusion criteria for CRT implantation, not all of them are CRT responders , and patHowever, detection of myocardial scar is possible not solely by CMR, as the presence of scars causes heterogeneous ventricular activity and alteration in the QRS morphology, leading to QRS complexes fragmentation , which mSelvester et al. also showed that myocardial scar all around left ventricle (LV) produced characteristic and quantifiable changes  on surfaIn the present investigation, to make more accurate our results avoiding confounder data, we analyze only patients with “true-LBBB” , which wThe primary endpoint of the present study is to compare the role of baseline SSc and fQRS in predicting response to CRT in a cohort of HF patients with true-LBBB. As a secondary endpoint, we aimed to evaluate the association of both scores with clinical outcomes, such as overall and cardiac mortality, HF hospitalizations, incidence of ventricular arrhythmias requiring ICD intervention, and major adverse cardiovascular event (MACE).V1 and V2, and mid-QRS notching or slurring in ≥2 of leads V1, V2, V5, V6, I, and aVL , NYHA class II-III despite optimal medical treatment and true-LBBB, who underwent CRT-D implantation from 2012 to 2016 in two Italian Centers . As previously described by Strauss et al. , true-LB and aVL . The stuDetection of ventricular arrhythmias was programmed for all devices in 3 consecutive zones, with limits slightly varying per manufacturer: a monitor zone (from 150 to 185 bpm), a ventricular tachycardia (VT) zone (from 185 to 210 bpm), and a fast VT/ventricular fibrillation (VF) zone (>210 bpm). Discrimination for atrial arrhythmia was enabled. Therapy settings were adapted only when clinically indicated .At both institutions, a standard 12-lead ECG  was performed before implantation with a commercially available electrocardiograph providing the automatic assessment of QRS duration and filed in a dedicated binder. For the present study, a single experienced cardiologist was blinded to all data but gender and age evaluated all ECGs. ECGs were excluded from analysis in case of poor quality, missing lead information or ventricular paced rhythm.Q wave, with >2 R waves (R'), >2 notches in the R wave, or >2 notches in the downstroke or upstroke of the S wave, in 2 contiguous leads.The SSc criteria described by Strauss and Selvester  Table 1Table 1 wFor all patients, a six-month follow-up included echocardiography and device interrogation. Response to CRT was defined as either the reduction of LV end-systolic volume (LVESV) of at least 15% or as the improvement of LVEF of at least 10%. All episodes of VT/VF leading to appropriate therapy were prospectively collected. Hospitalizations were assessed through hospital discharge reports. Deaths and cause of death were assessed by telephonic interviews.t-test or by the Mann–Whitney U test, as appropriate, while data at baseline and at follow-up were compared by the paired samples Student's t-test or by the related samples Wilcoxon signed rank test. Categorical variables were reported as raw data and percentages and compared by the chi-square test. Correlations were assessed by Spearman's test.Continuous variables were reported as mean ± standard deviation or as median (25th–75th percentile), according to their distribution; comparisons were made by the independent samples Student's p value < 0.05 was regarded as significant. Data were analyzed by means of IBM-SPSS 20.0 .The median value of LBBB-SSc was selected as cutoff for subsequent analysis, as suggested by Wieslander et al. . A bivarp < 0.001). No significant correlations were observed between SSc and either QRS duration , age , or rhythm at implant  and for sinus rhythm 6 (4–10), p=0.078).178 consecutive heart failure patients with true-LBBB underwent CRT-D implantation in the two centers. Mean age at implantation was 70 ± 10 years, males were 120 (70%), and mean QRS duration was 161 ± 18 ms. All patients were on optimized medical therapy. Nonischemic dilated cardiomyopathy (NIDC) was the prevalent underlying disease (64%). Among ischemic patients,  and  had a previous myocardial infarction. Patients' baseline demographic, clinical, and echocardiographic characteristics are summarized in p=0.024). Fragmentation was associated with longer QRS duration  and with higher SSc (median 7 (5–12) vs 6 (3–9), p=0.004), but not with age  and rhythm at implant (p=0.894).Overall, 74 patients (41.6%) showed QRS fragmentation at their preimplant ECG: in ischemic patients, 34 had fQRS (53.1%), while in nonischemic ones, the prevalence was significantly lower (35.7%) ; two patients developed persistent/permanent AF after the first six months of follow-up. Overall, the median value of biventricular pacing was 98% (95%–99%). No lead failures, dislodgements, or loss of capture were observed.p=0.022), in sinus rhythm at time of implantation , and with lower preimplant LVEF ; SSc was significantly lower in responders than in nonresponders (5 (3–8) vs 8 (6–12), respectively, p < 0.001) (p=0.457) . QRS duration was similarly reduced in both groups . Among r< 0.001) , while np=0.457) . No othep=0.457) .p=0.003), while the presence of fQRS at baseline ECG was not . Moreover, occurrence of echocardiographic response was independently associated with female gender, the absence of diabetes, sinus rhythm at implantation, and lower LVEF before CRT (p=0.004) (p=0.940 for the former and 0.695 for the latter).The multivariable logistic regression model confirmed that SSc ≥ 7 was significantly associated with the absence of echocardiographic response to CRT  . The Hosp=0.943), cardiac death , ventricular arrhythmias , hospitalizations due to heart failure , or for the composite endpoint of MACE .No patient was lost to follow up. Over a median follow-up of 24 (9–48) months, 28 deaths occurred (15.7%), of which 18 (10.1%) were classified as cardiac deaths. Thirty-four patients (19.1%) were admitted to hospital for acute heart failure and 20 (11.2%) experienced at least one VT/VF requiring ICD intervention. Three patients experienced inappropriate ICD therapies for supraventricular tachyarrhythmias. Distribution of SSc values and of fQRS according to clinical outcomes is reported in p=0.184; cardiac death: HR: 1.384, CI: 0.516–3.712, p=0.519; VAs: HR: 1.394, CI: 0.547–3.547, p=0.486; and heart failure hospitalizations: HR: 1.060, CI: 0.506–2.223, p=0.877). No significant correlation was observed for MACE and fQRS  either.Similar results were observed when assessing the correlation between fQRS and all secondary endpoints  were nonresponders. While no relationship was observed between fQRS and response, SSc ≥7  correlated directly with the absence of reverse remodeling. These findings are in agreement with Rickard et al.  who showIn the present study, we used the median value of SSc = 7 as cutoff for the analysis after Rosengarten et al.  who spliOn the other hand, the role of fQRS in predicting response to CRT is not clearly defined. While in the works of Rad et al.  and of ROther authors postulated that resolution of fragmentation with CRT may be the sign of effective cardiac resynchronization, which may translate in a higher degree of reverse remodeling, as demonstrated by Celikyurt et al. in a series of 67 patients with fQRS at baseline ECG . HoweverMyocardial scar not only impairs LV reverse remodeling but also represents a substrate for ventricular arrhythmias: Nazarian et al. demonstrated the association between myocardial scar, evaluated by CMR, and the inducibility of ventricular arrhythmias by programmed stimulation in 20 patients referred for ICD implantation , while FFinally, in our investigation, no difference in mortality was observed either in relation to either SSc or fQRS. Similarly, SSc did not differentiate patients experiencing VT/VF, sudden cardiac death (SCD), and non-SCD in the MADIT II study . On the On the other hand, a significant association between preimplant SSc and long-term mortality after CRT has been recently demonstrated by Atwater et al. in a retrospective study of 76 patients with true-LBBB ; the autThis study have some limitations. First, ECGs made before implantation were not performed by the same operator; therefore, it is possible that slight variations in the location of electrodes might have affected the computing of the scores. Furthermore, we did not reassess the presence of fragmentation at 6 months, as we focused our interest on the evaluation of preimplant ECGs.Third, due to the retrospective nature of the study, we were able to distinguish between patients with ischemic and nonischemic etiology of HF and, among the former, to identify those who had previous myocardial infarction, but were not able to assess the severity of the underlying coronary disease.Finally, the present study did not include the assessment of myocardial scar by CMR. However, our study was performed to define a clinically useful score for a tailored CRT implantation, and the assessment of effective extension of myocardial scar was not our aim. A future prospective study combining a complete preimplant ECG evaluation and CMR may help to identify the best approach to detect the amount of myocardial scar, detectable by electrocardiography, which negatively affects the response to CRT.Our findings indicate that in heart failure patients with true-LBBB and LVEF ≤35% eligible for CRT, myocardial scar assessed by calculating the SSc on preimplant ECG is an independent predictor of nonresponse after multiple adjustments while by fQRS is not. Therefore, SSc should be preferred to fQRS in order to identify patients who are likely not to benefit from CRT. However, neither SSc nor fQRS resulted associated with overall and cardiac death, ventricular arrhythmias, or hospitalization for heart failure at a 24-month follow-up.


