His bundle pacing is a new method for delivering cardiac resynchronization therapy (CRT).The authors performed a head-to-head, high-precision, acute crossover comparison between His bundle pacing and conventional biventricular CRT, measuring effects on ventricular activation and acute hemodynamic function.Patients with heart failure and left bundle branch block referred for conventional biventricular CRT were recruited. Using noninvasive epicardial electrocardiographic imaging, the authors identified patients in whom His bundle pacing shortened left ventricular activation time. In these patients, the authors compared the hemodynamic effects of His bundle pacing against biventricular pacing using a high-multiple repeated alternation protocol to minimize the effect of noise, as well as comparing effects on ventricular activation.In 18 of 23 patients, left ventricular activation time was significantly shortened by His bundle pacing. Seventeen patients had a complete electromechanical dataset. In them, His bundle pacing was more effective at delivering ventricular resynchronization than biventricular pacing: greater reduction in QRS duration , left ventricular activation time , and left ventricular dyssynchrony index . His bundle pacing also produced a greater acute hemodynamic response . The incremental activation time reduction with His bundle pacing over biventricular pacing correlated with the incremental hemodynamic improvement with His bundle pacing over biventricular pacing .His resynchronization delivers better ventricular resynchronization, and greater improvement in hemodynamic parameters, than biventricular pacing.  Left bundle branch block (LBBB) is deleterious in patients with heart failure. Biventricular pacing improves the activation pattern, instantly shortening left ventricular activation time (LVAT) and immediately improving cardiac function. Long-term studies show substantial reduction in morbidity and mortality Biventricular pacing (BVP) was first recognized as a potentially beneficial therapy from its clear hemodynamic effect His bundle pacing (HBP) has the potential to offer greater ventricular resynchronization because large reductions in QRSd have been observed when stimulating the His-Purkinje system in patients with LBBB In this prospective study, we tested the ability of HBP to deliver resynchronization. We then compared the electromechanical effects of His resynchronization against conventional BVP, using high-precision hemodynamic assessment We defined His resynchronization as HBP that significantly shortens LVAT. We measured LVAT using noninvasive epicardial electrocardiographic imaging (ECGI). Because the margin of error of this measurement is up to 10 ms, we defined shortening as 10 ms to assess true resynchronization effects rather than measurement variation.Patients at a single tertiary cardiac center  scheduled for conventional biventricular pacemaker implantation with or without defibrillator were recruited. Indications for BVP were based on standard clinical criteria Patients were fitted with a 252-electrode ECGI vest  Temporary HBP was achieved via either the femoral or subclavian approach. If the femoral route was used, a quadripolar electrophysiology catheter was placed on the bundle of His, and a second catheter was positioned in the right atrial appendage for sequential atrial followed by His (AH) pacing. If the subclavian route was used, a SelectSecure 3830 lead was delivered via either a C304-His deflectable sheath or C315 fixed curve sheath (leads and delivery system: Medtronic). The lead was not actively fixated. The atrial lead for the CRT device was used to allow AH sequential pacing. The atrial and His leads were connected to the Micropace pacing system  that allowed pacing at selected AH delays. To minimize the research protocol duration during implant procedures, we did not routinely measure capture threshold or LBBB correction thresholds, because we did not actively fixate the His lead. The Micropace pacing output was programmed to 25 mA for all patients. Although this is a high output, this does not reflect the threshold of correction and furthermore Ajijola et al. HBP was attempted from the right atrium in its typical location at the anteroseptal atrioventricular (AV) groove. The His bundle was located using the electrogram (EGM) signal obtained from the catheter/lead. His bundle capture was confirmed by analysis of the 12-lead surface ECG and the catheter/lead EGM. Selective His bundle capture was differentiated from nonselective capture using standard definitions Biventricular pacing was performed via the CRT device, which was implanted using the standard clinical technique . Some patients agreed to the study protocol but declined the additional invasive monitoring. In these patients, noninvasive beat-by-beat blood pressure was acquired , which has been previously validated for the assessment of acute hemodynamic changes in this setting We have previously shown the importance of performing multiple repeated hemodynamic measurements between a reference and tested setting, in order to prevent spontaneous fluctuations being misconstrued as a response to pacing therapy The peak blood pressure response and its CIs were calculated by fitting a quadratic curve to the data from each set of tested AV delays . Analysit-tests. The relationship between the hemodynamic response and change in activation time was analyzed using Pearson’s correlation. Statistical analyses were performed using the statistical environment R In the primary analysis, we included all patients with a complete dataset, in whom the His-paced LVAT-95 was at least 10 ms shorter than during intrinsic conduction. This was selected on the basis of the standard deviation of the difference for change in LVAT-95 being <10 ms so that changes larger than this could be attributed to true resynchronization effects rather than measurement variation. Furthermore, this stringent cutoff could be applied without the potential for unintentional bias introduced by the researcher  and assesses LV activation regardless of whether selective or nonselective capture occurs. The power calculation for this sample size is in the Twenty-three patients were recruited. In 4 patients, temporary HBP did not shorten LVAT-95 by ≥10 ms, and these patients were therefore excluded from the main analysis. In 1 patient, a technical fault prevented acquisition of ECGI data, and they were therefore also excluded from the analysis.Eighteen patients therefore demonstrated the 10-ms LVAT-95 shortening required by our definition of His resynchronization. In 1 of them, ECGI data could be collected during His pacing, but not during BVP.Therefore, the full dataset of ECGI and hemodynamic data for both HBP and BVP was available in 17 patients . Six hadBoth HBP and BVP significantly shortened 12-lead ECG QRSd . HBP resulted in significantly more QRS shortening compared with BVP: the mean within-patient change in QRSd from BVP to HBP was −18.6 ms  .Figure 2Using noninvasive epicardial mapping, both His bundle and BVP significantly reduced LVAT-95 compared with intrinsic activation . HBP reduced LVAT-95 significantly more than BVP: the mean within-patient change in LVAT-95 from BVP to HBP was −26.4 ms  . Using aBoth HBP and BVP significantly reduced the LVDI . HBP reduced LVDI significantly more than BVP: the mean within-patient change in LVDI from BVP to HBP was −11.3 ms  . An examBoth His bundle and BVP significantly increased acute SBP compared with AAI pacing  in the 18 eligible patients in whom the full hemodynamic dataset was acquired. The improvement in SBP was significantly higher with HBP than with BVP  .Figure 62 = 0.49, R = 0.70; p = 0.04) (There was a significant correlation (R = 0.04)  between In the 4 patients where HBP did not reduce LVAT-95 by >10 ms, there was still an increase in SBP with HBP .In this study we have, for the first time, quantified the acute effect of cardiac resynchronization therapy delivered with HBP, using high-precision hemodynamic measurements, and performed within-patient comparisons with BVP. We found that His resynchronization therapy delivers significantly greater improvements in acute hemodynamic response than BVP . We usedWe found that HBP successfully delivered ventricular resynchronization in 83% of patients. In these patients, where HBP convincingly shortens LVAT, His resynchronization therapy resulted in significantly greater improvements in acute hemodynamic function compared with BVP. His resynchronization therapy delivered approximately a 60% increase in acute SBP, compared with BVP .BVP is the current gold standard method for delivering CRT. Hemodynamic studies have consistently demonstrated acute improvements when BVP is delivered to patients with LBBB and LV impairment The correlation between activation time shortening and acute hemodynamic response suggests that the improved hemodynamic response with HBP is driven by more effective ventricular resynchronization .His resynchronization therapy provided more than twice as much reduction in LVAT-95 and LVDI compared with BVP. BVP therapy appears to deliver some of its beneficial effect by improving atrioventricular timing The ventricular activation maps obtained during His pacing typically showed resolution of the LBBB activation pattern seen during intrinsic conduction. Our finding that the degree of shortening of ventricular activation time is proportional to the improvement in function is potentially important. Ventricular activation could feasibly be quantified at the time of lead implantation. The His lead could then be positioned at the site of greatest activation time reduction, to facilitate maximal improvements in myocardial performance.His pacing has other potential advantages compared with BVP. It does not require the use of contrast and is not limited by diaphragmatic capture or the constraints of the coronary sinus anatomy.There are several possible explanations for how His Bundle pacing reduces activation time in bundle branch block. The simplest explanation is that the pacing lead is positioned distal to the site of block, thus recruiting distal conduction fibers that are longitudinally dissociated  Our study expands upon the existing published reports regarding correction of LBBB by HBP with important new consequences. Lustgarten et al. The study has many fewer patients than a long-term event trial. This is because when endpoints are continuous variables, rather than event counting, each patient contributes far more power. By using high-precision hemodynamic assessment and high-resolution electrical mapping, we were able to confidently assess the individual patient responses and correlate the electrical response to the hemodynamic response. The source of precision and statistical power is the large numbers of measurements per patient, which provided narrow error-bar measurements. This study was not specifically powered to discriminate different responses of ischemic and nonischemic cardiomyopathies to HBP. However, it was encouraging that we observed successful His resynchronization in both.This was an acute hemodynamic study. We do not know if the significant improvements in activation time and acute hemodynamic response we observed will translate into better hemodynamic outcomes with longer-term follow-up. The previous experience with BVP supports the concept that short-term resynchronization induced improvements translate into longer-term benefits. However, this question can only be answered by randomized controlled trials with long-term follow up. The findings from this study provide justification for these trials. Ventricular remodeling in response to chronic electrical resynchronization may contribute to the long-term clinical improvements seen with BVP. It is plausible that superior ventricular resynchronization with HBP may lead to greater long-term effects on ventricular remodeling, but this needs to be tested in dedicated studies.Biventricular pacing is reported to be variable in its response rate Although noninvasive ECGI mapping provides high-resolution data of activation and allows segregation of regional activation, there are potential problems including assumptions of static geometry and interpolation accuracy We did not observe successful ventricular resynchronization with HBP in all patients in this study, which is consistent with the findings of other studies PerspectivesCOMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: In patients with heart failure and LBBB, His bundle pacing is associated with more effective ventricular resynchronization and greater improvement in systolic blood pressure than cardiac resynchronization therapy with biventricular pacing.TRANSLATIONAL OUTLOOK: Randomized trials comparing His bundle pacing against biventricular pacing are needed to guide selection of optimum device-based therapy for patients with heart failure and LBBB.CRT delivered using HBP appears to be a very promising alternative to BVP in patients with LBBB and heart failure. It can deliver larger reductions in ventricular activation time, which leads to significantly greater improvements in acute hemodynamic function. The magnitude of these improvements suggest that His resynchronization therapy has the potential to produce better clinical outcomes than BVP.


