This study aimed to examine the relationship between measurements related to heart sounds and the origin of ventricular arrhythmia. We retrospectively evaluated 45 patients undergoing catheter ablation with contemporaneous digital acoustic cardiography of the first heart sound (S1) and the second heart sound (S2). The patients with baseline wide QRS morphology (>120 ms or aberrant conduction), heart failure, valvular heart disease, chronic pulmonary disease, and obesity were excluded. Ventricular arrhythmias from the left ventricle had an increased S1 complexity score and S1 duration in comparison to adjacent sinus beats. On the other hand, ventricular arrhythmia from right ventricle had decreased S1 complexity score and S1 duration in comparison to adjacent sinus beats. The difference of S1 (ΔS1) parameters between premature ventricular complex and sinus beat was significantly smaller in right ventricular arrhythmia group compared with and left ventricular arrhythmia group. For predicting the origin of ventricular arrhythmia, the ΔS1 duration provide better predictive accuracy  in comparison to ΔS1 complexity score . The change of S1 complexity and duration determined from acoustic cardiography could accurately predict the ventricular arrhythmia origin. Catheter ablation is an effective therapy in the treatment of frequent PVC or ventricular tachycardia (VT). Before the advancement of cardiac mapping techniques, the origin of ventricular arrhythmia (VA) was a matter of interest but lacked relevance. When therapeutic options became available, mapping tools to locate areas responsible for arrhythmias became important. By using the mapping tool, the electrophysiologist could correlate the surface electrocardiogram (ECG) of the VA with the area in the heart at which ablation could eradicate it.Premature ventricular contraction (PVC) is the most common cardiac arrhythmia in patients with or without any kind of diagnosed cardiac diseases2. Transesophageal echocardiography Tissue Doppler also provided an alternative method to identify the earliest onset of myocardial excitation in the animal study3. However, the application of these invasive tools was not clinically practical but only reserved for study with special facility. There is no other well-validated tool to identify the origin of ventricular arrhythmia currently. The ECG still remains the simplest and cost effective non-invasive diagnostic method for determining origin of VA4. It is useful to localize the site of origin of VA before intervention to facilitate catheter ablation5. Although many ECG criteria using the vectors from 12 lead recordingscan predict VA origin, it is limited by the need to record a 12-lead surface ECG with recording of PVC. Holter monitoring with fewer leads or a single lead strip is unable to predict VA origin due to the limited information from fewer vectors.Previous study demonstrated that the reverse splitting second heart sound (S2), which required additional carotid pressure tracing tool, was associated with the origin of ectopies6 studied 26 left bundle branch block (LBBB) subjects and 20 normal subjects with phonocardiogram using Cambridge microphones and a Cambridge fiberoptic multichannel physiologic recorder. With LBBB the first heart sound (S1) tended to be of reduced intensity and separate mitral and tricuspid components could not be identified. Brooks et al.7 studied 20 right bundle branch block (RBBB) subjects and 67 normal subjects with simultaneous echocardiogram of valves, electrocardiogram, and phonocardiogram. Wide splitting of the S1 was observed in RBBB subjects8. These studies demonstrated the wavefront of ventricular myocardial activation affect the timing of valvular closure, which could be detected and quantified by well-designed acoustic cardiography device.Burggraf9. Acoustic cardiography permits simultaneous acquisition of ECG and heart sound information and provides a computerized interpretation of these findings. Although, the application of heart sounds in prediction of the origin of VA has been intensively investigated, it is not clinically available because of the lack of objectivity11. The present study was designed to test whether acoustic cardiography could provide information in differentiating the origin of VA in clinical practice.Acoustic cardiography is a cost-effective technology, which incorporates hemodynamic information and electrocardiac signals for clinical assessment12.This was a retrospective, single center cohort study. From January 2015 to June 2017, 45 patients  undergoing catheter ablation of monoform VA with contemporaneous digital acoustic cardiography were enrolled. All patients routinely underwent transthoracic two-dimensional echocardiogram and 12 lead ECG. Exclusion criteria included the echocardiographic determination of heart failure (HF) and valvular heart disease due to possible acoustic abnormalities. Patients with chronic lung diseases and obesity were also excluded, as abnormalities of pulmonary function may confound the transmission of acoustic signals. Patients were