Fouling in food processing environment can cause the increase of production costs due to additional cleaning steps and risk of contamination of food products. There is a demand to introduce advanced techniques to detect fouling in food processing equipment. Cyclic voltammetry (CV) and square wave voltammetry (SWV) were probed in this work to detect the dairy fouling and the reconstructed dairy emulsion by platinum‐based interdigitated microelectrodes. The results demonstrated that both methods can potentially be used for the fouling detection, since the attachment of fouling to the microelectrode surface leads to lower current responses compared to the clean microelectrodes. Fouling in food processing environment can cause the increase of production costs due to additional cleaning steps and risk of contamination of food products. There is a demand to introduce advanced techniques to detect fouling in food processing equipment. Cyclic voltammetry (CV) and square wave voltammetry (SWV) were probed in this work to detect the dairy fouling and the reconstructed dairy emulsion by platinum‐based interdigitated microelectrodes. The results demonstrated that both methods can potentially be used for the fouling detection, since the attachment of fouling to the microelectrode surface leads to lower current responses compared to the clean microelectrodes. The presence of fouling leads to the significant decrease of the equipment's performance. In industrial processing equipment, different types of fouling can be found  in the bulk of the liquid being processed at higher temperatures. Many studies to explore the process of fouling have been reported by many researchers. However, a complete understanding of fouling mechanisms remains elusive due to the complexity of the dairy systems  and square wave voltammetry (SWV), to detect dairy fouling. The changes in current between the clean microelectrodes and the microelectrodes with attachment dairy fouling were determined. Surface of the microelectrodes after the fouling attachment was shown using microscopy.22.1). Potassium chloride 3 mol/L and crystal violet solution 1% were supplied by Merck . Ethanol 70% and meet extract were obtained from VWR . Powdered skimmed milk was purchased from Nestlé Deutschland AG .Potassium ferrocyanide 1% was obtained from Clin‐Tech  of powdered skimmed milk was 0.243 ± 0.032. The dairy emulsion was stirred for 5 min at approximately 120 rpm to achieve homogeneous dilution. The prepared dairy emulsion contained 0.023 g 100 ml−1 of fat, 1.3 g 100 ml−1 of carbohydrates, 0.9 g 100 ml−1 of proteins, and 0.028 g 100 ml−1 of salt. For incubation, the 6‐well plates were used . After cleaning and activation, the microelectrodes were immersed into wells. Then, 5 ml of the prepared dairy emulsion was added to each well. The 6‐well plates with microelectrodes and dairy emulsion were incubated for 18 hr at 30°C in the climate chamber. After 18‐hr incubation, the microelectrodes were removed from wells. Then, the microelectrode was used for electrochemical measurements. Both the dairy fouling that was formed of the microelectrode surface and dairy emulsions were measured and compared with the reference, the nonincubated dairy emulsion. Three types of samples were measured: (1) the reconstituted dairy emulsion after 18 hr of incubation, (2) the dairy fouling covering the microelectrode immersed in the reconstituted dairy emulsion after 18 hr of incubation, and (3) the nonincubated reconstituted dairy emulsion as the reference. Before each measurement, 5 µl of either the nonincubated reconstituted dairy emulsion or the reconstituted dairy emulsion after 18 hr of incubation was pipetted onto the surface of the microelectrodes.A reconstituted dairy emulsion was used for the formation of dairy fouling. The dairy emulsion was reconstituted by diluting 2.5 g powdered skimmed milk in 100 ml demineralized water at 22.5ºC ± 0.5ºC. Water activity  with four electrodes  were used. The working electrode has 120 feet pairs, which are 10 µm wide, with a 10 µm gap between each foot. The diameter of the electrochemical cell is 2.0 mm. A PalmSens BV bipotentiostat was used to run measurements. The measurements were performed at temperature 22.5ºC ± 0.5ºC.Before each use, the microelectrodes were cleaned using demineralized water and ethanol 70%. Then, the microelectrodes were activated electrochemically with 10 µl of 0.1 M potassium chloride by cyclic voltammetry . After activation, the microelectrodes were cleaned using sterile demineralized water.2.4begin = −0.5 V, Evtx1 = −0.5 V, Evtx2 = 1.0 V, and scan rate = 0.050, 0.100, and 0.250 V/s with overall duration of 255, 135, and 63 s, respectively. In the square wave voltammetry, the following settings were selected: Ebegin = −0.5 V, Eend = 0.05 V, Eamplitude = 0.024 V, and frequency = 25, 50, and 100 Hz with overall duration of 54, 35, and 25 s, respectively. In SWV measurements, anodic current was measured. The measurements were done in triplicate. Three scans were conducted during one measurement. A detailed description of the measurement methodology is shown in Figure In this work, cyclic voltammetry and square wave voltammetry were probed. In cyclic voltammetry, three cycles were applied to each microelectrode with the following parameters: E2.5TM PD‐30 & LuciPacTM Pen. For liquid samples, the swab stick was removed from its casing and soaked in reconstructed dairy emulsion. For microelectrode surfaces, the wetted swab stick of the LuciPacTM pen was wiped over the surface. Then, the stick was returned to the casing. The test tubing was shaken until the powdery luminescent reagent was dissolved completely. After this step, the swab stick was inserted in the device and the measurement was carried out within 10 s. The results are expressed in relative light units (RLU).The quantitative detection of the intra‐ and extracellular adenosine triphosphates (ATP) as well as adenosine monophosphate (AMP) was performed using an ATP bioluminescence method. The ATP bioluminescence method is a widespread biochemical technique to detect organic residues, like bacteria or food residues on surfaces and in liquids  was used for staining.A digital microscope  with bright‐field illumination was used to obtain microscopy images. Before taken images, the microelectrodes were dried for 2 − 3 min at room temperature. To improve the visibility of dairy fouling, 5 µl of crystal violet solution  the reconstituted dairy emulsion after 18 hr of incubation, (b) the dairy fouling covering the microelectrode with the reconstituted dairy emulsion after 18 hr of incubation, and (c) the nonincubated reconstituted dairy emulsion as the reference are depicted in Figure The cyclic voltammograms shown in the curves of Figure It can be seen that the errors from the dairy fouling and the incubated reconstituted dairy emulsion are higher than the errors from the reference at scan rates of 100 mV/s and 250 mV/s Figure b and to Table Table Figure P. fluorescens aggregation on electrodes, the pattern of the voltammograms obtained after 1, 2, 5, 10, and 100 scans approximated the voltammogram obtained for a surface without biofilm  and the sum of the variances (SV) for (1) the reconstituted dairy emulsion before incubation, (2) the dairy fouling, and (3) the reconstituted dairy emulsion after 18 hr of incubation at scan rates of 50 mV/s, 100 mV/s and 250 mV/s.Table As expected, the reconstituted dairy emulsion before and after incubation shows the lowest sum of the standard error of the mean and the sum of the variances. On contrary, the dairy fouling has the highest sum of the standard error of the mean and the sum of the variances. It can be attributed to the nonhomogeneous biofouling attachment to the surface of the microelectrodes Figure b. For al3.2The voltammograms of SWV measurements obtained at frequencies of 25 Hz and 50 Hz for (a) the reconstituted dairy emulsion after 18‐hr incubation, (b) the dairy fouling covering the microelectrode with the reconstituted dairy emulsion after 18‐hr incubation, and (c) the nonincubated reconstituted dairy emulsion as the reference are plotted in Figure The curves in Figure Table Table 3.3n = 9). After 18‐hr incubation, the RLU value slightly increased to 7,386 ± 159 RLU (n = 9). The RLU value of clean electrode surface without dairy fouling was 14 ± 6 RLU (n = 9). The RLU value of the electrode surface increased to 193 ± 60 RLU after 18 hr of incubation in the reconstituted dairy emulsion. In dairy industry, the method detects food/organic residues and offer proactive cleanliness management. Since the ATP bioluminescence test can detect all organic matter on food contact surfaces  and ɑ‐lactalbumin (ɑ‐LA), which are responsible for initial fouling formation, are of a globular nature and both proteins are act on heat. β‐Lactoglobulin is the dominant protein and also more heat sensitive than ɑ‐lactalbumin. In literature, it was shown that the initial binding of β‐LG to a metal surface is due to a chemical linkage (Visser & Jeurnink The cyclic voltammetry measurements of each sample showed that the current responses and the peak current magnitude increased with an increasing scan rate. Interdigitated ring array microelectrodes covered by dairy fouling showed the lowest current responses, when compared with the incubated and nonincubated dairy emulsions. This observation indicates that fouling on the working electrode represents an additional resistance, which extenuates the current response (Becerro et al., The study of Rouhana, Budge, Macdonald, & Roscoe, In square wave voltammetry, the current responses and the peak current magnitude of the voltammograms increased with the increasing frequency. As obtained in CV, microelectrodes covered by the dairy fouling showed the lowest current responses within their substance groups. Similarly to CV results, the adsorption of proteins to the surface can lead to the current's decrease. However, SWV was a less suitable method for the purpose of distinguishing dairy fouling from their corresponding substances with the chosen parametric setup. No oxidation peak currents could be detected. Only the current signal height could be used for the comparison between samples. This can be explained by the fact that SWV is better for quantitative analysis and therefore more sensitive in detecting specific analytes (Mirceski, Guziejewski, & Lisichkov, Also, emulsion, for example, dairy emulsions as measured in this work, is of importance and cyclic voltammetry allows them to be investigated. Through electrochemical investigations, the complex structure of dairy emulsions as mixture of immiscible liquids should be considered. According to Bagotsky, The presence of fouling is often assumed when poor process performance and decreased product quality are observed after production. Moreover, according to literature there is a lack of a reliable monitoring and detecting sensor system that allows to monitor both the fouling development and the cleaning processes in food processing equipment (Marchand et al., 5The results showed that cyclic voltammetry and square wave voltammetry measurements combined with interdigitated microelectrodes can potentially be used for the detection of dairy fouling. Cyclic voltammetry demonstrated good results for the fouling detection and for the differentiation between the dairy emulsion and the dairy fouling at different scan rates. The attachment of dairy proteins leads to the decrease in the current in cyclic voltammograms, which can be explained by the additional insulated layer on the microelectrodes that extenuates the current response. Square wave voltammetry can be recommended for the fouling detection at low frequencies. In future, electrochemical investigations under flow conditions should be performed. Moreover, the microelectrode integration into specific high‐risk parts of industrial dairy equipment has to be studied.The authors declare that they have no conflict of interest. Click here for additional data file.