It is now established that the entity often described as an “aortopulmonary septal complex” is better considered as an “outflow tract septal complex”. This change is crucial for appropriate understanding of not only malformations of the outflow tract, but also ventricular septal defects. Thus, the embryonic outflow tract, as it develops, is separated into its two components by fusion of a protrusion from the dorsal wall of the aortic sac with the distal end of the outflow cushions. The key point with regard to morphogenesis is that, with ongoing development, these structures lose their septal integrity, although they can still be identified as septal structures when the ventricular septum itself is deficient. In the normal postnatal heart, however, the aortic and pulmonary components have their own walls throughout the length of the outflow tracts. All of this is of clinical significance, since some current concepts of categorisation of the ventricular septal defects are based on the existence in the normal heart of a “conal septum”, along with a “septum of the atrioventricular canal”. In this review, we show how analysis of postnatal hearts reveals the definitive ventricular septum to possess only muscular and fibrous components in the absence of either discrete outflow or inlet components. We also show that this information regarding development, in turn, is of major significance in determining whether categorisation of ventricular septal defects is best approached, in the first instance, on the basis of the borders of the defects or the fashion in which they open to the right ventricle. When deOne of the systems currently used for the categorisation of ventricular septal defects  is basedOur own studies, based on extensive examination of normal hearts in the autopsy room , do not We have now validated our examinations made on the basis of dissection by using high-resolution magnetic resonance imaging of an intact autopsy specimen prior to its subsequent dissection. Thus, in We then provided further information regarding the inter-relationships of the ventricular components by interrogating computed tomographic datasets obtained during life from individuals undergoing assessment for suspected coronary arterial disease .The images confirm that there is no “outlet septum” to be found in the normal heart. Instead, it is a free-standing infundibular sleeve which lifts the leaflets of the pulmonary valve away from the base of the left ventricle C. It is It is the lack of any “outlet septum” in the normal heart that is directly relevant to the appropriate change in terminology from “aortopulmonary septal complex” to “outflow tract septal complex” as proposed by Poelmann and Gittenberger-de Groot . Our invWith ongoing development, it is the outflow cushions, rather than the aortopulmonary septum, which fuse to separate the developing aortic and pulmonary roots and the ventricular outflow tracts. Although initially having a septal function, these structures cease to interpose between the outflow channels subsequent to closure of the embryonic interventricular foramen. This is because, once separated, the aortic and pulmonary roots develop their own discrete walls, with no septal structures interposing between them. With the passage of time, the proximal parts of the outflow cushions also fuse and then muscularise. Subsequent to closure of the interventricular communication, the muscularised entities lose their septal function, becoming transformed into the free-standing muscular infundibular sleeve. Thus, by the time of birth, there are no septal entities interposing between the entire lengths of the right and left ventricular outflow channels. This means that although the structures are appropriately described as the “outflow tract septal complex” during the period of intrauterine development , they caOur developmental findings are also pertinent to the suggestion that there is within the normal muscular ventricular septum a component derived from “the septum of the atrioventricular canal” . It is nPoelmann and Gittenberger-de Groot  are corrIt is knowledge of their borders, rather than their geographical location, which provides the crucial clinical information regarding the disposition of the atrioventricular conduction axis . As we sThe defect shown in These confluent defects cannot currently be coded within the definitions submitted by the International Nomenclature Society for inclusion in the 11th iteration of the International Classification of Disease . It is r


Acute myocardial infarction (AMI) is one of the most deleterious conditions leading to cardiovascular diseases and mortality. The importance of an early and accurate diagnosis assures immediate medical treatments, which are fundamental to reduce mortality and improve prognoses. AMI is associated to an inflammatory response which includes the increase of circulating inflammatory cytokines, chemokines and immune cell activation. This study aimed to identify which are the very early immune-related biomarkers that may be used as predictors of myocardial infarction severity. In order to mimic the pathophysiological events involved in human myocardial infarction, a temporary occlusion (90 min) of the mid-left anterior descending coronary artery was performed in a swine animal model.Lymphocyte subsets analysis in peripheral blood revealed significant alterations in CD4+/CD8+ ratio and naïve and effector/memory T cell percentages at 1 h post-myocardial infarction. Changes in TH1/TH2-related cytokine, monocyte and neutrophil markers gene expression were observed in peripheral blood lymphocytes, as well. Additionally, significant correlations between cardiac parameters  and blood-derived parameters (cytokine expression and lymphocyte subset distribution) were found.Peripheral blood lymphocyte alterations are easily and swiftly detectable, so they may be good biomarkers for a very early prognosis and to predict myocardial infarction severity. Acute myocardial infarction (AMI) is one of the main death causes in the world. Only in the United States, over 795,000 myocardial infarctions occur each year . ConsequMyocardial infarction results from the occlusion of a coronary artery and the subsequent myocardial ischemia. The generated ischemia results in cell death, initiating an inflammatory response ultimately resulting in scar formation . During Preclinical studies in cardiovascular research are necessary for the translation of basic research to the clinic. Animal models are widely used in the research of cardiovascular disease pathogenesis and drug therapy . Swine aSeveral evaluation methods and follow up procedures have been established for the swine myocardial infarction model. Biomarker tests combined with electrocardiographic analysis are the most used procedures for AMI diagnosis. Moreover, echocardiography and cardiac magnetic resonance imaging are commonly performed for the non-invasive detection of myocardial and scar mass, left ventricular volumes, geometric remodelling, scar reduction, contractility, myocardial perfusion and viable myocardial mass regeneration. On the other hand, cardiac enzymes can be detected in plasma at 4–6 h post-infarction and are the currently preferred diagnosis biomarkers for AMI . The aimThe phenotypic analysis of peripheral blood lymphocytes (PBLs) in the animal model was analyzed by flow cytometry before and 1 h after myocardial infarction model creation. Statistically significant differences were found in peripheral blood T-cell subsets. The percentage of CD4+ T cells (gated as CD4+ CD8–) was significantly increased, while CD8+ T cells (gated CD4- CD8+) percentage decreased 1 h after myocardial infarction, in comparison to pre-AMI levels. Consequently, the CD4/CD8 ratio was significantly raised at 1 h after model creation. No statistically significant difference was found in NK cells (gated as CD3- CD8- CD4- CD16+) percentage  and effector/memory T cells (CD45RA–CD27–) were compared before and 1 h after myocardial infarction. No significant changes were observed in CD4+ T cells. Nevertheless, the percentage of CD8+ naïve T cells and CD8+ effector/memory T cells exhibited substantial statistically significant differences (p‹0.001). While the CD8+ naïve T cell subsets significantly increased 1 h after myocardial infarction, the CD8+ effector/memory T cell subsets had a substantial decrease 2, IFNγ, Tumor Necrosis Factor α (TNFα), IL12) decreased 1 h after myocardial infarction, but only IFNγ showed significant differences (p‹0.01)  and Troponin I) was found at 24 h when compared to baseline levels. Cardiac Magnetic Resonance at day 7 after myocardial infarct induction showed a significant decrease of Left Ventricular Ejection Fraction (% LVEF) as well as a significant increase of myocardial infarction Table .Table 1DCorrelation analysis between cardiac parameters  and immunological markers (T cell subsets and gene expression) was performed since it may be useful for the evaluation and follow-up of myocardial infarction in this animal model.p = 0.0367)  were found to be strongly and positively correlated, as well as CK-MB at 7 days and CELA at 1 h . Contrarily, strong negative correlations were identified between Troponin I at 24 h and IL2 at 1 h , CK-MB at 7 days and IFNγ at 1 h  and % LVEF at 7 d and IL5 at 1 h  .AMI is defined as myocardial necrosis after a marked ischemia. Tissue injury generates endogenous signals that activate the innate immune system. The immune cells identify these signals and induce molecular pathways that lead to the recruitment of inflammatory cells in the healing infarct . Our resMore precisely, we have found that the ratio CD4+/CD8+ T cells increases due to an increase of percentage of CD4+ T cells and a decrease of CD8+ T cells. These findings are consistent with the results found in AMI patients diagnosed no more than 12 h from the onset of symptoms . In thisRegarding lymphocyte differentiation/activation status, an increase in naïve T cells (CD8+ CD45+ CD27+) and a decrease in the effector/memory T cells (CD8+ CD45- CD27-) could be detected at 1 h post-infarction. The loss in peripheral blood CD8+ memory T-cell subsets may be caused by entrapment in the coronary microcirculation early after the onset of reperfusion, as shown in myocardial infarction patients . MoreoveCytokines are secreted as cellular signalling proteins that can mediate effector and regulatory effects on the immune response playing an essential role during T cell differentiation. Cytokine levels have been used as biomarkers for the diagnosis of multiple diseases such as rheumatoid arthritis , multiplRegarding peripheral blood monocytes, these cells migrate to the site of injure and infiltrate as macrophages. Using the coronary ligation technique in mice, it was observed that a large proportion of these