also excluded if complete RBBB or LBBB was observed (QRS duration >120 ms)Patients were classified into two groups  based on electrophysiological study and three-dimensional electroanatomic mapping. VAs from outflow tract (OT) was documented in 15 (62.5%) patients within Group 1 and 11 (52.4%) patients within Group 2.Institutional Review Board at Taipei Veterans General Hospital, Taipei, Taiwan approved this study without requiring patients’ informed consent (VGH-IRB Number: 2014-09-012A). All patients signed their written informed consent according to the institutional guidelines of the Taipei Veterans General Hospital. All methods were performed in accordance with the relevant guidelines and regulations.15.Each subject underwent the acoustic cardiographic examination before the electrophysoplogical study . Acoustic cardiographic raw data were transferred to Inovise Medical and were analyzed by the computerized algorithm for the measurement of heart sound parameters and systolic time intervals. This algorithm has been validated by blinded interpretation of heart sound tracings by experts, and the relationship of these variables to hemodynamic measurements obtained by invasive and non-invasive methods has been previously reportedThree acoustic cardiographic characteristics of S1 and S2 were analyzed: intensity, complexity, and splitting duration. A value for heart sound intensity is generated based on the peak-to-peak amplitude of the sound and expressed in mV units. Heart sound complexity is a correlate of the auditory perception of valve sound crispness and is determined using time-frequency measures of width, intensity and frequency content of the signal, which is influenced by valve splitting or closure abnormalities. Based on spectral analysis, complexity is expressed as a dimensionless index. Splitting duration was measured by the algorithm from the onset to the end of the heart sound. Figs  ElectromAll patients previously failed treatment with at least one antiarrhythmic drug. Anti-arrhythmic drugs were discontinued for a minimum of five half-lives before radio-frequency catheter ablation (except for amiodarone). After obtaining informed consent from the patients, we performed standardized electrophysiological study in the fasting non-sedated state for the endocardial procedure and the sedated condition for epicardial approaches, respectively. In the absence of spontaneous VA, rapid ventricular pacing and/or programmed stimulation of up to three extra-stimuli were performed from the RV apex and/or the RV outflow tract (RVOT). If the VAs were not inducible, intravenous isoprenaline at 1–5 μg/min was infused in order to achieve at least a 20% increment in the heart rate. If spontaneous VAs were not inducible during pharmacological provocation, the induction protocol was repeated. The QRS morphologies of spontaneous and/or induced VAs were compared with the clinically documented VAs.The localization of the successful ablation focus was performed using a 3D mapping system . During the ablation procedure inside the LV, intravenous heparin was administered in order to maintain an activated clotting time of >250 s. Pace mapping was performed in all cases using the distal bipolar electrodes at a pacing cycle length of 500 ms and stimulus amplitude of 1 mA greater than the late diastolic threshold up to a maximum output of 25 mA and pulse width of 4.0 ms. Activation mapping was intentionally performed in all cases in order to identify the earliest activation site. Figs .Radiofrequency energy was delivered via an irrigated tip catheter  with a maximal power of 30–40 watts, while targeting an impedance drop of 10 Ohms, maintained for a minimum of 120 s at the site of termination or elimination in VA. Once the VA was suppressed within 30 s, additional energy was applied up to a maximum of 5 burns, followed by substrate modification of the nearby abnormal potentials, including isolated or fractionated late potentials, if present. Acute procedural success was defined as complete elimination of spontaneous or inducible VAs under the infusion of isoprenaline (up to 5 μg/min), following the same induction protocol for 30 min in order to exclude acute recurrences.Patients were followed up in the cardiology outpatient clinic with 12-lead ECGs, 24-hour Holter, monitoring, and echocardiography after the catheter ablation every 3 months for the first year, and then 6 months thereafter. For patients who could not come for outpatient follow up in our institution, they were contacted over the telephone for recurrent symptoms and recurrent arrhythmias. They were advised to visit our affiliated institutions to complete the follow-up screening, and transfer the data to the main hospital. The medical reports were obtained from those affiliated institutions. Recurrence was defined by recurrences of sustained VTs, nonsustained VTs, or greater than 1000 ventricular PVCs, as confirmed by the morphology criteria using the 24-hour Holter ECG.All analyses were performed using SPSS statistical software, version 20.0 . Continuous data are