Purpose: Metabolic impairment is one key contributor to heart failure (HF) pathogenesis and progression. The major causes of HF, coronary heart disease (CHD), dilated cardiomyopathy (DCM), and valvular heart disease (VHD) remains poorly characterized in patients with HF from the view of metabolic profile. We sought to determine metabolic differences in CHD-, VHD-, and DCM-induced HF patients and identify significantly altered metabolites and their correlations.Procedure: In this study, a total of 96 HF cases and 97 controls were enrolled. The contents of 23 amino acids and 26 carnitines in fasting plasma were measured by a targeted liquid chromatography and mass spectrometry (LC-MS) approach.Results: Nine metabolites  were found to be related with the occurrence of HF. Arginine, Glutamine and hydroxytetradecanoyl-carnitine could effectively distinguish CHD and DCM patients, and hydroxytetradecanoyl-carnitine and aspartic acid were able to classify CHD and VHD cohorts.Conclusion: This study indicated that circulating amino acids and long-chain acylcarnitine levels were closely associated with progression of heart failure. Monitoring these metabolic alterations by LC-MS may help the differentiation of CHD, VHD, and DCM in the early stage, and provide new diagnostics targets or therapeutic interventions. Cardiovascular disease remains to be an enormous clinical and economic burden worldwide. Due to the progressive aging of the general population and improved treatment strategies for ischemic heart disease and myocardial infarction , heart fCoronary heart disease (CHD), dilated cardiomyopathy (DCM) and valvular heart disease (VHD) are the three most common causes of HF. The clinical picture of CHD is defined by an atherosclerotic plaque-induced narrowing of the coronary arteries, which results in myocardial ischemia, infarction, and post-infarction HF. DCM may arise as a result of structural and functional myocardial abnormalities that are characterized by systolic dysfunction and dilation of the left and/or right ventricles , 3. VHD A considerable body of evidence suggests that myocardial substrate and energy metabolism play a key role in affecting the development and prognosis of HF , 11, 13.Clinical data were extracted from the medical records of patients from the First Affiliated Hospital of Dalian Medical University, Liaoning, China. Between December 2018 and December 2019, 119 consecutive patients and 97 normal individuals were enrolled in this study. Individuals enrolled were aged 18–90 years. Inclusion criteria conforms to the diagnostic criteria of Framinghan heart failure, New York Heart Association . Pure water was purified by a Milli-Q system . N-butanol, acetyl chloride, amino acids and carnitines were purchased from Sigma-Aldrich . Isotopic internal standards were purchased from Cambridge Isotope Laboratories , and were all mixed and dissolved in 2 mL pure methanol and stored at 4°C. The working fluid was diluted 100 times to extract metabolites.A circle 3 mm diameter from each dried blood spot was made. Then, 3 mm-blood-stains were placed in Millipore multilayer 96-well plates  for metabolite extraction. Every 100 μL of working fluid was added to the hole containing the dried blood spot paper to make a circle with a diameter of 3 mm. After 20 min of slight oscillation, the 96-well plate was centrifuged at 1,500 g for 2 min, and filtrate collected through the lower layer of the 96-well plate. Four blank holes were randomly selected from each plate, and two low controls and two high controls were placed separately. QC and filtrate were blow-dried with pure nitrogen at 50°C. The dried samples were derived with a mixture of 60 μl acetyl chloride and n-butanol (volume ratio 1:9) at 65°C for 20 min. Then, the derived samples were dried using the method mentioned previously. Each dry sample was dissolved with 100 μl fresh mobile phase solution for metabolite analysis.The AB Sciex 4000 QTrap system  was used for the direct sampling mass spectrometry metabolites analysis. The equipped ion source is an electrospray ion source that scans all analytes in positive ion mode. The injection volume was 20 μl, with mobile phase of 80% acetonitrile aqueous solution, and initial flow rate of 0.2 mL/min. Then, the flow rate decreased to 0.1 mL/min within 0.08 min, remained constant until 1.5 min, returned to 0.2 mL/min within 0.01 min, and remained unchanged for another 0.5 min. The ion spray voltage was 4.5 kv, the curtain gas pressure was set to 20 psi, the ion source gas 1 and gas 2 were set to 35 psi, and the auxiliary heating temperature was set to 350°C. The Analyst v1.6.0 software (AB Sciex) was used to control the system and collect data.http://www.metaboanalyst.ca/; Wishart Research Group, McGill University, Canada) was used for outlier identification and to assess quality, homogeneity, and dominating trends of the group separation inherent in the data set with unsupervised principal component analysis (PCA). Additionally, it was used to distinguish between the classes, to identify the differential metabolites with partial least squares discriminant analysis (PLS-DA), and to generate variable importance in the projection (VIP) value of the PLS-DA model. Student's t-test or Mann–Whitney test were performed to determine the difference in metabolites between the two groups. One-way analysis of variance  and correlation analysis in Galley package (R version 3.6). The receiver operating characteristic (ROC) and the respective area under the ROC curve (AUC) were calculated using the ROC package of the R software (version 3.6). ROC curve analysis estimated the optimal cut-off values maximizing sensitivity and specificity between low and high levels of methylation. The statistical analysis was performed on GraphPad Prism 8.0. The results with p < 0.05 were considered statistically significant.MetaboAnalyst 4.0 . Overall, 38 out of 49 metabolites were significantly different between the control and HF groups , Glutamine (Gln), Valine , hydroxyhexadecenyl-carnitine (C16:1-OH), acylcarnitine (C22), hydroxytetradecanoyl-carnitine (C14-OH), and free carnitine (C0) were the most important features with respect to HF metabolism   >35% were excluded. As shown in  < 0.05) , illustrThe metabolic changes between CHD and DCM were analyzed. Patients with left LVEF%>35% were excluded. The CHD cohorts were separated from the DCM cohorts in the two-dimensional score plots . SimilarThe top 9 candidates associated with HF were further evaluated for their capacity to differentiate control from HF patients. To estimate the AUC value, we performed ROC analysis. In this analysis, we observed good sensitivity and specificity. The AUC values of His, Cit, Gln, Val, C16:1-OH, C14-OH, and C0 were 0.90, 0.85, 0.89, 0.82, 0.81, 0.84, and 0.90, respectively . C22 andAdditionally, we examined the significantly changed metabolites between CHD and VHD, as well as between CHD and DCM. ROC analysis showed that AUC values are 0.77 for Val, 0.80 for C14-OH, and 0.78 for Asp between CHD and VHD . Furtherr = 0.28), BUN (r = 0.37), CRE (r = 0.34), Chol (r = −0.28), and LDL (r = −0.31) (r = 0.49), while it had a weak correlation with BNP (r = 0.29), CRE (r = 0.26), and LVEF% (r = −0.20) (r = −0.33) and Asp (r = −0.26) (r = 0.22) , and index of renal function  were tested . Signifi= −0.31) . At the = −0.20) . Additio= −0.26) , while L = 0.22) .r = −0.33) between HF and control groups , and LVEF% was negatively correlated with Arg (r = 0.22) in a dose-dependent manner  production and a key modulator of vascular tone whose ratio (asymmetric dimethylarginine/symmetric dimethylarginine) functions to monitor pathophysiological states in cardiovascular diseases –41. In ot manner . As obset manner . It was t manner .r = 0.28), BUN (r = 0.37), and CRE (r = 0.34) (It is worth noting that Cit is positively correlated with urea cycle metabolites BNP ( = 0.34) . Cit is  = 0.34) , 54. Und = 0.34)  in an in = 0.34) , 56, it  = 0.34) .Abundant evidence has demonstrated that DCM, characterized by left ventricular or biventricular dilation and impaired contraction, is the result of heart remodeling and fibrosis , 57, 58.Either pathological remodeling of the valve tissues or secondary consequences of a change in the anatomy and geometry of the cardiac structures will result in VHD , 66. ShoThe different potential causes of HF, such as CHD, VHD, and DCM, and the often-slow progression from initiation of cardiac damage to eventual signs and symptoms of HF make medical intervention in early stages to prevent irreversible damage particularly challenging. In this study, His, Cit, Gln, Val, C16:1-OH, C14-OH, and C0 were sensitive (AUC>0.8) in differentiating HF patients from the control group . At the This study investigated the role of targeted metabolomics in relation to different causes in patients with HF. The metabolic profile in patients with DCM and VHD were altered in comparison to patients with CHD. Therefore, metabolic signature was a marker for disease diagnosis in addition to LVEF%, left ventricular end-diastolic diameter (LVEDD), and left ventricular end-systolic diameter (LVESD). This also suggests that functional recovery of the heart is reflected in the metabolic signature. From the metabolic analysis, CHD-, VHD-, and DCM- induced HF all shared insufficient supply of cardiac capacity. However, VHD is characterized by abnormal regulation of glycolipid metabolism, while CHD hypoxia reflects major metabolic changes, and DCM shared similar metabolic changes with CHD but was closer to the control group than CHD in its metabolite profile. These metabolic alterations, including amino acid  and carnitine  alterations, imply potential treatment targets. For example, Cit supplementation seemed to improve cardiac function in patients with preserved ejection fraction or HF –71. BettMyocardial remodeling is an important pathological factor leading to the development of HF, at present, imaging examinations such as echocardiography and nuclear magnetic resonance can only evaluate the remodeling of the heart structure, but not the molecular level. For patients with HF, after standard anti-heart failure drug treatment or device treatment, may experience improvement in ventricular function and/or structural recovery, which is called “reverse remodeling” –75. StudThere are several limitations for the present study. Firstly, we used only one-time-point plasma samples instead of samples collected from a time course, the latter of which are much more difficult to obtain. Thus, the identified metabolic changes among HF patients  cannot be firmly confirmed as effective early diagnostic tools to monitor heart conditions. Secondly, our study reported the metabolic phenotype differences among HF groups; however, more clinical or elementary experimental studies about the prognosis effects of these phenotypes and differential metabolites in the pathogenesis remains to be clarified in the future. Thirdly, the patients were enrolled from a single center and each group had a relatively small sample size. Our future studies will search for multi-center cooperation to collect a larger number of clinical samples as external validation cohort.In conclusion, rapid diagnosis of CHD, VHD, and DCM metabolite profiles could be achieved by using a simple LC/MS approach, which only needs a small spot of blood and is easy to collect. These may lead to a future home-based medical service for people with HF for monitoring heart condition and underlying disease processes.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The study was approved by the ethics committee of the first affiliated hospital, Dalian medical university. The patients/participants provided their written informed consent to participate in this study.CL: data acquisition, analysis, and writing original draft. RL: data acquisition. YL: data interpretation. ZL: article revising. YS: data analysis. PY: conceptualization, writing—reviewing, and editing. RH: conceptualization and revising. All authors: contributed to the article and approved the submitted version.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.