newly recruited monocytes were provided by the spleen, increasing the blood monocytes before the recruitment into infarcted cardiac tissue . This thAdditionally, in order to correlate lymphocyte subset distribution and gene expression levels with “classical” cardiac parameters, a correlation analysis was performed with the data from cardiac magnetic resonance imaging (% LVEF and Infarct area) and cardiac enzymes (Troponin I and CK-MB). In our analysis, serum Troponin I levels at 7 days post-infarction showed a positive correlation with CD4 + IFNγ+ lymphocytes, suggesting that patients with a high percentage of CD4 + IFNγ+ lymphocytes at 1 h post-infarction may have higher circulating Troponin I levels at 7 days. The correlation between IL2 and Troponin I levels indicates that a low expression level of IL2 at 1 h after infarction could be associated with a higher Troponin I level at 24 h. On the other hand, IFNγ, iNOS and CELA expression levels were also related with the serum levels of CK-MB at 7 days. Additionally, high expression levels of IL5 detected at 1 h post-infarction could be associated with a lower % LVEF at 7 days in patients.Although it is well known that cardiac enzymes are relevant and predictive biomarkers for the diagnosis of AMI, our swine myocardial infarction model -performed under controlled conditions- suggests that early inflammatory biomarkers may be useful in the follow-up of patients who have suffered an AMI. These biomarkers are easily and swiftly detectable, which means they could be candidates for early prognosis, predicting the severity of myocardial infarction in a clinical scenario. It is important to note that the usefulness of these biomarkers in AMI patients with concomitant immune-mediated diseases may be compromised, since immune biomarkers may be masked in patients with pre-existing immune disorders.n = 12) weighting 30–35 kg at the beginning of the study, were used for all experimental procedures. These animals were provided and housed by the Animal facility of the Jesús Usón Minimally Invasive Surgery Centre. At the end of experiments all animals were euthanatized by intravenous administration of 2 mmol/kg of potassium chloride. All experimental protocols were approved by the Ethics Committee on Animal Experiments of the Jesús Usón Minimally Invasive Surgery Centre, in accordance with the recommendations outlined by the local government (Junta de Extremadura) and the Directive 2010/63/EU of the European Parliament on the protection of animals used for scientific purposes.Young female Large White pigs  was used throughout the procedure. Systemic heparin  was intravenously injected (150 UI/kg) prior to percutaneous sheath placement.A closed chest reperfused myocardial infarction was created in the operating theaters of the Jesús Usón Minimally Invasive Surgery Centre as previously described . BrieflyBlood samples were drawn by puncture of the cranial vena cava before myocardial infarct induction and 1 h after the balloon deflation and collected in EDTA containing tubes for further analysis.6 PBLs were stained with fluorescent-labeled monoclonal antibodies against extracellular porcine CD4, CD8α, CD14, CD16, CD27, CD45RA, CD56 and SLAII . For the detection of intracellular antigen IFNγ, PBLs were fixed and permeabilized using Fix&Perm  and stained with the appropriate antibody (AbD Serotec). The cells were washed and re-suspended in PBS.The PBLs were isolated by centrifugation over Histopaque-1077 . 1 × 105 events. Cells were primarily selected using forward and side scatter characteristics and fluorescence was analyzed using CellQuest software (BD Biosciences). Appropriate isotype-matched negative control antibodies were used in all the experiments.Flow cytometric analysis was performed in a FACScalibur cytometer  after acquisition of 10-∆Ct expression. Duplicates of all samples were analyzed separately and normalized using GAPDH as a reference gene.For transcriptional analysis studies, total RNA from isolated lymphocytes was extracted and purified by using the mirVana miRNA Isolation Kit , following the manufacturer’s instructions. RNA quality was evaluated through spectrophotometry and cDNA was synthesized from 1 μg of RNA in reverse transcription reaction with the iScript Reverse Transcription Supermix . qPCR was performed with commercial gene expression assays  Table , using TCardiac Magnetic Resonance studies  were performed at day 7 post-infarction. Retrospective cardiac triggering was used. A 4 elements phase array coil was placed around the animals’ chest. Images were acquired in the intrinsic cardiac planes: short axis, vertical long axis and horizontal long axis views. In order to measure left ventricular function and mass breath hold gradient, echo cine images were obtained over the entire left ventricle. For infarct size measurements, short axis images were acquired 5 to 15 min after the injection of 0.2 mmol/kg of a gadolinium-based contrast agent  using a breath-hold 3D gradient-echo inversion-recovery sequence.p-values ≤0.05 were considered statistically significant.Data were statistically analyzed with SPSS-21 software . Normality was assessed using a Shapiro-Wilk test. Paired comparisons were performed using a Student t-test for parametric data or Wilcoxon sign test for non-parametric data. Correlations were calculated using the Pearson coefficient correlation and “r” value was interpreted as follows: − 1.0 to − 0.5 or 0.5 to 1.0: Strong correlation, − 0.5 to − 0.3 or 0.3 to 0.5: Moderate correlation, − 0.3 to − 0.1 or 0.1 to 0.3: Weak correlation, − 0.1 to 0.1: None or very weak correlation. All


Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycemia in patients with type 2 diabetes, but heart rate increases have been observed.N = 4595) of 10–30 weeks’ duration from the exenatide once-weekly (QW) development program evaluated heart rate with exenatide QW (intervention group) and exenatide twice daily (BID), liraglutide, and non-GLP-1RAs  (comparison groups). The time course and size of heart rate changes from baseline and the relationship of heart rate change with baseline heart rate were studied. A multivariate analysis  examined associations between patient characteristics or treatments and heart rate increases.A pooled post hoc analysis of 11 randomized clinical trials (n = 2096), 75.8 ± 8.7 bpm with exenatide BID (n = 606), 75.2 ± 8.9 bpm with liraglutide (n = 450), and 74.5 ± 8.6 bpm with non-GLP-1RAs (n = 1443). Least-squares mean ± standard error changes from baseline to final heart rate were + 2.7 ± 0.2, + 1.0 ± 0.3, and + 3.0 ± 0.4 bpm with exenatide QW, exenatide BID, and liraglutide, respectively, and − 0.8 ± 0.2 bpm with non-GLP-1RAs. The size and direction of heart rate changes in individual patients varied within each treatment group at all time points. At posttreatment follow-up, heart rate reverted to the baseline level after GLP-1RA discontinuation. Heart rate changes correlated negatively with baseline heart rate for all therapies (r = − 0.3 to − 0.4). Baseline heart rate was the strongest predictor of increased heart rate.Mean baseline heart rate ± standard deviation was 75.0 ± 8.5 beats per minute (bpm) with exenatide QW  contains supplementary material, which is available to authorized users. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are indicated with diet and exercise for the improvement of glycemic control in adults with type 2 diabetes mellitus (T2DM), many of whom are taking background oral glucose-lowering medications such as metformin and sulfonylureas. Exenatide was the first-in-class GLP-1RA and is available worldwide in twice-daily (BID) and once-weekly (QW) formulations for administration via subcutaneous injection. The slow pharmacokinetics and inherent titration of the extended-release formulation achieves minimal effective concentrations in 2 weeks and steady-state concentrations in 6–7 weeks, compared with the intermittent exposure of exenatide achieved with BID dosing. Liraglutide is a GLP-1RA that is available as a once-daily (QD) subcutaneous injection, and maximum concentrations are achieved 8–12 h postdose ) was measured at baseline see “” and dur“Baseline” heart rate was defined as the average of all heart rate measurements for each patient before receiving the first randomized study medication. The “final” heart rate was defined as the last heart rate measurement for each patient while on treatment. The “posttreatment” heart rate was defined as the heart rate measurement taken at 10 weeks’ posttreatment in the studies with a treatment period of ≥ 26 weeks in which this was assessed. For the multivariate regression analysis, the “average postbaseline” heart rate was defined as the average of all postbaseline heart rate measurements in each patient.http://www.who.int/medicines/publications/druginformation/en/), which included β-blockers, calcium channel blockers, agents acting on the renin–angiotensin system, diuretics, and other antihypertensive agents.“Antihypertensive medications” were defined based on the anatomic therapeutic chemical classifications of the World Health Organization drug dictionary  mean heart rate changes were computed for treatment groups of interest, and the A multivariate analysis was conducted to identify patient characteristics associated with increases in heart rate from baseline. The data for this analysis came from nine studies, each of 24–30 weeks’ duration. The mean heart rate change postbaseline, calculated as the difference between the baseline heart rate and the average postbaseline heart rate at weeks 10, 14, 18, 22, 26, or 30 when data were available, was examined in a stepwise regression, weighted by the number of observations used to compute the average postbaseline heart rate in each patient. Treatment effect was examined for exenatide QW, exenatide BID, and liraglutide using the pooled non-GLP-1RA treatments  as the reference group. Variables for demographics, baseline characteristics, prior and baseline glucose-lowering therapy (metformin and sulfonylurea combination vs. others), antihypertensive medication use at baseline (yes vs. no), and postbaseline changes in blood pressure and body weight were examined. Closely correlated variables were excluded from modeling to avoid collinearity. The base model included treatment group, baseline heart rate, and study identifier. All other covariates were then subject to a stepwise model selection, and the model with the smallest Akaike information criterion value was selected as the best model.http://www.R-project.org/) for the multivariate analysis and SAS  for all other analyses.Statistical analyses were performed with R , exenatide BID (n = 606), liraglutide (n = 450), pooled GLP-1RAs (n = 3152), or non-GLP-1RAs (n = 1443) in the overall population  and non-GLP-1RAs (74.5 ± 8.6 bpm). Demographic