expressed as mean standard deviation and as percentages for categorical variables. All continuous data were tested using the 1-sample Kolmogorov-Smirnov test against a normal distribution. Continuous variables were compared using the independent Student t test. For comparison of dichotomous variables, the chi-square test was used. A p value of < 0.05 was considered statistically significant. Receiver operator characteristic curves (ROC) and areas under the receiver operator characteristic curves were analyzed for the significant parameters to determine the optimal cut-off point for VA origin (Youden index).The baseline characteristics of these patients are presented in the Table There was no significant difference in acoustic cardiographic measurement of sinus beats between Group 1 and Group 2 .In the patients with LV origin VAs, the subtracted acoustic cardiographic parameters (PVC-SR) in non-OT VAs exhibited a positive change in S1 intensity than that in the OT group .In the patients with RV origin VAs, the subtracted acoustic cardiographic parameters (PVC-SR) in non-OT VAs exhibited a negative change in S1 intensity than that in the OT group , following the same induction protocol for 30 min. Figures We investigated the value of PVC S1 duration, ΔS1 complexity, and ΔS1 duration for the detection of VA origin (right side or left side) by constructing ROC curves to assess the predictive performance. As shown in Fig. Regarding the traditional ECG criteria used to discriminate origin of VA, 24 (100.0%) RV VAs were presented with LBBB morphology, 17 (81.0%) LV VAs were presented with RBBB morphology. Four (19.0%) LV VAs were presented with LBBB morphology with early precordial transition before V2. The overall sensitivity and specificity was inferior to ΔS1 duration in the present study.In the patients with LV VAs, we investigated the value of ΔS1 intensity for the detection of OT VAs by constructing ROC curves to assess the predictive performance. As shown in Fig. In the patients with RV VAs, we also investigated the value of ΔS1 intensity for the detection of OT VAs by constructing ROC curves to assess the predictive performance. As shown in Fig. After a median follow-up of 16 ± 6 months (range 3 to 32 months), VA recurrences were documented in 4 patients (8.9%) after a mean follow-up of 7.5 (4–14) months. There was no statistical significance in the VA recurrences between the two groups . The QRS morphology of recurrent VA was similar to that before the catheter ablation in the 4 patients and repeated catheter ablation at the similar location eliminated the recurred VA smoothly.6. The reduced intensity of the S1 in LBBB is caused mainly by the decreased amplitude of the mitral valve excursion at the onset of left ventricular contraction. In our study, LBBB morphology PVC (RV origin) demonstrated non-significant reduced intensity, decreased complexity and shortened S1 slitting duration. Our result echoed the previous findings that reduced complexity and splitting duration of S1 in PVC with RV origin is caused mainly by the decreased amplitude of the mitral valve excursion at the onset of LV contraction and the decreased tension on the closed mitral valve resulting from the slow rate of LV pressure rise at the onset of the S116.To the best of our knowledge, this is the first study to evaluate the value of acoustic profile on prediction of origin of ventricular arrhythmia. With LBBB the S1 tends to be of reduced intensity as shown in a previous studyIn our study population, 4 patients had left ventricular outflow tract (LVOT) VAs with LBBB morphology. This finding suggested that the acoustic parameter might provide better predictive value than traditional Holter with 3 ECG channels.8. In this study, RBBB morphology PVC (LV origin) was characterized by increased S1 duration and complexity, which were compatible with previous findings.With RBBB the S1 tends to be widely spitted with a preserved amplitude and a larger late component. as shown in a previous study17. To eliminate the individual anatomic difference, we also evaluated the difference of acoustic profiles between PVC and SR beats. We observed that the complexity and splitting duration of S1 were significantly increased in left side PVCs compared to that in SR. Reversely, reduced complexity and splitting duration of S1 were found in right side PVCs compared to that in sinus beats. The difference of PVC and SR (PVC-SR) in S1 duration was shown to be a better parameter in differentiating VA origin.The acoustic profiles of S1 and S2 during sinus rhythm didn’t significantly differ between Group 1 and Group 2. It is well understood that the intensity of precordial heart sounds is influenced by anatomic factors such as body surface area, characteristics of the thoracic cage and cardiac axisTo the best of our knowledge, there was no study to evaluate the acoustic difference between OT-VA and non-OT VAs. Our presented study demonstrates that the OT-VA and non-OT VA had different acoustic parameter as S1 intensity in LV VA and S2 duration and S2 complexity in RV