To date, native T1 measurements in DMD have been reported predominantly at 1.5T. This study uses 3T CMR: (1) to characterize global and regional myocardial pre-contrast T1 differences between healthy controls and LGE + and LGE− boys with DMD; and (2) to report global and regional myocardial post-contrast T1 values and myocardial ECV estimates in boys with DMD, and (3) to identify left ventricular (LV) T1-mapping biomarkers capable of distinguishing between healthy controls and boys with DMD and detecting LGE status in DMD.Cardiovascular disease is the leading cause of death in patients with Duchenne muscular dystrophy (DMD)—a fatal X-linked genetic disorder. Late gadolinium enhancement (LGE) imaging is the current gold standard for detecting myocardial tissue remodeling, but it is often a late finding. Current research aims to investigate cardiovascular magnetic resonance (CMR) biomarkers, including native (pre-contrast) T1 mapping using a modified Look-Locker inversion recovery (MOLLI) sequence. Pre-contrast T1 mapping was performed on all boys, but contrast was administered only to boys with DMD for post-contrast T1 and ECV mapping. Global and segmental myocardial regions of interest were contoured on mid LV T1 and ECV maps. ROI measurements were compared for pre-contrast myocardial T1 between boys with DMD and healthy controls, and for post-contrast myocardial T1 and ECV between LGE + and LGE− boys with DMD using a Wilcoxon rank-sum test. Results are reported as median and interquartile range (IQR). p-Values < 0.05 were considered significant. Receiver Operating Characteristic analysis was used to evaluate a binomial logistic classifier incorporating T1 mapping and LV function parameters in the tasks of distinguishing between healthy controls and boys with DMD, and detecting LGE status in DMD. The area under the curve is reported.Boys with DMD  and healthy age-matched boys  were prospectively enrolled and underwent a 3T CMR exam including standard functional imaging and T1  and increased within-slice standard deviation (SD)  compared to healthy controls. LGE− boys with DMD also demonstrated significantly increased lateral wall native T1  compared to healthy controls. LGE + boys with DMD had decreased global myocardial post-contrast T1  and increased global myocardial ECV  compared to LGE− boys. In all classification tasks, T1-mapping biomarkers outperformed a conventional biomarker, LV ejection fraction. ECV was the best performing biomarker in the task of predicting LGE status (AUC = 0.95).Boys with DMD had significantly increased global native T1 compared to healthy, sex- and age-matched controls, even in the absence of LGE. Post-contrast T1 and ECV estimates from 3T CMR are also reported here for pediatric patients with DMD for the first time and can distinguish between LGE + from LGE− boys. In all classification tasks, T1-mapping biomarkers outperform a conventional biomarker, LVEF.Boys with DMD exhibit elevated native T Cardiovascular disease is the leading cause of death in patients with Duchenne muscular dystrophy (DMD) –3—a fataOngoing efforts to develop DMD-specific therapies may prolong life as they delay the onset of cardiomyopathy in this patient population. However, evaluating the cardiovascular response to novel therapies proves challenging due to the lack of validated cardiac imaging biomarkers for DMD disease progression. Echocardiography and cine cardiovascular magnetic resonance (CMR) imaging enables quantitative estimates of global left ventricular (LV) function including systolic and diastolic volumes, myocardial strain, and LV ejection fraction (LVEF). These metrics, however, are only sensitive to overt functional changes and do not provide insight to microstructural remodeling that may contribute to subclinical changes in heart health, fomenting myocardial fibrosis, and overall disease progression.Cardiac microstructural remodeling in DMD has been identified on pathology as progressive fibrofatty infiltration in the sub-epicardium of the LV free wall, most notably at the base of the heart , 5. This.1 years . Due to 1-mapping, whereby tissue-specific changes can be monitored over time in several cardiac pathologies  and lower LVMi . Among boys with DMD, 17 out of the 28 (61%) presented with reduced LVEF. There were no significant differences in LVEDVI, and LVESVIi between the two groups, but boys with DMD had a smaller LVEDVI and larger LVESVI compared to healthy controls. Indices of LV function are displayed in Table Boys with DMD had significantly reduced LVEF  compared to LGE− patients. For all LGE+ boys with DMD, the clinicians observed enhancement present at the lateral LV wall, but in two boys, enhancement was also present at the septal wall. LGE+ patients with DMD had a significantly larger LVEDVi  and LVESVI  and lower LVEF than LGE− patients with DMD .Nine (32%) of the DMD boys were LGE+ with at least one myocardial segment. Figure 1 values between healthy controls  as seen in Fig. 1 measurements from all controls and boys with DMD, the blood hematocrit, and the average time after contrast injection for boys with DMD (Table p = 0.03] between Site-A and Site-B and in the blood hematocrit measurements , respectively.We performed an agreement analysis between the two sites (i.e. Site-A and Site-B) and found no statistically significant differences in the measured native Tols Fig. a and boyols Fig. b. Similaols Fig. d betweenMD Table . Signifi1 maps were analyzed for the healthy controls. Within the DMD cohort, three patients were unable to complete the entire CMR exam resulting in 27 (96%) native T1, and 25 (89%) post-contrast T1 and ECV maps analyzed. Figure 1 maps (columns A-B), ECV maps (column C), and LGE images (column D) for three boys with DMD at varying stages of cardiac involvement. Guided by previous studies  and within-slice native T1 SD  and lateral  myocardial native T1 compared to LGE− boys with DMD respectively  ms vs 1277 (58) ms; p = 0.02; Fig. 1 differences for the three groups . Compared to the lateral myocardium, the septal region had significantly lower pre-contrast T1 values in both DMD subgroups. No significant within-group regional differences were observed in the healthy myocardium. LGE− boys with DMD with normal LVEF were compared against LGE− boys with reduced LVEF, but no significant differences were observed in native T1 measurements , respectively.LGE+ boys with DMD had significantly increased native T1 and ECV measurements from the cohort of boys with DMD. The following septal, and lateral myocardial post-contrast T1 values were observed: 639 (112) ms, and 591 (128) ms, respectively. A pattern of decreased post-contrast T1 in the lateral wall compared to measurements in the septal wall was observed, but this difference only reached significance in LGE+ boys with DMD . This pattern of shortened post-contrast T1 in lateral myocardium is also clearly depicted in Fig. Figure p = 0.001; Fig. p = 0.001; Table p = 0.73; Table 1, no significant differences were observed in post-contrast T1  or ECV  measurements between LGE− boys with normal LVEF and LGE− boys with reduced LVEF.ECV measurements demonstrated significant differences between the septal and lateral myocardium in patients with DMD , native T1 and LVMI , and post-contrast T1 and LVEF  were significantly correlated. In LGE− boys with DMD, a significant correlation was observed between post-contrast T1 and LVEF only . No T1 and functional metrics were correlated in healthy controls. Additional file Significant correlations between T1-mapping biomarkers and LVEF are significant predictors of DMD and LGE status (AUC > 0.50); Fig. 1 was comparable to LVEF (AUC = 0.88 vs. AUC = 0.87), but the combination of pre-contrast T1 and LVEF yielded the best performance (AUC = 0.93). Figure 1, LVEF, and the combination of the two biomarkers (AUC = 0.84 vs. AUC = 0.83 vs. AUC = 0.87), respectively. In the task of predicting LGE status, ECV (AUC = 0.95) outperformed pre- and post-contrast T1 , and LVEF (AUC = 0.84). The combination of native T1 and LVEF (AUC = 0.88) again, performed better in the task of distinguishing between LGE + vs. LGE− boys with DMD compared to each biomarker performing individually.The ROC evaluation revealed that a binomial logistic regression classifier using each biomarker in combination with the age, BMI, heart rate, and LVMI as features in all classification tasks resulted in a better model performance than each biomarker alone. Furthermore, the ROC analysis illustrated that all T1 mapping to define the cardiac microstructural differences found between pediatric patients with DMD and healthy, sex- and age-matched controls at 3T. To our knowledge, this is the first study to evaluate T1 mapping in a pediatric DMD study population at 3T. Therefore, these data help to establish reference values for both boys with DMD and healthy controls at 3T. Additionally, the study presented here is the first to investigate a classification model for identifying T1 mapping differences between boys with DMD and healthy controls and for predicting the presence of pathology associated with LGE status in DMD without requiring contrast. This study further provides evidence to support non-contrast exams in pediatric DMD patients specifically, and can be expanded to investigate T1 mapping in other cardiomyopathies, particularly in settings when the use of contrast might be contraindicated.This study used T1 values reported from this study are elevated relative to previously reported 1.5T pre-contrast T1 values   . They al1 differences observed in this study (and the above mentioned studies) between DMD patients and healthy controls are consistent with known pathological findings such as fibrosis resulting from extracellular matrix expansion in DMD muscle [1 to detect other pathologies [1. As shown by the agreement analysis between Site-A and Site-B, pre-contrast T1 is also more consistent, which makes it better for direct comparisons across sites. Importantly, native T1 could be used as an early, non-invasive surrogate biomarker for monitoring subclinical cardiac microstructural changes in DMD, thereby enabling earlier and more patient-specific treatment options.The native TD muscle , 9, 27. hologies  coupled hologies , 29 furt. [. [. [The ECV values reported herein are consistent with previously published pediatric studies , 26, 30,.  The stud. [.  and Pano1 and ECV mapping confirms the disease pattern of fibrosis in the myocardium of boys with DMD. This disease pattern is reported in pathology and imaging studies [1 and ECV, and significantly decreased post-contrast T1 are observed in the lateral wall compared to septal wall of boys with DMD. These findings are consistent with previously published studies noting that affected myocardial segments predominate in the lateral LV [The regional analysis of pre-contrast and post-contrast T studies . Signifiteral LV , 31–33. teral LV .1 mapping are also consistent with the regions in which LGE is present within the DMD myocardium  measure for each individual boy that could provide a way to better monitor microstructural changes over time. Figures 1 and ECV, suggesting that microstructural changes due to DMD predominantly appear in the myocardial lateral wall compared to the septum. In this study, post-contrast T1 appears to be a weaker determinant of disease stage and severity, as this data only demonstrates significant differences between the septum and lateral myocardium within the LGE+ DMD group. The observation that regional differences are apparent within boys with DMD provides a valuable internal control that mitigates the problems associated with not having post-contrast T1 values in the control group. These findings further motivate continued use of native T1 mapping to monitor subclinical changes in the myocardium.Furthermore, given the pattern of involvement, T1 in boys with DMD compared to healthy controls in both global and regional myocardial measurements, which could provide a biomarker of myocardial tissue heterogeneity. The T1 values obtained are a complex makeup of signal coming from both cardiomyocyte and extracellular matrix components, thus this finding warrants a T1 texture analysis to better understand the myocardial tissue differences between