and baseline characteristic data for all individual treatment groups are shown in ESM Table S2.Baseline characteristics were generally similar among patients treated with exenatide QW (n = 901), exenatide BID (n = 243), liraglutide (n = 411), or a non-GLP-1RA treatment (n = 507); the pooled GLP-1RA group for posttreatment follow-up included 1555 patients.The posttreatment follow-up analysis included data from three studies, each with a treatment period of ≥ 26 weeks (ESM Table S1) , 16, 22.The multivariate regression analysis included data from nine studies, each with a treatment period of 24–30 weeks (ESM Table S1). Patients for whom a full set of observations for dependent and independent variables was available were assessed in the regression models, which included 3903 patients.Data pooled from the controlled periods of all 11 studies showed fluctuations in mean heart rate over time across all treatments. Early increases in mean heart rate were observed by week 2 in the pooled GLP-1RA (mean change + 1.8 bpm), exenatide QW (+ 1.4 bpm), exenatide BID (+ 0.6 bpm), and liraglutide (+ 4.0 bpm) groups, while the mean heart rate remained stable over time in the pooled non-GLP-1RAs group (mean change at week 2: 0.0 bpm)  than with non-GLP-1RAs (− 0.8 bpm) , exenatide BID , liraglutide , pooled GLP-1RAs , and pooled non-GLP-1RAs  treatment groups  among patients treated with GLP-1RAs.Because β-blockers are known to reduce heart rate , changesThe mechanism by which GLP-1RAs increase heart rate among patients with diabetes has yet to be established . HoweverIncreased heart rate appears to be dependent on the GLP-1RA dose, with an associated heart rate increase of 2–3 bpm observed in a meta-analysis of randomized controlled trials of exenatide and liraglutide .Doses of liraglutide QD and exenatide QW are active throughout the day or longer, and in our analysis they were associated with greater mean heart rate increases than exenatide BID. The onset of heart rate changes appeared to be more rapid with liraglutide than with exenatide QW.Reviews and analyses on the effect of GLP-1RAs on heart rate have also found differences between long- and short-acting formulations. One meta-analysis found that exenatide QW and liraglutide, but not exenatide BID, were associated with increases in heart rate in comparison to placebo . A revieThe cardiovascular safety of T2DM therapies is of central importance because patients with T2DM are at increased risk of cardiovascular disease. The risk of cardiovascular events has been shown to increase with heart rate in epidemiological studies, although higher heart rate was not usually associated with drug therapy in these populations and the data were not stratified by baseline heart rate. Furthermore, patients with higher heart rate may have underlying health conditions, giving rise to potential selection bias in these epidemiological studies. An increase in the resting heart rate of 15 bpm has been found to be associated with an increased risk of cardiovascular disease mortality . IncreasP < 0.01 for superiority). The Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes  evaluated semaglutide or placebo, given in addition to standard care, in 3297 patients with T2DM and high cardiovascular risk [P < 0.001 for noninferiority; P = 0.02 for superiority). The incidence of nonfatal stroke , but not cardiovascular death or nonfatal MI, was significantly lower with semaglutide than with placebo. Lixisenatide was compared with placebo among patients with T2DM who recently experienced an acute coronary event in the phase 3b Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial (NCT01147250) [P = 0.01).Ongoing and recently completed cardiovascular safety outcome trials will help resolve questions surrounding the clinical implications of heart rate increases with GLP-1RA therapy. To date, published results from cardiovascular outcome trials have demonstrated that GLP-1RA treatment was either noninferior or superior to comparators in reducing cardiovascular end-point events in different patient populations with T2DM. The available data thus far do not indicate that GLP-1RA treatment, despite the associated increases in heart rate, is associated with an increased risk of cardiovascular events. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial (NCT01179048), an international placebo-controlled study, evaluated the effect of liraglutide compared with placebo, added on to standard care, on cardiovascular events in 9340 patients with T2DM and high cardiovascular risk . After alar risk . After 1P < 0.001) but not superior to placebo for efficacy (P = 0.06) [P < 0.001).Results from the Exenatide Study of Cardiovascular Event Lowering , a placebo-controlled phase 4 trial examining exenatide QW for effects on cardiovascular outcomes in 14,752 patients with T2DM, of whom more than 70% had prior cardiovascular disease, showed no increase in cardiovascular events compared to placebo . Assessm = 0.06) . An LS mP = 0.033), in addition to reducing cardiovascular mortality (P < 0.007) and all-cause mortality (P < 0.002) [A meta-analysis of the LEADER, SUSTAIN-6, ELIXA, and EXSCEL trials found that GLP-1RAs significantly reduced the risk of the composite end point of cardiovascular death, nonfatal MI, or nonfatal stroke (< 0.002) . The effThe limitations of the current analysis include its post hoc nature and the relatively short duration of the included studies. Limitations of the data are that heart rate measurements were part of clinical procedures for collecting vital signs for clinical trials and were therefore not a standardized procedure, as would occur in a clinical study focused on heart rate data. The collection of heart rate data also varied among studies because of different study schedules, resulting in variations in patient numbers for each time point. Because heart rate was measured during clinic visits, it was not possible to examine changes outside these visits or the general variability in heart rate within individual patients. Another limitation is the considerably larger number of patients included in the exenatide QW group compared with the other treatment groups after pooling studies and treatments. This imbalance may limit the interpretation of results, although data were reported for the individual GLP-1RAs to avoid the potential impact of this imbalance on results for the pooled GLP-1RAs. Limitations associated with the multivariate analysis include lack of adjustment for multiplicity and the use of postbaseline factors, such as change in body weight. Nevertheless, this was justified by the post hoc nature of the multivariate analysis and the difficulty of distinguishing the direct effect of study medication on heart rate change and the indirect effect of study medication on body weight change and subsequently heart rate change. Although only the potential effect of background treatment with metformin plus a sulfonylurea was investigated in the analysis, this was the most frequently used background therapy combination. Patients receiving background therapy with metformin plus a sulfonylurea were likely to have been older and to have had a longer duration and greater severity of diabetes than patients on monotherapy background treatments. Because of these limitations, the multivariate analysis to identify potential risk factors for increased heart rate should be considered hypothesis-generating and to require validation.This analysis showed that treatment with GLP-1RAs was associated with an increase in heart rate among patients with T2DM, although the heart rate remained within normal ranges. Baseline heart rate was the strongest predictor of heart rate changes; however, further studies are required to confirm the results from this multivariate analysis. While the clinical relevance of increases in heart rate with GLP-1RA therapy is unclear, the results from GLP-1RA cardiovascular outcome trials to date do not indicate that increased heart rate is associated with an increased rate of cardiovascular events.Supplementary material 1 (PDF 352 kb)Below is the link to the electronic supplementary material.


Levo-transposition of the great arteries (L-TGA) is a rare congenital heart anomaly associated with the increased risk of developing heart failure (HF) as well as complete heart block at a young age. Due to limited data regarding the treatment strategy in the adult L-TGA sub-population, shared medical decision-making should occur between the patient and a team of physicians. Clinical status, age, and associated cardiac lesions or rhythm disturbances can affect patient outcomes. These factors should be considered prior to pursuing a surgical versus a medicinal approach. Levo-transposition of the great arteries (L-TGA) is a rare congenital anomaly leading to progressive dysfunction of the systemic ventricle, which is a morphologic right ventricle (RV). These patients are at increased risk of heart failure (HF) as well as complete heart block at a younger age, and early preventative efforts should be made when possible . We presA 37-year-old asymptomatic adult male with previously diagnosed L-TGA presented to the clinic to establish care. He reported normal development without cyanosis or functional limitation. On physical exam, III/VI holosystolic murmur and S4 were appreciated. The electrocardiogram demonstrated left axis deviation and Q waves in the early right precordial leads. Transthoracic echocardiogram demonstrated atrial to ventricular (AV) and ventricular to arterial (VA) discordance consistent with corrected transposition of the great arteries, as seen in Figure L-TGA patients typically present with nonspecific HF symptoms at an early age due to the morphologic RV functioning as the systemic pump. Although there is increasing favor for performing a double switch operation  in infants and young children with L-TGA, older teens and adults have not fared as well with this procedure -3. MedicThe goal of treatment is to reduce afterload and slow remodeling in order to improve or mitigate RV dysfunction, as the RV is not built to sustain the role of the left systemic ventricle in the long term. The principle behind this strategy is to decrease the pressure on the wall of the RV during ejection, similar to the medical approach in HF. Two such agents that will reduce afterload and may slow the remodeling process include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACE-I/ARBs) -7. In adDue to limited data in the adult L-TGA sub-population, medical management options are not well-supported by evidence. Therefore, each case should be tailored to the individual being treated. Factors such as clinical status, age, and associated cardiac lesions or rhythm disturbances should be reviewed by specialists prior to shared medical decision-making with the patient.