VA. Further prospective studies with systemic approaches are warranted to prove this finding.18. Ventricular ectopy from LV activated LV myocardium and initiate mitral valve closure first. Late onset of RV contraction secondary to a mean 25.7 msec transeptal conduction time19 contributed to the prolonged S1 during LV PVC, which was caused by delayed onset of the right ventricular pressure pulse and tricuspid closure. Our present study demonstrated a positive change of S1 splitting duration of LV PVC in comparison to SR, which echoed the previous concept of hemodynamic and electrophysiological aspects.The S1 is produced by vibrations generated by the closure of the mitral and the tricuspid valves. There is normal asynchrony in the closure of mitral and tricuspid valves, the mitral closure preceding tricuspid closure by 20 to 30 msec6, mitral valve closure occurred earlier than tricuspid valve in 27% of the subjects. Some hemodynamic studies have been conducted to determine the delay in onset of left ventricular contraction in LBBB morphology beats and the reversed splitting was not consistently observed on the phonocardiograms22. Our present study revealed a negative change of S1 duration with large standard deviation (−18.66 ± 11.78 ms) of RV PVC in comparison to SR beats, which echoed the previous reports.In the previous study, the atrioventricular valve closure times during LBBB morphology beatsIn view of electrophysiological hemodynamic points, the LV PVC exaggerated the normal asynchrony through transseptal conduction time. On the other hand, the RV PVC shortened or reversed the naturally splitting sequence of atrioventricular valve closure and produced a relatively negative change of S1 during comparing to LV PVCs.Conventional Holter examination could only provide the information regarding the presence of arrhythmia. In addition to the ECG strip, the acoustic cardiography was automatically analyzed for the measurement of heart sound parameters, which effectively provided the information of potential VA origin. The acoustic cardiographic examination can be used to determinate the dominant PVC origin with our documented 12-lead ECG or symptomatic PVC origin and guide the clinical decision making before and during interventional electrophysiologic procedures. After successful ablation, the acoustic cardiography could provide the information regarding the pattern of recurrence (same origin or not). Before our present study, invasive electrophysiological study and 12 leads surface ECG were the only clinically available methodology in determining VA origin. The clinical value of conventional ECG was limited by the short recording time (10 seconds strip with 2.5 seconds in each lead). The acoustic cardiography not only provided the information of the presence of arrhythmia but also the origin of ventricular ectopic beats. Based on this additional information, clinician can be informed of the potential benefit and procedure related complication in detail.Several limitations merit consideration. First, the sample size was relatively small, which provided a weak power for the generalization of the conclusion. We adjusted for possible inter-subject anthropomorphic differences by calculating the difference between PVC and SR beats. Second, this study is limited by its retrospective nature. Third, although it’s clinical value has been established in previous literatures, acoustic cardiography is easily affected by environmental interference. Carefully review and manual editing by experienced technician were required. Fourth, although the change of S1 complexity, and S1 splitting duration displayed potential predictive utility for the discrimination of VA origin, the study cohort was preselected to elucidate the physiological underpinnings of transmitted heart sounds, and thus patients with valvular abnormalities and conduction disorders were excluded. Fifth, the clinical value of acoustic cardiography for VA in the patients with structural heart disease or valvular heart disease was not clear because of the study design. Additionally, this present study included patients with distinctive VA origin from RV and LV. Various impact of activation wavefront might affect our observation on the heart sound change. Further prospective trial with different cohort and larger samples is warranted for validation and confirmation.The difference of S1 splitting duration between SR and PVC could accurately predict the chamber of VA origin. Further acoustic analysis might help differentiate the OT VA and non-OT VA. Increased PVC S1 duration compared to that of SR beats was altered in the left side VA group. In the group with LV VA, OT origin VA was presented with negative change in S1 intensity during PVC. In the RV VA, OT origin VA was presented with positive change in S1 intensity during PVC. These findings extend our mechanistic understanding of the relationship between ventricular arrhythmia and the precordial acoustic profile. Further prospective study is warranted for applying the acoustic data in differentiating the location of VA.