boys with DMD and healthy controls.We note significantly greater within-slice standard deviation of native T1 mapping [1 mapping results. In order to mitigate the heart rate dependencies on T1 mapping, the sequence parameters used in this study were within recommended guidelines [The study limitations include the general, well-known limitations related to myocardial T mapping , 37. Imp mapping . As boysidelines , 40.1 measurements between Site-A and Site-B maybe described, in part, by the contrast injection method used at each site. At Site-A, contrast was administered via contrast media autoinjector, while hand injection was the method of choice at Site-B. Kinetic measurements of the contrast injection were not acquired, thus it is not currently possible to further assess the individual contrast dynamics and their overall impact on the group-wise comparisons. This particular sub-analysis is further limited by the group sample sizes.The CMR data obtained for this study was within known institution-specific ranges and followed very controlled protocols within and between sites. The discrepancy in post-contrast myocardial and blood pool TRecruiting subjects with a rare, complex genetic disease whose cardiac involvement is understudied, is a difficult task—even more so to recruit a well-matched  control group. Therefore, this study is limited by its sample size, which further limits subgroup analyses. Herein, the control group did not undergo post-contrast CMR as this would generally be contraindicated and impractical.1 and ECV estimates in boys with DMD distinguish LGE+ from LGE− myocardium. ROC analysis revealed that in all classification tasks, T1 mapping biomarkers outperform LVEF, a conventional biomarker. Importantly, both native and post-contrast T1 and ECV estimates are promising diagnostic CMR biomarkers for assessing myocardial remodeling in Duchenne muscular dystrophy.3T CMR native T1 demonstrates the ability to characterize myocardial differences in boys with DMD and healthy, age- and sex-matched controls. Additionally, post-contrast TAdditional file 1: Figure S1. Example case from a boy with DMD showing the regions of interest (ROI) manually drawn on a mid-ventricular short-axis (A) pre-contrast/native and (B) post-contrast T1 map and (C) an extracellular volume (ECV) map. (D) The corresponding late gadolinium enhancement (LGE) image with areas of enhancement on the lateral free wall (arrows).Additional file 2: Figure S2. Pre-contrast T1 as a function of LVEDVi (A) and LVMi (B) and Post-contrast T1 as function of LVEF (C) and LVESVi (D) in healthy controls (gray circles), LGE− (red diamonds) and LGE+ (green squares) boys with DMD. The red solid lines indicate the linear regression fit. Significant correlations are outlined by the dashed-lined rectangles. Significant correlations were observed in the LGE+ group only for the following: 1) native T1 and LVEDVi; 2) native T1 and LVMi; and 3) post-contrast T1 and LVEF. In LGE− boys with DMD, a significant correlation was observed between post-contrast T1 and LVEF only. No T1 and functional metrics were correlated in healthy controls.


Cardiac catheterization therapies to treat or palliate infants, children and adults with congenital heart disease have developed rapidly worldwide in both technical innovation and device development in the previous three decades. By reviewing of current status of novel or development of devices and techniques, we will discuss what is likely to happen in paediatric heart intervention in the next decade.Recently, biodegradable stents and devices, transcatheter pulmonary valve implantation for the native right ventricle outflow tract and MRI-guided interventions have been progressing rapidly with good immediate to early results. These are expected to be introduced and spread in the next decade although there are still challenges to overcome.The future of paediatric heart intervention is very promising with rapid development of technological progress. Cardiac catheterization therapies for infants, children and adults with congenital heart disease (CHD) have progressed rapidly worldwide since Dr. William Rashkind reported the first balloon atrial septostomy for transposition of the great arteries in 1966 , 3. StenFor congenital heart disease, biodegradable stents will likely have the most utility in small infants and children. Implantation of balloon-expandable metal stents is the primary technical tool to treat vascular stenosis. The major limiting factors using bare metallic stents for paediatric field are lack of growth as the child grows, and limited expansion potential, which might require complicated surgical reintervention, in addition to other common complications, such as stent thrombosis and late in-stent stenosis. The concept of biodegradable stent (BDS) has found traction as an alternative to bare metallic stents, both in adult and paediatric applications. BDS has a number of advantages over existing bare metallic stent designs. Once biodegraded, they potentially leave behind a healed endothelialized natural vessel with further growth potential. Furthermore, BDS can act as a platform similar to their metal counterparts for either drugs or genes to promote vessel growth. Finally, BDS is readily compatible with MRI and CT imaging.Preclinical and clinical coronary studies showed late positive remodeling with normal vasomotor function after the stent disappears. BDSs have the potential to eliminate the need for repeated interventions. Long-term animal studies are warranted to confirm late positive remodeling and evaluate vessel growth and function following complete stent degradation and assess risks associated with stent fragment embolization during the degradation process.Case reports using coronary artery bioresorbable stents in paediatric patients with small vessels off-label in Europe have emerged. Zartner et al.  have desTranscatheter closure is the current standard of care for the treatment of atrial septal defects worldwide. The current devices utilize a metal framework to support the occlusive material and to permanently clamp the septum. The long-term presence of a significant amount of metal in the heart leads to rare but serious complications such as erosion, arrhythmias and thrombus formation, most likely related to incomplete endothelialization –28. In aThe Carag bioresorbable septal occluder (CBSO)  is a self-centering, double-disc device without any metal framework, composed of poly lactic-co-glycolic acid. Endothelialization of the device seems to be completed within 3 months, while the device usually starts to be resorbed after 6 months and completely resorbed within 2 years. CBSO has 3 size options: small for 4–12-mm defects, intermediate for 13–20 mm, and large for 21–25-mm defects. The animal trials were completed in 24 German Landrace pigs with created interatrial septal defects. All occlusion devices were observed to be correctly positioned without any residual shunt or dislocation after implantation, and there were no procedural or device-related complications. Complete endothelializations covered by thin and smooth whitish tissue layers were achieved in all specimens. No cellular inflammation reaction was observed •. The CBBiodegradable stents have additional challenges to overcome. Infants and children with CHD often need larger diameter stents to dilate obstructed blood vessels such as the aorta and pulmonary arteries. There are significant biomedical and engineering challenges related to durability from repeat collapse pressure and increasing elastic recoil with manufacture of larger diameter stents, especially when constructed from polymers. As ideal absorption time is unknown, there are ongoing concerns for morbidity related to thromboembolism of the BDS fragments to distal vasculature and local reactions to the degrading stents. However, there is a huge need for BDSs, which are desirable in children.Biodegradable devices are a promising future. Some devices will be introduced into the market and may be able to replace metal devices. It makes it realistic to use the devices for small children and patients with severe metal allergies, who have been hesitant to be treated percutaneously. Furthermore, it is expected that similar techniques will be applied to other devices, such as patent ductus arteriosus occluder, ventricular septal defect occluder or other plug devices.Pulmonary regurgitation after surgical repair of tetralogy of Fallot (ToF) is almost inevitable and, in the past, has required repeat surgery for replacing the regurgitant pulmonary valve. After 2000, percutaneous pulmonary valve implantation (PPVI) with balloon-expandable valves has replaced the surgical approach in a select group of patients. However, PPVI with the commercially available balloon-expandable valves have limitations because of their size, and being applicable to right ventricle-pulmonary artery conduits or bioprosthetic valves , 47. TheAll three valves are a porcine pericardial tissue valve mounted on a self-expanding nitinol frame and have proximal and distal flares that anchor the valve in the right ventricular outflow tract. The Venus P-valve is one of the leading valves, which has an asymmetrical covering design, in which the pulmonary artery end flare is not covered, permitting unobstructed flow into the branch pulmonary arteries. Currently, the Venus P-valve is available in diameters from 16 to 36 mm with 2-mm increments, with each diameter available in 20-, 25-, 30- and 35-mm straight section lengths  is another self-expandable valve with good immediate result of first human study . The AltWith further developments in the technology, a significant majority of patients may be potentially treatable by transcatheter valve technology within the next decade. The number of patients in whom transcatheter valve therapy may be an option has expanded with the advent of novel valves designed specifically for use in the larger, non-conduit, outflow tracts. Once this technology and valve-in-valve strategy are established, it will be possible to avoid repeat midline sternotomy and reduce the risk of repeat open surgery for the majority of ToF patients. In the not too distant future, if designing a percutaneous valve made of large scaffold with leaflets made of stem cell technology becomes a reality, it may be possible to avoid reoperations.Diagnostic and interventional cardiac catheterization is routinely used in the diagnosis and treatment of CHD. However, the use of radiation during repetitive x-ray–guided catheterization has led to concerns relating to the risk of solid tumours in later life, and that is particularly true in children, in whom increased radiation sensitivity, coupled with the possibility of repetitive exposure to diagnostic and interventional x-ray procedures, can lead to a significant increase of cancer risk –70. MagnInitial work using MRI catheterization employed fusion of x-ray and MRI techniques, with x-ray fluoroscopy to guide catheter placement and subsequent MRI for anatomical and hemodynamic assessment. Image overlay of previously acquired 3D MRI datasets with live fluoroscopic imaging has also been used to guide catheter procedures . More reThere have been a number of animal studies showing the safety and efficacy of interventional cardiovascular magnetic resonance (CMR) for congenital cardiac procedures. Animal interventional CMR has been used to facilitate procedures such as balloon angioplasty of arterial stenosis –81, atriMR imaging–guided cardiac catheterization has become a clinical reality Fig. , after yPaediatric heart intervention has progressed from the initial balloon atrial septostomy performed in the 1960s. The future of interventions is very promising and exciting with the development of devices, techniques and imaging modalities. Bioresorbable stents and devices may be available commercially for use in CHD, and more patients will benefit from transcatheter pulmonary valve implantation. MRI-guided interventions in children will be introduced for wider clinical use in not too distant future. Technological progress is occurring at a tremendous pace. Innovative technology such as stem cell techniques and newer device development will be applied for treatment in paediatric cardiology.