In order to gain a deeper understanding of the rheological development of hydrating ordinary Portland cement (OPC) pastes at initial state, and to better understand their underlying processes, quantitative X-ray diffraction (XRD) analysis and rheological measurements were conducted and their results combined. The time-dependent relation between phase development and flow behavior of cement paste was investigated at two different temperatures (20 and 30 °C), over a period of two hours. Regarding the phase development during hydration, ettringite precipitation was identified as the dominant reaction in the first two hours. For both temperatures, the increasing ettringite content turned out to correlate very well with the loss of workability of the reacting cement paste. An exponential relationship between ettringite growth and flow behavior was observed that could be explained by applying the Krieger-Dougherty equation, which describes the influence of solid fraction on the viscosity of a suspension. The workability of fresh cementitious mixtures is of great interest for the construction industry as well as for academia. New technologies, like 3D-printing and the construction of supertall buildings, put special requirements on the performance and longleivity of cementitious systems ,2,3. ForThe early cement hydration of ordinary Portland cement (OPC) is primarily controlled by two chemical reactions: (1) The silicate and (2) the aluminate reaction, which run simultaneously. The silicate reaction can be represented schematically by the following equation:The dissolution of alite leads to the precipitation of poorly-crystalline calcium silicate hydrate (C–S–H) and portlandite  (p. 113)3A with water in the presence of sulfate carriers, mainly anhydrite, bassanite and gypsum, according to the following equation [During the aluminate reaction ettringite is formed by the reaction of Cequation  .6.9,10,11However, which particular chemical reaction is controlling the flow behavior in the first period of hydration (commonly the first 2 h) is still under debate. Roussel et al.  suggest 3A content—as the critical phase for the aluminate reaction of the dry cement—has a significant influence on the rheological parameters of mortar. Furthermore, Uchikawa et al. [3A contents concerning their ettringite precipitation and yield stress development during hydration. They observed that for higher C3A contents in cement, the amount of ettringite formed during hydration and the yield stress, increased as well. Their conclusion was therefore, that ettringite is the main responsible phase for changes in flow behavior of cementitious systems, which is also supported by Winnefeld et al. [Other authors argue that ettringite may be the crucial hydrating phase controlling the rheology of the paste at the beginning of reaction. Gołaszewski  found oua et al.  comparedd et al. . They inHowever, not only the hydration time decreases the workability of cement paste, also the ambient temperature is an important factor, which influences the hydration kinetics as well as the rheological properties. Therefore, hot weather environments can interfere the workability and may cause problemes during concrete transport and placement . At highwhere the concentration of the solid fraction In the early stage of hydration, cement paste is a suspension consisting of cement phases, hydrate phases, and water (including air). The flow behavior of a suspension is strongly influenced by the volume concentration of particles and their interactions, which can be modeled by applying the Krieger-Dougherty equation . It is d and Sun  modeled t pastes . Althougarameter , which sIn order to gain a more significant insight in the underlying processes responsible for the development of the rheological behavior of hydrating cement pastes, in-situ X-ray diffraction (XRD), heat flow calorimetry and rheological measurements were performed. Additionally, Scanning Electron Microscope (SEM) images were taken and the development of the flow behavior of cement paste was modeled by applying the Krieger-Dougherty equation . In the An ordinary Portland cement (OPC) of type 42.5 R was used for this study. The cement was provided within the SPP 2005 program of the DFG (Deutsche Forschungsgemeinschaft) “Opus Fluidum Futurum—Rheology of reactive, multiscale, multiphase construction materials” . The chaThe cement and the deionized water were equilibrated at the experimental temperatures before mixing. Two temperatures were used for the experiments: 20.0 ± 0.5 °C and 30.0 ± 0.5 °C. The mixing was performed in a KitchenAid 5K45 mixer, and started with 58 rounds per minute (rpm) for 15 s. Then the speed was raised to 125 rpm for 45 s, and after that to 220 rpm for 30 s. This was followed by a 90 s mixing break during which the sides of the bowl were scraped off. In the following 60 s the cement paste was remixed at 220 rpm. For all experiments except the heat flow calorimetry, 650 g cement, and 234 g deionized water (w/c = 0.36) were mixed. For each experimental setup, three measurements were performed for both temperatures.The heat flow of the cement pastes was recorded with a TAM Air calorimeter. In order to measure meaningful values during the first hour, a custom made internal mixing tool  was used® polyimide film water evaporation and CO2 intake were avoided. Every 10 min a diffraction pattern was recorded by a diffractometer (Bruker AXS D8 Advance) in Bragg-Brentano geometry. A step width of 0.0236° 2θ was employed, and the resulting patterns ranged from 7° to 55° 2θ. The diffraction patterns were refined by the Rietveld method using the software TOPAS 5.0 (Bruker AXS) [The phase development of the cement hydration in the first five hours of hydration was determined by in-situ XRD measurements. In order to ensure a constant experimental temperature (20.0 ± 0.2 °C and 30.0 ± 0.2 °C) during the whole timeframe, the cement paste was transferred into a custom made heating and cooling device. By covering the paste with a 7.5 µm thick Kaptonker AXS) . Additioker AXS)  was applIn order to determine the rheological development of cement paste, rheological measurements were performed by a speed-controlled rotational rheometer (Schleibinger Viskomat NT). The torque was measured by using a fishbone paddle geometry at a velocity of 2 rpm. The advantage of this geometry is that the surface of the tool is small and thus it is possible to measure the cement paste rheology during ongoing hydration process for a long time after water addition. For this geometry it is not possible to calculate the viscosity nor the yield stress. Therefore, here the rheological properties are expressed by the generated torque. The measuring range of the torque is between 0 and 500 N·m, and the angle accuracy of the rheometer is 0.02 degrees. To avoid destruction of the freshly formed hydrading phases, and its effect on the rheology of cement paste, a low velocity of 2 rpm was applied. A new sample was prepared for each measurement and stored at the designated experimental temperature until testing. Pre-shear was waived to avoid the destruction of the first forming crystals. A velocity of 2 rpm was applied for 30 s, and meanwhile, every second one data point was recorded. A plot of a measurement performed after two hours of hydration at a speed of 2 rpm is shown in For SEM investigations the cement hydration was stopped after three defined times of hydration  by an exchange of the water with isopropanol. This exchange was done three times. After that, the sample was dried by freeze drying. The dried powder was analysed by a Scanning Electron Microscope . Before the measurement, the sample was covered by a 4.5 nm thick gold layer. For the images a secondary electron (SE) detector in a high vacuum was used and the electrons were accelerated in an electric field with a voltage of 15 kV.3; belite 3.30 g/cm3; anhydrite 2.93 g/cm3; bassanite 2.73 g/cm3; quartz 2.65 g/cm3; brownmillerite 3.74 g/cm3; C3A 3.04 g/cm3; periclase 3.58 g/cm3; calcite 2.71 g/cm3; gypsum 2.30 g/cm3; ettringite 1.80 g/cm3; water 1.00 g/cm3. With the resulting volume of each phase in cm3/100g the whole volume of the cement paste and consequently, the vol. % of every single phase could be calculated effectively. The solid fraction of the cement paste is then the sum of all solid phases (non-dissolved cement phases and precipitated hydrate phases).The equation of Krieger and Dougherty  consider2 = 0.9999) to fit the evolution of solid-phase content in the experimental data.Regression and interpolation analysis was performed using the Levenberg–Marquardt method of optimization in software Origin Pro. The solid phase content of the experimental data was interpolated to the hydration time values corresponding to torque measurements, using a (Hill) growth function (resulting in RIt should be taken into account that gypsum is not present in the dry cement CEM I 42.5 R and is thus a hydrate phase which precipitates during the first minutes of hydration (before the first pattern was recorded). The highly soluble sulfate carriers like bassanite and arcanite are totally dissolved within the first 10 min and are therefore not shown in the figure.In By comparing the phase evolution of cement paste at initial reaction, analyzed by in-situ XRD measurements and the external standard method (G-factor), with the development of the measured torque at two different temperatures (20 °C and 30 °C) during the first two hours of hydration, the influence of hydrate phases on the workability of the cement paste could be quantified. As shown in Gypsum precipitation during cement hydration indicates an over-sulfated cement and could cause undesirable rapid stiffening of the paste    and additional surface area evolved due to the precipitation of the hydrate phase. The high water consumption by ettringite precipitation strongly influences the water/solid ratio in the hydrating cement paste. Therefore, it can be observed from Furthermore, the ettringite content in cement paste also correlates with the increased torque as measured by the rheometer, evident shown in It should be taken into account that the results of the rheological measurements have to be scaled logarithmically to achieve a good correlation with the ettringite content, heat release and solid fraction of the paste, which are scaled linearly. Therefore, it can be assumed that the effect of ettringite precipitation on the rheological properties of the cement paste is of exponential order. With increasing ettringite content during hydration, the effect on the flow behavior becomes much larger. The ongoing water consumption of precipitating ettringite increases the solid fraction in the cement suspension and thus intensifys the interaction between particles. This exponential influence with increasing ettringite content can be modeled by applying the Krieger-Dougerthy equation . Due to t ≈ 0.1 h, but as a function of w/c, i.e. considering only an initial cement volume fraction of 0.35–0.50. In this paper, the initial solid volume fraction of cement is fixed to 0.45 , and the rheological measurements are