Adverse fibrotic remodeling is detrimental to myocardial health and a reliable method for monitoring the development of fibrotic remodeling may be desirable during the follow-up of patients after heart transplantation (HTx). Quantification of diffuse myocardial fibrosis with cardiovascular magnetic resonance (CMR) has been increasingly applied and validated histologically in adult patients with heart disease. However, comparisons of CMR findings with histological fibrosis burden in children are lacking. This study aimed to compare native T1 times and extracellular volume fraction (ECV) derived from CMR with the degree of collagen on endomyocardial biopsy (EmBx), and to investigate the association between myocardial fibrosis and clinical as well as functional markers in children after HTx.EmBx and CMR were performed on the same day. All specimens were stained with picrosirius red. The collagen volume fraction (CVF) was calculated as ratio of stained collagen area to total myocardial area on EmBx. Native T1 values and ECV were measured by CMR on a mid-ventricular short axis slice, using a modified look-locker inversion recovery approach.p < 0.005 and 0.30 ± 0.03 vs 0.22 ± 0.03, p < 0.0001, respectively). CVF showed a moderate correlation with native T1  as well as ECV . Native T1 time, but not ECV and CVF, correlated with ischemia time .Twenty patients  after HTx were prospectively enrolled, at a median of 1.3 years (0.02–12.6 years) post HTx, and compared to 24 controls . The mean histological CVF was 10.0 ± 3.4%. Septal native T1 times and ECV were higher in HTx patients compared to controls  contains supplementary material, which is available to authorized users. In spite of substantially improved survival following paediatric heart transplantation (HTx) over the past two decades , signifiVentricular dysfunction in HTx recipients has been linked to previous or acute episodes of organ rejection and to coronary allograft vasculopathy (CAV). Both rejection and CAV are suspected to cause myocardial fibrotic remodeling –5 which,Histological evaluation of tissue is the gold standard and has been the only available method for quantification of myocardial fibrosis. However, its invasive nature and the exposure to ionizing radiation during cardiac catheterization represent significant barriers to serial endomyocardial biopsies (EmBxs), especially in children. Furthermore, the biopsied region may not be representative of the majority of the myocardium and may be affected by scarring due to previous sampling in the same location. More recently, cardiovascular magnetic resonance (CMR) techniques based on T1 relaxometry have been refined and applied in adults with a variety of cardiac diseases, including in HTx recipients –20. CMR-The aims of this study in children after HTx were 1) to compare CMR native T1 times and ECV with the degree of fibrosis on histological samples and 2) to investigate the association between the histological degree of fibrosis and CMR-derived fibrosis markers on the one hand and markers of cardiac health and transplant-related factors on the other.Following approval by the Hospital for Sick Children Research Ethics Board (project # 1000013662), all HTx children and adolescents who were scheduled for a clinical EmBx for rejection surveillance in asymptomatic patients between April 2010 and October 2011 were invited to participate in the study. Following informed written consent by the patients and/or their legal guardian(s), patients underwent a research CMR immediately prior to the catheterization with the EmBx procedure.CMR studies were also performed in 24 controls, consisting of children with a family history of arrhythmogenic right ventricular cardiomyopathy or with non-specific chest pain who were referred for anatomical coronary artery imaging. Only children who had an entirely normal CMR examination as well as normal results on all other tests were included.The CMR examinations were performed using a 1.5 Tesla system . Ventricular volumes were assessed with a stack of multiphase short axis slices, acquired with a steady-state free-procession (SSFP) sequence in the routine clinical fashion . A modifImages were acquired in diastole at a single mid-ventricular short axis slice before and 10 min after the administration of 0.2 mmol/kg gadopentetate dimeglumine . Breathholds were used in awake and cooperative patients; all other patients and anaesthetized patients were scanned during free breathing or ventilation. The presence of late gadolinium enhancement (LGE) was assessed qualitatively on long and short-axis phase sensitive inversion recovery images in the usual clinical fashion.Longitudinal relaxation times T1 times) were measured using a curve-fitting algorithm within commercially available software . Regions of interest were drawn manually on the raw images of MOLLI mid-ventricular short axis slices to represent the