Coronary angiography can assess the anatomy of collaterals but is of limited value for evaluating their functional significance. In clinical practise, the size of collateral connection correlates is assessed by 3 grades: CC0, no continuous connection between donor and recipient artery; CC1, continuous, thread-like connection; and CC2, continuous, side branch-like connection. Its direct validation by myocardial perfusion imaging has not been established so far. The aim of this study was to assess the impact of collateral connection on infarct size and myocardial perfusion reserve by adenosine cardiovascular magnetic resonance (CMR) perfusion imaging in patients with single-vessel chronic total occlusion (CTO).Forty-two consecutive patients with CTO (occlusions older > 3 months) underwent adenosine CMR perfusion prior to percutaneous coronary intervention. Grading of collateral connection (CC0-CC2) was carried out in multiple angiographic projections prior to recanalization. Myocardial perfusion reserve index (MPRI) , the amount of infarcted area, and the number of non-viable segments were calculated and corrected for the dimension of area at risk. Data are expressed as mean ± SD or median and range (min-max), as appropriate.The angiographic grading demonstrated that 11 patients had no continuous connection (CC0), 14 patients had continuous thread-like connection (CC1) and 17 patients continuous side branch-like connection (CC2). In 75% of the patients MPRI was reduced (<2). MPRI >2 was present in 25% of patients and its prevalence significantly increased from 0% to 23.1% to 43.7% in CC0, CC1 and CC2 respectively, p = 0.03.The percentage of infarcted myocardium in the area at risk was significantly different among the three groups: 39% 0–91%) in CC0, 9% (0–79%) in CC1 and 12% (0–75%) in CC2, p = 0.038 .  is more frequently associated with smaller infarct size and a lower number of non-viable segments in the risk area. More developed collaterals are also associated with a higher prevalence of normal myocardial perfusion reserve in the area at risk. CMR perfusion is a useful non-invasive method to assess the functional significance of collateral connections.


Chronic kidney disease is highly prevalent, affecting 10% to 15% of the adult population worldwide and is associated with increased cardiovascular morbidity and mortality. As chronic kidney disease worsens, a unique cardiovascular phenotype develops characterized by heart muscle disease, increased arterial stiffness, atherosclerosis, and hypertension. Cardiovascular risk is multifaceted, but most cardiovascular deaths in patients with advanced chronic kidney disease are caused by heart failure and sudden cardiac death. While the exact drivers of these deaths are unknown, they are believed to be caused by uremic cardiomyopathy: a specific pattern of myocardial hypertrophy, fibrosis, with both diastolic and systolic dysfunction. Although the pathogenesis of uremic cardiomyopathy is likely to be multifactorial, accumulating evidence suggests increased production of fibroblast growth factor‐23 and αKlotho deficiency as potential major drivers of cardiac remodeling in patients with uremic cardiomyopathy. In this article we review the increasing understanding of the physiology and clinical aspects of uremic cardiomyopathy and the rapidly increasing knowledge of the biology of both fibroblast growth factor‐23 and αKlotho. Finally, we discuss how dissection of these pathological processes is aiding the development of therapeutic options, including small molecules and antibodies, directly aimed at improving the cardiovascular outcomes of patients with chronic kidney disease and end‐stage renal disease. AFatrial fibrillationESRDend‐stage renal diseaseFGF23fibroblast growth factor 23LVleft ventricularLVHleft ventricular hypertrophySCDsudden cardiac deathChronic kidney disease (CKD) and end‐stage renal disease (ESRD) requiring dialysis are complex, chronic conditions with a combined prevalence of 10% to 15% of the adult population worldwide.The purpose of this article is to review the current state of the art on 2 newly postulated drivers of uremic cardiomyopathy, elevated circulating fibroblast growth factor‐23 (FGF23) and reduced αKlotho, and discuss how recent insights into the pathophysiological processes has led to development of potential therapeutic options aimed at reducing the cardiovascular risk of patients with CKD/ESRD.The term uremic cardiomyopathy arose in the 1980s with reports of common abnormalities in cardiac function and structure in patients with CKD/ESRD, including increased left ventricular (LV) mass and left ventricular hypertrophy (LVH); diastolic and systolic dysfunction; as well as profound myocardial fibrosis on histology.2 have LVH on echocardiography,Increased LV mass and LVH are common manifestations of uremic cardiomyopathy. Forty percent of patients with an eGFR <30 mL/min per 1.73 mDiastolic dysfunction is highly prevalent in patients with CKD, with over two thirds affected in CKD stages 2 to 4Overt LV systolic dysfunction, as manifested by reduced ejection fraction, is uncommon in predialysis CKD with a reported prevalence of 8% and no association with eGFR.It has been suggested that increased interstitial myocardial fibrosis may be the unifying pathophysiological process underlying uremic cardiomyopathy.Studying myocardial fibrosis in CKD/ESRD has been challenging given that myocardial biopsies are not without risk, especially in multimorbid patients and therefore are not always clinically and ethically justified.The hormone FGF23, first discovered in 2000, is a circulating growth factor secreted by osteocytes whose main physiological role is to increase urinary phosphate excretion.FGF23 can also exert cellular effects via αKlotho‐independent mechanisms.2, long before increased concentrations in PTH or phosphate are observed.One of the first clinically detectable signs of CKD is an elevation in serum FGF23, probably in response to increased extracellular phosphate, although the details of the stimulus and its detection are still unclear, with levels rising steeply as kidney function worsensThe kidney is the principal source of circulating soluble αKlotho.The heart has been shown to respond to FGF23, increasing LV mass independently of blood pressure, promoting cardiac fibrosis and reducing LV systolic function in animal models.Every third to fourth cell in the heart is a fibroblast. Fibroblasts produce the extracellular matrix in the heart and act as regulators of the cardiac interstitium.Patients with CKD/ESRD are at increased risk of a wide spectrum of cardiac arrhythmias, including supraventricular tachycardias, particularly AF, and potentially lethal ventricular arrhythmias.FGF23 distrupts intracellular calcium cycling within the cardiomyocyte, which is an important risk factor for arrhythmogenesis.Large observational studies in patients with CKD or AF and in the general population have found an association between elevated FGF23 and increased risk of developing AF.Several therapies exist that directly or indirectly target FGF23, αKlotho, and abnormalities in bone metabolism. These are reviewed below and summarized in Studies in healthy subjects have shown that circulating FGF23 levels are associated with dietary phosphate intake levels,3, blocks FGF23‐induced activation of FGFR4 and cardiomyocyte growth.2 analogue) treatment did not reduce LV mass.There is strong experimental data supporting vitamin D as a potential treatment for FGF23‐mediated uremic cardiomyopathy. Calcitriol, the synthetic analogue of vitamin DIn patients on dialysis, the clinically available allosteric modulators  of the calcium‐sensing receptor, cinacalcet and etelcalcetide, are used to treat hyperparathyroidism and consistently lower circulating FGF23.In CKD patients not requiring dialysis, randomized‐controlled trials of cinacalcet have reported significant reductions in FGF23, but also poor suppression of PTH as well as high rates of hypocalcemia and hyperphosphatemia.Intensified dialysis treatment,The mechanism(s) regulating FGF23 synthesis are poorly understood and no “phosphate‐sensor” has yet been found in mammals.Indiscriminate FGF23 neutralization with monoclonal antibodies has been shown to worsen hyperphosphatemia, and increase vascular calcification and mortality in rat models of CKD.In animal studies, administration of αKlotho protein has been shown to be effective in protecting against progression of CKD.Elevated FGF23 and decreased circulating αKlotho are observed in both aging and in CKD,To date, small molecule αKlotho modulators have been identified from a high‐throughput screen of 150 000 compounds with those showing most promise being αKlotho transcription activators. Furthermore, extracellular signal‐regulated kinase phosphorylation in FGFR‐transfected cells increased, demonstrating an effect on FGF23 signaling.While patients with early stages of CKD are at increased risk of atherosclerotic complications, later stages of kidney disease are associated with heart failure and sudden death caused by uremic cardiomyopathy. Significant progress has been made over the past 2 decades in our understanding of, and ability to study the pathological basis of uremic cardiomyopathy using native T1 mapping. There are clear clinical data illustrating an association of increased FGF23 and reduced αKlotho with uremic cardiomyopathy in patients with CKD, and in heart failure and AF in subjects without known CKD. However, whether FGF23 has a truly causal relationship in uremic cardiomyopathy remains controversial. Characterization of the receptors and molecular pathways by which FGF23 might mediate LVH, cardiac fibrosis, and arrhythmias will help to identify therapeutic targets. Further work is required to identify the interplay between FGF23, cardiomyocytes and fibroblasts, and the effects of these interactions on the subsequent cardiac remodeling to reveal the molecular and cellular targets of FGF23 and αKlotho. Improved understanding is likely to enable the development of novel therapeutic interventions capable of effectively reducing the excess cardiovascular risk associated with CKD/ESRD, and perhaps even the risk of AF and heart failure in patients without CKD.This work was supported by the British Heart Foundation Accelerator Award ; British Heart Foundation Clinical Research Training Fellowships ; and British Heart Foundation Grants .None.