performed as a function of hydration time. In contrast to [t ≈ 0.1 h (0.27 Pa s) is scaled to be higher  than the model viscosity from [The model parameters are taken from , which wtrast to , in thisity from  (0.12 Paity from ). FurtheThe amount of ettringite formation strongly depends on temperature and is the main process that drives the change in rheology during initial hydration of cement paste before setting. With increasing ambient temperature the initial ettringite formation is accelerated, which results in higher measured torque values. No other phase in the cement paste could be identified in the initial state to be affected by ambient temperature changes;The effect of ettringite precipitation on the rheological properties of cement paste is exponential with hydration time. With increasing ettringite content in the cement paste the effect of additionally formed ettringite on the workability of the cement paste is increased. The high water consumption and the formation of (low density) ettringite changes the water/solid ratio of the paste significantly and, thus, strongly controls the flow behavior of paste. This effect can also be observed from the hydration at different temperatures, as with higher ettringite contents at 30 °C, the measured torque increases faster with the formation of comparable amounts of ettringite than for the measurements at 20 °C;The exponential increase of the measured torque of cement paste during initial hydration was correlated by applying the Krieger-Dougherty equation. The correlation between measured torque and modeled viscosity was scaled, but provides a first indication for a logarithmic dependency between the torque and the ettringite content;Considerable increase in the solid volume fraction of the cement paste (+4.5 and +5.6 vol. % ettringite) during hydration , is correlated to the increase of the modeled viscosity.State-of-the-art quantitative Rietveld values combined with the external standard method (G-factor) were used to gain more insight into the underlying mechanism that determines the rheological properties of fresh OPC paste. From this the following conclusions could be drawn:


Diastolic dysfunction (DD) identified on echocardiography predicts mortality after cardiac surgery, however the most useful diastolic parameters for assessment and the association of DD with prolonged mechanical ventilation, ICU re-admission, and hospital length of stay are not established.We included patients that underwent coronary artery bypass grafting (CABG), aortic valve replacement (AVR) or a combined procedure (CAB-AVR) from 2010 to 2016, and who had preoperative transthoracic echocardiography (TTE) at our institution within 6 months of the operation. Diastolic function was graded using the transmitral E and A waves and the septal tissue Doppler velocity. We performed logistic regression to assess the association of grade of DD with a composite endpoint of death, prolonged mechanical ventilation, ICU readmission during hospitalization, and hospital length of stay longer than 14 days.Between 2010 and 2016, 577 patients were eligible for inclusion. DD was common, with 42% of the cohort manifesting grade II or grade III DD. Rates of death and prolonged ventilation increased across grades of DD and across quartiles of increasing LV filling pressure, assessed by the E/e’ ratio. Adjusting for age, sex, procedure, systolic and diastolic function, both systolic (odds ratio 0.68 95% CI 0.55–0.85 per inter-quartile increase in LVEF) and diastolic function (odds ratio 1.31 95% CI 1.04–1.66 per increasing DD grade) both independently predicted outcome.Diastolic dysfunction is common among patients undergoing cardiac surgery and is associated with death, prolonged mechanical ventilation, and prolonged hospital and ICU length of stay independent of systolic dysfunction. Diastolic dysfunction (DD) consists of abnormalities in myocardial relaxation and increased left ventricular stiffness leading to elevated cardiac filling pressures and, in the extreme form, decreased stroke volume , 2. DD iThe purpose of this study was to assess the association of pre-operative diastolic function assessed by echocardiography with post-operative outcomes following coronary artery bypass grafting (CABG), aortic valve replacement (AVR) or combined CABG and AVR. We hypothesized that a higher grade of DD would be associated with an increased risk of postoperative mortality, prolonged hospital length of stay, and need for prolonged mechanical ventilation after surgery.We performed a retrospective study to determine the association of echocardiographic DD with outcomes after CAB, AVR, or CAB-AVR. We hypothesized that higher grade of DD assessed using the transmitral E and A waves and the septal tissue Doppler velocity (e’) and higher cardiac filling pressures estimated by the ratio of E to e’ velocity would both be associated with higher risk of postoperative mortality, prolonged hospital length of stay, and need for prolonged mechanical ventilation after surgery. The study was approved by the Johns Hopkins Hospital institutional review board.Between 2010 and 2016, 2596 patients underwent CAB, 809 patients underwent AVR, and 386 underwent CAB-AVR. The present study included patients undergoing isolated CAB, isolated AVR and combined CAB-AVR between July 2010 and July 2016 who had a full transthoracic echocardiogram at our institution within the 6 months prior to surgery, who were in sinus rhythm pre-operatively, and had measurable mitral inflow pattern, systolic function, and tissue Doppler as described below. Using these criteria, 577 patients were included in the current study.Grade 0: normal left ventricular ejection fraction, e’ > 7 cm/s and E/e’ < 14Grade I: E/A < 0.9 and E < 50 cm/sGrade I: E/A < 0.8 with E > 50 cm/s or 0.8 < E/A < 2 AND E/e’ < 14Grade II: E/A < 0.8 with E > 50 cm/s or 0.8 < E/A < 2 AND E/e’ > 14Grade III: E/A >  2We extracted data from echocardiography reports for eligible patients. Studies were performed by certified sonographers and interpreting physicians were expert practicing echocardiographers at the Johns Hopkins Hospital. Diastolic function was assessed using transmitral diastolic flow profile including peak early diastolic velocity (E wave velocity) and peak late diastolic filling velocity (A wave velocity) , 2. We aP value less than 0.05 was considered statistically significant. All analyses were performed using StataSE version 14.0 .Demographic and clinical characteristics were compared across grades of diastolic function using the Kruskal-Wallis test for continuous variables and Pearson’s chi-squared test for categorical variables. We report the percentage of patients suffering death, prolonged mechanical ventilation or both across grades of diastolic function and across quartiles of E/e’ ratio. We performed logistic regression to assess the association of grade of DD with a composite endpoint of events of a priori clinical interest: death within 30 days, prolonged mechanical ventilation, ICU readmission during hospitalization, and hospital length of stay longer than 14 days. Univariate models and models which adjusted for clinical factors of a priori clinical interest were performed. Covariates included age, sex, procedure (CABG v. AVR v. CAB-AVR), and systolic function. A two-tailed Between 2010 and 2016, 577 patients were eligible for inclusion. The specific procedures included CABG alone in 77%, AVR alone in 16% and a combined procedure in 6%. A median of 4 (interquartile range (IQR) 1.5–10) days passed between the transthoracic echocardiogram used to grade diastolic function and the operation. DD was common, with 42% of the cohort manifesting grade II or grade III DD compared to 58% of the group with grade 0 or grade I. Most patients had preserved systolic function, with median LVEF 55% (IQR 45–60%).Demographic and clinical characteristics are shown in the Table p < 0.001).Outcomes across grades of diastolic function are shown in the Table p = 0.031). In the AVR group, 4.7% of the group with diastolic function grade 0 or 1 suffered the composite endpoint compared to 18.2% of those with Diastolic dysfunction grade 2 or 3 (p = 0.035).Figure Univariate logistic regression models for associations with the composite endpoint of death, prolonged mechanical ventilation, ICU readmission, and hospital length of stay longer than 14 days are shown in Fig. In a cohort of 577 patients undergoing cardiac surgery, we report the association of echocardiographic diastolic function with outcome. Our major findings include 1) DD is common among patients undergoing CAB, AVR or both, 2) higher grade of DD and higher LV filling pressure assessed by echocardiography is associated with higher risk of mortality and need for prolonged ventilation and 3) both systolic and diastolic function independently predict outcome after cardiac surgery.We report that DD is common among patients undergoing cardiac surgery, with 42% of patients manifesting grade II or higher DD. These findings are consistent with community based cohorts, demonstrating abnormal diastolic function in between 27 and 56% of a community based sample , 20 and We demonstrate that DD is associated with prolonged ventilation, death, and longer ICU and hospital length of stay. Other studies have also correlated diastolic grade with mortality , 13 and We report that echocardiographic systolic and DD both predict outcome independently. While systolic function is commonly utilized as a risk marker prior to cardiac surgery , 26, 27,Although there are no treatments targeted specifically at the cellular perturbations underlying DD , severalLimitations of our study include its retrospective, observational nature. Thus, we can assess for associations but cannot infer causality of DD and post-surgical outcomes. Our study focuses only on those patients in sinus rhythm in whom diastolic function can be graded, however patients with paced rhythms, mitral valve disease, and mitral annular calcification, and arrhythmia such as atrial fibrillation are major subsets of the cardiac surgical population; thus, although diastolic function cannot always be graded in these populations, markers of left ventricular filling pressure such as E/e’ ratio should be used. Our data set did not include details on completeness of revascularization and detailed conduct of cardiopulmonary bypass, and the association of diastolic function with these parameters needs to be more fully characterized in future studies. Finally, not all patients in practice will have adequate transthoracic echocardiographic windows and image quality for assessment of diastolic function, and correlation of our findings with those on intra-operative trans-esophageal echocardiography would be useful.In conclusion, DD is common among patients undergoing CAB, AVR and CAB-AVR and is associated with death, prolonged mechanical ventilation, and prolonged hospital and ICU length of stay independent of systolic dysfunction. Future studies should assess treatments targeted at improving diastolic function in cardiac surgical patients and the impact of therapy on post-operative outcomes.