interventricular septum (IVS)  model ) and the times weFeature tracking analysis was performed with the TomTec 2D CPA MR software  using standard SSFP cine images, with 20 phases per cardiac cycle, as previously described . In brieVentricular volumes were obtained from the cine short axis stack using dedicated software  according to the Society for Cardiovascular MR guidelines for reporting cardiovascular MR examinations . VentricTransvenous right ventricular biopsies were obtained from the right ventricular aspect of the IVS immediately following the CMR in the routine clinical fashion. Three to six samples were taken in each individual. Samples  were immediately fixed in 10% buffered formalin, processed and embedded in paraffin, and serially sectioned, with every second slide stained with hematoxylin and eosin as per standard protocol. A mid-level unstained section was selected and stained with picrosirius red for the analysis of collagen. Stained sections were digitalized with a Pannoramic 250 Flash IIslide scanner . Low-power views were was used to select appropriate areas for analysis, excluding superficial endocardial fibrous tissue and sites of scarring from previous biopsies at the discretion of the interpreting pathologist , quantifying the total area of stained collagen and that of myocardium, excluding areas of white backgrounds in each sample Fig. . This mep values are two sided. Statistical significance was defined as p ≦ 0.05.Statistical analyses were performed using JMP pro version 11 software . Data are presented as mean ± standard deviation or median with range, as appropriate; categorical variables are reported as number and percentage. Paired comparisons were performed by using Student t test or the Mann-Whitney U test for non-normally distributed data between patients and controls, and between groups of patients, where applicable. Linear regression analysis was performed by using the Pearson correlation coefficient for normally distributed data. Correlations were analyzed with use of Spearman’s rank correlation coefficient test for non-normally distributed data. Interobserver variability for native T1 times and ECV were assessed using the Bland-Altman method. All Patient characteristics are summarized in Table p < 0.05). However, the organ age which was calculated as the sum of the donor age at demise and the time since HTx, was similar between the two groups. (Table n = 10) and amlodipine for arterial hypertension (n = 6). No patients were treated for diabetes mellitus. No patient had coronary angiography performed within 6 months of CMR.Twenty patients  who had undergone HTx at a median age of 8.6 years , and 24 controls were enrolled. Some of the results in a subgroup of patients were reported previously as part of a different study, exploring the association between CMR-derived fibrosis markers and cardiac function by echocardiography . Patientp < 0.005 and p < 0.0001, respectively, Table p < 0.0001, Table r = 0.53, p < 0.05 and r = 0.46, p < 0.05, respectively, Fig. Myocardial biopsy was collected without complication in all subjects. The mean histological CVF in all patients was 10 ± 3.4% . Seven patients (35%) had had at least one previous episode of acute cellular rejection (ACR) with an ISHLT grade ≥ 2 R. No differences in CVF, native T1 time, or ECV were identified between patients with and without previous 2 R ACR (p = 0.78). One patient had experienced an episode of antibody-mediated rejection 2.8 years after transplantation and 2.2 years before CMR, requiring extracorporeal membrane oxygenation and intensification of immunosuppression. This patient had the second highest CVF of all patients with 15.2% and highest native T1 time with 1070 ms, both in the IVS.No correlation existed between CVF and heart age at the time of CMR or between either native T1 values or ECV and heart age. At the time of CMR, no patient had clinically significant rejection as per EmBx on the same day .No correlation existed between organ ischemia time at the time of HTx and CVF. Native T1 time, but not ECV, in the IVS correlated with ischemia time . No significant difference existed in LV mass between patients with and without antihypertensive medications .The six patients on antihypertensive medications did not have different CVF, native T1 or ECV in any of the investigated regions (IVS and entire LV) as compared to normotensive patients . The ‘early’ group did have higher ECV in the IVS and the entire LV, while CVF was not different in these 4 patients as compared to the other HTx patients who were investigated at least three months after HTx. . One patient had ISHLT grade 1 CAV 1 year after CMR and deceased 1.5 years after coronary angiography. Another patient demonstrated ISHLT grade 2 CAV three years after CMR. The remaining 13 patients had normal coronaries at the time of coronary angiography.p < 0.0001 and p < 0.0005, respectively, Table