Thirty-eight-year-old male presented for evaluation of abdominal swelling, lower extremity edema and dyspnea on exertion. Extensive work-up in search of the culprit etiology revealed the presence of an Anomalous Right Upper Pulmonary Venous Return (ARUPVR) into the Superior Vena Cava (SVC). During the attempted repair, the pericardium was found to be thickened and constrictive. Only one other case of co-existent partial anomalous pulmonary venous return and constrictive pericarditis (CP) has been reported. The patient underwent a warden procedure with pericardial stripping with good outcomes at 45 days post-operatively. Thus, the presence of severe heart failure symptoms in the setting of ARUPVR should prompt further investigations. Also, further cases are needed to help guide management in these patients. Partial anomalous pulmonary venous return (PAPVR) is a rare congenital anomaly that is found in about 0.4–0.7% of autopsies. Once present, patients can be asymptomatic or present with non-specific cardiorespiratory symptoms . ConstriA 38-year-old gentleman presented to the heart failure clinic for evaluation of abdominal swelling, lower extremity edema, dyspnea on exertion and decreased functional capacity that has progressed over the past 2 years. Recently, he was having recurrent ascites requiring paracentesis. He underwent a GI work up that was negative and was started on diuretics. Physical examination findings were as follows: blood pressure: 121/79 mm Hg, heart rate: 86 beats/min, respiratory rate: 16 breaths/min, temperature: 36.7°C, oxygen saturation of 100% on room air. Jugular venous pressure was elevated. Shifting dullness over the abdomen, and 3+ bilateral lower extremity pitting edema was present. Lungs were clear and no murmur was heard on cardiac auscultation.Medical history is significant for obesity with a BMI of 37, type 2 diabetes mellitus, hypertension, chronic kidney disease stage 3, mild obstructive sleep apnea compliant with CPAP.The differential diagnosis of lower extremity edema, ascites, and dyspnea on exertion in this patient included: right sided heart failure, restrictive cardiomyopathy, pulmonary hypertension, left sided heart failure, constrictive pericarditis, congenital heart disease, and valvular disease. In this setting, an extensive work up was started in search of the culprit etiology.A 12-lead electrocardiography showed sinus rhythm with low QRS voltage and nonspecific T wave abnormalities. BNP was 110 pg/ml. A transthoracic echocardiography was performed and showed a resting Left Ventricular Ejection Fraction (LVEF) of 50%, normal left atrial and ventricular cavity size, right atrial and ventricular dilatation, elevated RA pressure (>15 mmHg using IVC dynamics), and septal “bounce” without other echocardiographic evidence of constrictive physiology . No atriThis case was discussed in our Adult Congenital Heart Disease Multidisciplinary Conference. There was consensus that a surgical repair is recommended to prevent further deterioration of his overall function and heart failure. He was admitted for medical optimization including diuresis and a milrinone infusion. During the operation, the pericardium appeared thickened and constrictive. A subtotal pericardiectomy was performed prior to cardiopulmonary bypass, and 6.5 × 5.2 cm and 5 × 4 cm of pericardial tissue was excised. A Warden procedure was necessary given the high implantation of the ARUPVR. After cardiopulmonary bypass was initiated, and prior to myocardial arrest, the superior vena cava was transected and directly implanted into the right atrial appendage. The heart was then arrested to permit atrial septectomy and construction of an intra-atrial baffle with an expanded polytetrafluoroethylene patch. The patient's postoperative course was uneventful. On pathology, the pericardium showed fibrosis with calcification and was negative for malignancy, acid fast and gram stains .Partial anomalous pulmonary venous return is a rare congenital anomaly that is found in about 0.4–0.7% of autopsies. Patients with isolated PAPVR tend to be asymptomatic until adulthood . This caThe patient was seen in advanced heart failure clinic 10 days after procedure for follow up. His dyspnea of exertion, lower extremity swelling, and ascites were greatly improved. At 1-month post-op, he presented to the cardiothoracic surgery clinic. His symptoms further improved, his weight remained 13 lbs. lower than his discharge weight and he did not require any cardiovascular rehospitalizations. Repeat echocardiogram done at 45 days post-op showed normal LV and RV systolic and diastolic function, along with mild right atrial and RV dilation.The combination of ARUPVR and CP is a rare occurrence. It can be difficult to diagnose and may be overlooked until older age. When ARUPVR is diagnosed, the presence of severe heart failure symptoms should prompt further investigations as patients are mostly asymptomatic in its pure form. Early recognition of this combination leads to appropriate and timely management. A Warden procedure with pericardial stripping may alleviate right heart overload with an acceptable risk profile. Further cases are needed to help guide management in these patients.The presence of right heart dilatation prompts scrutiny of the pulmonary venous anatomy.Severe heart failure symptoms in the setting of ARUPVR warrants further investigations to rule out additional culprits.To highlight a rare combination of ARUPVR and non-surgical CP.A warden procedure with pericardial stripping seems to offer good outcomes in patients presenting with ARUPVR and CP.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.RB took the lead in writing the manuscript. All authors cared for the patient, provided critical feedback, and helped shape and edit the final 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.


Left ventricular (LV) ejection fraction (EF) and LV volumes were reported to have prognostic efficacy in cardiac diseases. In particular, the end-systolic volume index (LVESVI) has been featured as the most reliable prognostic indicator. However, such efficacy in patients with LVEF ≥ 50% has not been elucidated.  We screened the patients who received cardiac catheterization to evaluate coronary artery disease concomitantly with both left ventriculography and LV pressure recording using a catheter-tipped micromanometer and finally enrolled 355 patients with LVEF ≥ 50% and no history of heart failure (HF) after exclusion of the patients with severe coronary artery stenosis requiring early revascularization. Cardiovascular death or hospitalization for HF was defined as adverse events. The prognostic value of LVESVI was investigated using a Cox proportional hazards model. P/dt, LVEF, LV end-diastolic volume index (LVEDVI), and LVESVI were associated with adverse events. A correlation analysis revealed that LVESVI was significantly associated with log BNP level , +dP/dt , −dP/dt , and tau . Multivariable analysis with a stepwise procedure using the variables with statistical significance in the univariable analysis revealed that aging, an increase in BNP level, and enlargement of LVESVI were significant prognostic indicators . According to the receiver-operating characteristic curve analysis for adverse events, log BNP level of 3.23 pg/ml (BNP level: 25.3 pg/ml) and an LVESVI of 24.1 ml/m2 were optimal cutoff values .  A univariable analysis demonstrated that age, log BNP level, tau, peak − d In patients with LVEF ≥ 50%, an increased LVESVI is related to the adverse events. LV contractile performance even in the range of preserved LVEF should be considered as a role of a prognostic indicator. Left ventricular (LV) ejection fraction (EF) and LV end-diastolic and end-systolic volumes  are commonly used as clinical parameters reflecting global LV systolic performance or LV remodeling , 2. Of nIn consecutive 465 patients who underwent cardiac catheterization to diagnose possible coronary artery disease and comprehensive cardiac function analysis from May 1999 to January 2011, LVESV as well as LVEDV was measured using biplane contrast left ventriculography and LV pressure was recorded using a catheter-tipped micromanometer. In this cohort, we retrospectively enrolled a total of 355 patients who satisfied the eligible inclusion and exclusion criteria of this study. The inclusion criteria consisted of age, 20 years or older; LVEF ≥ 50%; no history of hospitalization for HF prior to the enrollment; and no change in baseline drug therapy for 1 month prior to the enrollment. The exclusion criteria were acute coronary syndrome requiring urgent coronary revascularization and severe coronary artery stenosis with symptoms suggestive of myocardial ischemia or coronary stenosis from 50 to 90% with myocardial ischemia. The myocardial ischemia was diagnosed by exercise or drug-induced stress electrocardiogram, myocardial nuclear perfusion imaging, or echocardiography; serum creatinine level > 2.5 mg/dL; old myocardial infarction resulting in LVEF < 50%; hypertrophic cardiomyopathy or infiltrative cardiomyopathy such as amyloid cardiomyopathy; cardiac rhythm other than sinus rhythm including pacemaker rhythm; hemodynamically significant aortic or mitral valve disease; and any serious noncardiovascular disease expected to live within 6 months such as malignancy.dP/dt) and computed a time constant tau of LV pressure decay during isovolumic relaxation using the method proposed by Weiss et al. [We collected data on demographics, laboratory values, medication, LV volumes, and LV function parameters. Before using contrast agents in cardiac catheterization, we first computed cardiac output (CO) with a thermodilution method and calculated the cardiac index (CI) where CO was normalized by the body surface area. We then obtained LV pressure using a catheter-tipped micromanometer  and it was recorded on a polygraph system  and also on a digital data recorder  at a sampling interval of 2 ms. From the LV pressure recording, we determined peak positive and negative first derivatives of LV pressure  curve analysis for the composite endpoint of this study. Then, the whole study patients were divided into 2 groups using the optimal cutoff values. The Kaplan-Meier event-free survival curves in these 2 groups were compared by the log-rank test.Continuous data are presented as the mean ± SD, and categorical variables are summarized as frequency and percentage. We evaluated