Cirrhotic cardiomyopathy historically has been confused as alcoholic cardiomyopathy. The key points for diagnosis of cirrhotic cardiomyopathy have been well explained, however this entity was neglected for a long time. Nowadays the diagnosis of this entity has become important because it is a factor that contributes significantly to morbidity-mortality in cirrhotic patients. Characteristics of cirrhotic cardiomyopathy are a hyperdynamic circulatory state, altered diastolic relaxation, impaired contractility, and electrophysiological abnormalities, particularity QT interval prolongation. The pathogenesis includes impaired function of beta-receptors, altered transmembrane currents and overproduction of cardiodepressant factors, such as nitric oxide, cytokines and endogenous cannabinoids. In addition to physical signs of hyperdynamic state and heart failure under stress conditions, the diagnosis can be done with dosage of serum markers, electrocardiography, echocardiography and magnetic resonance. The treatment is mainly supportive, but orthotopic liver transplantation appears to improve this condition although the prognosis of liver transplantation in patients with cirrhotic cardiomyopathy is uncertain. For many years, cardiac dysfunctions associated with liver cirrhosis were attributed to the direct toxic effects of alcohol on the heart. However, in 1953, Kowalski and Abelmann –5. SuccInterference of liver disease with the cardiac and circulatory performance would be expected, considering that the liver receives 25% of the cardiac output. The term CCM was introduced more than three decades ago to describe a spectrum of chronic cardiac dysfunction in cirrhotic patients in the absence of known heart disease, regardless of the etiology of cirrhosis ,6.Hepatic cirrhosis leads to a hyperdynamic circulatory state, which induces cardiac dysfunctions that characterize the CCM syndrome. This syndrome includes, in addition to the hyperdynamic circulation, a combination of systolic  and diasCCM is a condition easily tolerated, remaining asymptomatic for months to years because of the near-normal cardiac function at rest, manifesting only under conditions of physical or pharmacological stress. Therefore, the diagnosis of CCM is difficult and the exact prevalence of this condition remains unknown .However, it has been estimated that 40–50% of patients who underwent liver transplantation have some signs of cardiac dysfunction, which means that these patients underwent surgery under a condition of CCM ,11,14. FAs CCM is a relatively recent entity, the purpose of this review is to provide an explanation about its definition. Its pathophysiological mechanisms, criteria, and supplemental exams for its diagnosis are also included to show CCM relevance. Although the treatment of this condition is mainly supportive, the actions that should be taken to approach CCM are also commented.Structured medical subject headings (MeSH) were used to search original articles and reviews about CCM in MEDLINE by means of the PubMed database. The term "cirrhotic cardiomyopathy" was used. A total of 275 complete articles, published until March 2018, were identified. All articles selected in the search were in English, and abstracts for oral presentations and letters to the editor were ignored. We also searched for further relevant articles in the reference lists of articles. First, titles and abstracts were read to know whether they fit the purpose of reviewing the issue. If their eligibility remained unclear, the full-text reports were then considered. Ninety studies were selected and organized to provide the authors of the present study with the means to write a narrative review including history, definition, epidemiologic data, clinical findings, diagnosis, and treatment.A consensus diagnostic criterion for CCM  was estaThese diagnostic criteria are still in use. However, suggestions have been made to improve these criteria by including the dysfunction of the right ventricle as an important parameter of cardiac damage caused by cirrhosis . Tissue Because alcoholism is the leading cause of hepatic cirrhosis, it is important not to confuse CCM with alcoholic cardiomyopathy, whose underlying mechanisms responsible for structural and functional cardiac abnormalities are pathophysiologically and clinically different . The maiAlthough the major circulatory changes that lead to CCM were indicated more than half a century ago, these mechanisms have been more clearly understood only recently. Portal hypertension leads to a state of peripheral vasodilatation due to a release of vasodilator mediators such as nitric oxide (NO), carbon monoxide, and prostacyclin –22.Progressive hepatic decompensation results in blood volume redistribution, with increased splanchnic blood flow and relatively decreased central circulation. The baroreceptors may be deactivated to compensate for the reduction in the central and arterial blood flow, with increased sympathetic nervous activity and consequent increase in HR and cardiac output (CO) . TherefoPatients with advanced cirrhosis exhibit hyperdynamic circulation with increased CO. This hyperdynamic state arises from a marked splanchnic arterial vasodilation and reduced systemic vascular resistance . IncreasAt rest, the intra-cardiac pressures are normal because the reduced afterload secondary to the systemic vasodilation compensates for both preload reduction and contractile dysfunction. This circulatory state, which resembles those of high CO, results from increased blood flow and is defined as heart failure due to volume overload. Thus, the hyperdynamic circulation in cirrhosis is secondary to the low systemic vascular resistance and increased arterial compliance –30.Several studies have shown that the left ventricular ejection fraction is normal at rest ,30. NeveOther inhibitory pathways contribute to decrease the cardiomyocyte contractility and, hence, decrease the systolic function in cirrhosis. Usually, the cannabinoid signaling system is minimally expressed in healthy individuals. However, a significant upregulation of the cannabinoid signaling pathway is observed in patients with cirrhosis . In addiIn summary, various studies have shown that the left ventricular ejection fraction is usually normal in patients with chronic liver disease who are at rest. In this condition, the reduced afterload, which is secondary to systemic vasodilation, compensates the preload reduction and contractile dysfunction. However, systolic dysfunction is unmasked under stress situations. Thus, cirrhotic cardiomyopathy is characterized by normal or high cardiac output. However, systolic dysfunction occurs when the heart is challenged. In such condition, the heart is unable to maintain adequate arterial circulation.Diastolic dysfunction is characterized by a decreased rate of left ventricular relaxation, restricted blood flow into the ventricle, and increased end-diastolic pressure. According to Glenn et al. , alteratPrevalence and extent of systolic dysfunction in cirrhotic patients is variable whereas various elements of diastolic dysfunction are more frequent . Other aIn the World Congress of Gastroenterology 2005 , howeverThus, tissue Doppler imaging could be considered to quantify left ventricular diastolic function . SpeckleCirrhotic patients primarily manifest diastolic dysfunction with normal systolic function at rest . In cirrProlonged QT interval is the most common electrophysiological alteration, occurring in more than 50% of cirrhotic patients ,52. ThisLoss and/or dysfunction of the membrane potassium channels play a role in delayed ventricular repolarization, which may lead to QT interval prolongation . HoweverChronotropic incompetence is the inability of the sinus node to increase HR after exercise or pharmacological stimulation. In CCM and under stress conditions, the sympathetic nervous system is not able to respond with adequate acceleration of the atrial and ventricular rate . The mecCCM is a relatively silent condition under stable situations. Peripheral vasodilation protects the heart by reducing the afterload and heart failure does not appear at rest. In patients suffering from cirrhosis, with intolerance to exercise and without underlying known cardiac disease, CCM should be suspected.Although new exams are improving diagnosis accuracy, echocardiogram and electrocardiogram are essential exams to diagnose this condition.Prolongation of the QTc interval (>440 ms) can be observed in cases of portal hypertension with or without cirrhosis. The frequency of QT prolongation in cirrhotic patients is in the range of 30–60% and positively correlates with the severity of liver disease ,63.As heart rate affects the length of the QT interval, its correction by the heart rate is always necessary. Thus, applying the Fridericia’ formula instead of the Bazett formula is preferable as the latter incompletely suppresses the relationship between QT and heart rate .Echocardiography is essential in all patients with suspicion of CCM. In contrast with systolic dysfunction, diastolic dysfunction is a prominent characteristic of CCM and seems to be its first manifestation . In addiStress echocardiography is a method that should be used in patients with advanced liver disease as it can detect subtle systolic and diastolic dysfunctions before the ventricular ejection fraction is decreased. This stress test should be considered in the diagnostic approach to CCM to avoid under-diagnosis .The structural protein troponin is a specific marker of myocardial lesion. Troponin I is a thin filament of cardiac muscle protein, which is a marker of cardiac lesions. The levels of such marker are elevated in patients with ischemia. Patients with liver cirrhosis can present high levels of troponin I ,69.The atrial natriuretic peptide (ANP) is secreted in response to volumetric atrial distention, as a result of atrial overload and ventricular hypertrophy in cirrhotic patients. As patients with uncompensated cirrhosis usually exhibit changes in volume and cardiac pressures, the ANP is frequently elevated in these cases .The brain natriuretic peptide (BNP) and its pro-hormones are also produced by the ventricles as a consequence of volume overload, increase in ventricular pressure, and ischemia . BNP andSupplemental exams, which can contribute to the diagnosis of CCM, are presented below.Until now, MR is considered the best exam to study heart morphology. In addition, MR with gadolinium contrast can be used to determine the chamber volumes, ejection fraction, and possible fibrosis and edema . The MR In patients with liver cirrhosis, cardiac dysfunction may be related to arterial hypertension and ischemic and alcoholic heart disease. Hepatic disease may likewise cause anemia, which also affects cardiac structure and function. Therefore, the relationship between cirrhosis and cardiac disease cannot be assured .CCM is a clinically silent or mild entity, and symptoms of heart failure become evident when stress occurs. Thus, there is little interest or necessity in treating CCM at the asymptomatic stage. As far as is known, there is no clinical study on the management of CCM. When some form of stress occurs, and heart failure clinically manifests, the guidelines for the treatment of chronic heart failure in non-cirrhotic patients can be followed. However, in advanced phases of cirrhosis, reduction in cardiac afterload is not recommended, as these patients are already significantly vasodilated .Liver transplantation can be a definitive treatment for patients with cirrhosis, but the unavailability of organ donors and cost concerns should be considered. The candidates must be well evaluated, as patients are at risk of death by heart failure, coronary artery disease, tachyarrhythmias, and other cardiac deaths in the post-operative term of liver transplantation. Thus, there are no accurate data on prognosis for liver transplantation in patients with CCM. However, diastolic dysfunction significantly worsens after transplantation in these patients .Patients with CCM should be recommended to avoid physical effort and other forms of stress, and oxygen should be provided in some situations. Medications can have adverse effects or weak response in patients with CCM, and specific pharmacological treatment with proven efficacy in CCM is not currently available now. However, when some form of stress occurs and heart failure becomes evident, the guidelines for treatment of chronic heart failure can be followed at least in the pre-ascites phase.Non-selective beta-blockers have shown to reduce the prolonged QT interval and might reduce the hyperdynamic load in patients with cirrhosis, but whether the correction of QT interval has a positive effect on prognosis is doubtful . In addiIn a revision of 10 hemodynamic studies on liver cirrhosis, Tripathi and Hayes  concludeAngiotensin converting enzyme inhibitors can improve diastolic function in patients with cirrhosis by decreasing the ventricular thickness and dilation, but they should be used in the early phases of cirrhosis because of the risk of hypotension and hepatic-renal syndrome in later phases . Even thSpironolactone is a competitive aldosterone inhibitor and should be used as a diuretic in patients with severe heart failure as it has been shown to reduce the frequency of hospitalization and mortality . In addiLiver transplant is the only effective treatment established for patients with final stage liver disease associated with CCM. Liver transplantation has been shown to reverse the systolic and diastolic dysfunction and prolonged QT interval .However, many cardiac complications and some cardiac deaths have been reported in patients undergoing liver transplantation. This fact can be attributed to cardiac dysfunction due to previous CCM .Unfortunately, no reliable method to identify patients susceptible to develop perioperative cardiac complications is currently available .Liver cirrhosis can induce cardiac abnormalities characterized by an impaired stress response, diastolic dysfunction, and electrocardiographic changes (CCM). No symptom is seen at rest, but heart failure can be unmasked under stress conditions. This occurs because at rest the diastolic and systolic dysfunctions are counterbalanced by the specific hyperdynamic state of cirrhosis. Pathogenesis of CCM includes mechanisms such as increased activity of the vasodilator pathway through the actions of NO, carbon monoxide, cytokines, and cannabinoids, decreased beta-adrenergic function, and sodium and calcium transport kinetics downregulation in the cardiac muscle, leading to an impaired contractile function of the cardiomyocyte. Echocardiogram and the electrocardiogram are the most important exams for diagnosis of CCM, but cardiac magnetic resonance imaging and biomarkers are currently becoming more relevant than before.The treatment of CCM is directed to left ventricular failure, with sodium restriction, diuretics, and afterload reduction. Liver transplantation may improve or normalize cardiac function.


Global left atrial strain (LA) has been used as a novel assessment tool to evaluate left atrial function. However, not much has been investigated to study the effect of percutaneous balloon mitral valvotomy (BMV) in patients with rheumatic severe mitral stenosis on global LA strain. We studied the relationship between global left atrial (LA) strain and severe mitral stenosis and the effect of BMV on LA strain.p < 0.001). There was a significant decrease in mitral mean gradient (MMG)  and systolic pulmonary artery pressure (sPAP)  after BMV. Mitral valve area (MVA)  significantly increased after BMV. Results were compared with 30 age- and sex-matched healthy controls.A total of 29 patients satisfying the criteria for severe mitral stenosis underwent balloon mitral valvotomy . Global left atrial strain was assessed by speckle tracking echocardiography before and after valvuloplasty. Global LA strain was impaired in patients with severe mitral stenosis and improved 24–48 h following BMV (13.4 ± .75% vs 17.37 ± 6.95%, Global LA strain can be taken as an indicator of left atrial function, and its improvement following valvotomy may be taken as a good indicator of successful BMV. Rheumatic heart disease is the most common acquired cause for mitral stenosis. Rheumatic heart disease causes chordal shortening, commissural fusion, and decrease in mitral valve area. Balloon mitral valvotomy (BMV) is a treatment of choice for rheumatic mitral stenosis.Mitral valve is the most commonly involved valve in rheumatic heart disease and usually presents with exertional dyspnea, pulmonary hypertension, and right heart failure. Exertional dyspnea occurs secondary to increased left atrial pressure leading to increase in pulmonary capillary wedge pressure. Severe mitral stenosis leads to left atrial enlargement leading to LA longitudinal lengthening which is recorded as positive strain. Quantification of global LA strain by two-dimensional speckle tracking echocardiography is a diagnostic tool for assessment of left atrial function. This study was done to assess LA function by global LA strain and its reversibility following balloon mitral valvotomy.We performed a prospective case control study from December 2014 to November 2016. Twenty-nine patients satisfying the inclusion criteria were studied and underwent detailed echocardiographic assessment pre- and post-balloon mitral valvotomy. Sample size was calculated with alpha of 1%, clinical significant difference (d) of 2, and power of 90% using the following equation:A sample size of 29 was reached based on the above formula.Patients with severe rheumatic mitral stenosis in normal sinus rhythm with valve suitable for BMV and who underwent successful BMV were included in the study. Patients in atrial fibrillation , more than mild mitral regurgitation (MR), aortic regurgitation (AR), diabetes mellitus, hypertension, and renal failure were excluded from the study. Control group included 30 age- and sex-matched healthy volunteers.2), less than grade 2+ mitral regurgitation, and favorable morphology of mitral valve. All patients underwent balloon mitral valvuloplasty using Inoue balloon method. Successful BMV procedure was defined as achieving either a final MVA > 1.5 cm2 or increase in MVA by 40% and mitral regurgitation grade ≤ 3+ [Indications for BMV in mitral stenosis included symptomatic severe mitral stenosis  was used to define the absolute changes in the valve area and gradients across the mitral valve pre- and post-BMV.For speckle tracking, apical four-, three-, and two-chamber views were obtained using standard 2D gray scale echocardiography with breath hold and stable electrocardiographic recording. The average of three cardiac cycles was recorded. The frame rate was set at 60–80 frames/s. These settings are recommended to combine temporal resolution with adequate spatial definition and to enhance the probability of the frame-frame tracking technique [First, the endocardial left atrial surface was traced manually using the point and click method in apical four-, three-, and two-chamber views, following which epicardial surface was traced automatically by the software system creating a region of interest involving the entire myocardial thickness. Lastly, the system generates two strain curves for each atrial segment. In total, 12 segments were analyzed after acquiring decent image quality  were compared using paired t test. p value, i.e., level of statistical significance, was set at < 0. 05.SPSS.v.16.0 software was used for analyzing statistics. Continuous variables were expressed as mean +/− SD. Categorical data were analyzed using chi-square test. Differences between groups (case vs control) were evaluated with independent From December 2014 to November 2016, 29 patients satisfying the inclusion criteria were included in the study and underwent detailed echocardiographic assessment pre- and post-balloon mitral valvotomy. The patients’ baseline clinical and echocardiographic profiles are shown in Table p = 0.06; females, 69% vs 66%, p = NS) .The mitral valve area increased and the mean mitral gradients decreased significantly post-BMV (1.045 ± 0.17 mmp < 0.001)  Table .Rheumatic carditis causes left atrial dilatation, myocyte necrosis, interstitial fibrosis, and disorganization of atrial muscle bundles. This structural remodeling impairs both contraction and relaxation functions of atrial myocytes. Also, narrowing of mitral valve secondary to stenosis leads to increased afterload of the left atrium. These structural and hemodynamic changes cause progressive impairment of left atrium mechanical function , 5.The left atrium mechanical function assessed by echocardiography can either be load dependent or load independent. Conventionally, atrial function is usually assessed by atrial volumes which is load and operator dependent and does not accurately evaluate atrial reservoir function. Two-dimensional transthoracic speckle tracking echocardiography (2D STE) allows the assessment of global left atrium mechanic –8. CardiThough many studies have been done studying the impact of balloon mitral valvotomy on atrial volumes, atrial pumping function, and atrial reservoir functions –11, not The present study has the following limitations. It was a non-randomized study. Also, the prognostic effect of speckle tracking echocardiography following balloon mitral valvotomy was not evaluated as patients were not followed up. We did not study the effect of balloon mitral valvotomy on either right or left ventricular strain, nor study the left atrium active emptying fraction for patients with mitral stenosis before and after valvotomy.Global LA strain can be taken as an indicator of left atrial function, and its improvement following valvotomy may be taken as a good indicator of successful BMV. However, whether this improvement in left atrial strain leads to a reduction in rate of atrial fibrillation during mid- and long-term follow-up needs further studies.Additional file 1: Raw data from patients with mitral stenosis before and balloon mitral valvotomy and in controls.