the contribution of each clinical variable to the relative hazard of experiencing the composite endpoint of this study using a Cox proportional hazards model. Then, we assessed the correlations of LVESVI with the variables which reached statistical significance in the univariable analysis. Furthermore, we evaluated the contribution of clinical variables using a multivariable Cox regression analysis with a stepwise procedure using the variables with a statistical significance in the univariable analysis. We defined the day of cardiac catheterization as the time of enrollment of a patient in this study. And we adopted the duration of observation as the time from the enrollment to the occurrence of a terminal endpoint or the last censoring when patients were survived without adverse events during the follow-up period. Besides, when the study patients needed percutaneous coronary revascularization or surgical coronary artery bypass grafting during their follow-up period, these patients were defined as censored cases and the duration between the enrollment and the time of coronary interventions was adopted as an observation period for them. A All statistical analyses were performed with SPSS version 23.0 software . This study was conducted in full accordance with the Declaration of Helsinki, and it received approval from the Institutional Review Boards and Ethics Committees of the Nagoya City University Graduate School of Medical Sciences.The clinical characteristics of the whole patients are shown in During the follow-up period , 9 cardiovascular deaths and 15 hospitalizations for HF were documented. Among 355 patients who were enrolled in this study, 41 patients needed percutaneous coronary revascularization and 2 patients underwent surgical coronary artery bypass grafting during their follow-up period. All of them did not experience concomitant HF.P/dt, LVEF, LVEDVI, and LVESVI showed significant associations with adverse events. The correlation analyses were performed to examine the associations of LVESVI with these parameters and CI  as well as the peak ± dP/dt, and tau .In s and CI . We founp=0.024; log BNP, HR: 1.533, 95% CI: 1.090 to 2.156, p=0.014; LVESVI, HR: 1.051, 95% CI: 1.011 to 1.093, p=0.013, respectively).In the multivariable Cox proportional hazards model which used all parameters with statistical significance in the univariable analysis, aging, an increase in BNP level, and enlargement of LVESVI were selected as significant predictors of the adverse events . Compared to the patients with log BNP level ≤3.23 pg/ml, those with log BNP level >3.23 pg/ml showed significantly worse event-free survival (log-rank test: p < 0.001)    . In addi< 0.001) . Comparep=0.001) .In the current study, we demonstrated that an enlargement of LVESVI as well as an increase in BNP level and aging had a significant power to predict cardiac death and de novo HF even in patients with LVEF ≥50%. In contrast, LVEF and LVEDVI were not selected as an independent parameter related to the outcome in the multivariable analysis. BNP and N-terminal proBNP (NT-proBNP) are described in the current guidelines as gold standard biomarkers for the diagnosis and evaluation of the prognosis of HF. Furthermore, natriuretic peptide level-guided risk stratification of patients with symptoms suggestive HF is used in clinical practice , 13. ConIn patients with HF, LVEF and LV volumes are reflecting global LV systolic performance or associated with LV remodeling , 2. CoinThe reliability of LVESV as a prognostic indicator may arise from the higher sensitivity of LVESV for the ventricular contractile performance change. LVESV is determined directly by LV contractility as well as afterload to the left ventricle and not dependent on LVEDV. LVEDV is determined by the mechanism presented by Frank and Starling according to the given LVESV . Hence, Most patients with HFpEF showed normal LV filling pressure at rest; however, an abnormality in LV filling pressure developed during physiological stress like exercise or volume loading –23. CompP/dt, suggesting that strong elastic recoil force existed concurrently with good contractile performance in the left ventricle [P/dt. These findings suggested that an increase in LVESVI concomitant with impairment of LV relaxation could be a prognostic indicator of new-onset HF.A small LVESV indicated that LV maintained not only good contractility but also a strong elastic recoil force of myocardium. Thus, it has been used as a parameter of elastic recoil of the left ventricle , 25. Durentricle . SimilarThis study had several limitations. First, we analyzed data retrospectively in a single institution. Second, the study patients were with a low incidence of new-onset HF. Most patients had some risk factors for HFpEF, such as hypertension, diabetes mellitus, and coexistence of coronary arteriosclerosis not requiring early revascularization. In addition, the median BNP level was in the normal range and all patients were in sinus rhythm. Thus, a future prospective study is needed to strengthen our conclusions, with a larger study cohort that includes more patients with a history of hospitalization for HFpEF.2 is associated with the future occurrence of the adverse events in such patients. Even in patients with LVEF >50%, LV contractile performance does have an impact on the patient's prognosis.In conclusion, in addition to an increase in BNP level and aging, an enlargement of LVESVI has significant prognostic power for adverse events even in patients with LVEF ≥ 50%. An enlargement of LVESVI exceeding 24.1 ml/m


BackgroundObstructive sleep apnea (OSA) has been described as a risk factor for cardiac arrhythmias. Its association with atrial fibrillation has been established. However, relationships with other arrhythmias and conduction disorders have not been fully studied.MethodsWe used the National Inpatient Sample database from 2009 to 2011 to explore the relationship between OSA and arrhythmias and conduction disorders. The presence of diagnosis was determined based on the International Classification of Disease-9 (ICD-9) codes. Univariate and multivariate logistic regressions were used to establish mortality risks among all groups.ResultsMultivariate logistic regression showed increased mortality in patients with OSA in comparison to patients without OSA and patients across all categories of arrhythmias and conduction disorders. One significant finding was the increased association of cardiac arrest in patients with OSA versus patients without OSA .ConclusionsOSA is significantly associated with non-atrial fibrillation arrhythmias, conduction disorders, and sudden cardiac arrest. Awareness regarding this association is important for early screening for OSA in obese patients to prevent cardiovascular morbidity and mortality. The use of continuous positive airway pressure (CPAP) might be beneficial against all kinds of arrhythmias and sudden cardiac death. In the United States, 35.5% of adult men and 35.8% of adult women are obese . The obeExcept for atrial fibrillation, the risk of arrhythmias with OSA has not been fully established ,6. CintrIn our study using a US national database, we try to explore the possible association of mortality in hospitalized patients with OSA and significant rhythm disorders such as atrial fibrillation, ventricular fibrillation, complete heart block, and cardiac arrest.Study populationWe utilized the National Inpatient Sample (NIS) database from the years 2009 to 2011. NIS is the largest all-payer inpatient care database in the US and contains discharge level information of 7-8 million hospital stays. This is a 20% stratified clustered sample from all US hospitals. It is federally sponsored by the Agency for Healthcare Research and Quality . PatientStatistical methodsSTATA version 13.0  was used for the analysis of this survey sample data. Categorical data were expressed as a percentage with Chi-square testing used to compare percentages. Continuous variables were reported as means with standard errors. Associations of mortality in OSA with various arrhythmias were compared by univariate and multivariate analyses with logistic regression. Multivariate analyses were controlled for age, sex, race, smoking, obesity, dyslipidemia, diabetes, ischemic heart disease, valvular heart disease, heart failure, transient ischemic attack, stroke, hypothyroidism, chronic kidney disease, and Charlson comorbidity index. A two-tailed p-value of p < 0.05 was considered significant.The total number of discharge records in the NIS database from 2009 to 2011 was 23,634,793 . Over 16,857,367  records were used for analysis after exclusion as explained in Figure The baseline characteristics of OSA patients are presented in Table Different mechanisms have been proposed regarding the pathogenesis of arrhythmias and conduction disorders in OSA. OSA causes repeated hypoxia/hypoxemia during episodes of apnea/hypopnea throughout sleep . This reNegative intrathoracic pressure generated during apnea/hypopnea in OSA has also been described in the pathogenesis of arrhythmias by increasing direct tension on the intrathoracic structures such as the heart. This was found to shorten the atrial refractory period and enhance single premature beats to induce atrial fibrillation ,20. GamiNegative intrathoracic pressure can also be simulated by the Muller maneuver and inspiratory threshold device. The tension generated by fluctuations in intrathoracic pressure in OSA may also cause QT-prolongation with an effect on cardiac repolarization, leading to an increased sympathetic activation. Prolonged QT interval is another risk factor for fatal arrhythmias such as torsades de pointes leading to cardiac arrest . Gami etRoche et al. noticed a greater incidence of nocturnal sinus bradycardia and sinoatrial paroxysmal block in OSA but not significant conduction disorders such as complete AV block . KoehlerDoherty et al. found a significant reduction in cardiovascular deaths (not contributed by arrhythmia) in OSA patients using continuous positive airway pressure (CPAP) in comparison to OSA patients not using CPAP  . In contOSA patients are at greatest risk for sudden cardiac death during sleep hours; midnight to early morning. Thus, using a CPAP at night may still be beneficial against the prevention of arrhythmias, conduction disorders, and sudden cardiac arrest. It will be interesting to see studies exploring this in the future.