Global LV radial strain and strain rate were higher in HTx patients compared to controls (The results of ventricular size, mass, and ejection fraction analysis are summarized in Table Native T1 time and ECV in the IVS correlate with histological degree of fibrosis in EmBx specimens.Septal native T1 times are higher in patients with longer ischemia times at the time of transplantation.Despite a variety of candidate etiologies the morphological substrate for graft dysfunction following HTx is incompletely understood. Adverse fibrotic myocardial remodeling is a suspected longterm sequelae of HTx. However, until recently, it has not been feasible to quantify myocardial fibrosis non-invasively. The present study adds the following to our understanding of myocardial health in paediatric patients after HTx:Both ECV and native T1 times have been validated against the histological gold standard in adults with valvular heart disease, as well as ischemic and non-ischemic cardiomyopathy , 23–25. 14C inulin or 14C mannitol in a rat model [In the present study as in other validation studies, ECV measured by CMR was higher than the histological CVF. Picrosirius red stains collagens which are the most abundant macromolecules in extracellular matrix. On the other hand, ECV depends on the uptake of gadolinium in the entire extracellular space. As such, it is a marker for the relative size of the extracellular matrix which contains other proteins like elastin, adhesive glycoproteins and proteoglycans in addition to collagen, as well as vascular volumes. As a result, although there is an association between the two ECV exceeds CVF. The average ECV in our paediatric controls was 0.22 ± 0.03, as compared to 0.25 ± 0.04 in adults . These lat model .We demonstrated that ECV was significantly higher in patients early after HTx as compared to remaining patients. Exposure to cardiopulmonary bypass, reperfusion injury of the organ and other perioperative factors as well as possible episodes of early ACR are all factors which potentially promote myocardial edema as well as fibrotic remodeling .Fibrosis within cardiac allografts is a well-documented phenomenon in adults , 43. TheWe did not observe a relationship between LV or RV ejection fraction and histological or CMR markers of fibrosis, however, ejection fraction is a relatively insensitive marker of a decline in myocardial function . ChildreBland-Altman analyses revealed only a small bias but relatively wide limits of agreements between the two observers. Breathholds were used for the MOLLI acquisition in 30% of patients, and a motion correction algorithm was not available at the time of data acquisition. In fact, Fig. First, the modest sample size of this pilot study may have obscured further differences between controls and patients as well as associations between fibrosis markers and other parameters. Second, T1 and ECV were measured on a single short axis slice and the assumption that these values are representative of the LV myocardium from base to apex may be erroneous. Third, it is possible that the difference in T1 and ECV between patients and controls was amplified by the lower hematocrit levels in HTx recipients, given the linear relationship between lower hematocrit and higher T1 and due to the fact that all myocardial regions of interest also sample small volumes of blood within the intramyocardial capillaries. However, if hematocrit, and not expansion of the extracellular space, was the primary determinant of T1, one would expect a correlation between hematocrit and native myocardial T1. No association between T1 and hematocrit was present, in the patient cohort. Furthermore, when comparing patients in the highest T1 quartile with those in the lowest T1 quartile we did not see a difference in hematocrit. Therefore, we do not believe that the differences in T1 and ECV are entirely or mainly due to variations in hematocrit. Finally, coronary angiography was not available in close proximity to CMR and EmBx for ethical reasons. Therefore, CAV, one of the candidate etiologies of fibrotic myocardial remodeling, could not be investigated.Native T1 time and ECV correlate with histologically determined collagen volume in paediatric patients after HTx. The graft organs in children after HTx undergo accelerated myocardial fibrotic remodeling, and higher native T1 times are associated with longer ischemia times.


The time-course and relationships of myocardial haemorrhage and oedema in survivors of acute ST-elevation myocardial infarction (STEMI) are uncertain.30 STEMI patients  male) treated by primary percutaneous coronary intervention underwent serial cardiac magnetic resonance imaging: 4 - 12 hours, 3 days, 10 days and 7 months post-reperfusion. Native T2 and T2* were measured in regions-of-interest in remote and injured myocardium. Myocardial haemorrhage was taken to represent a hypointense infarct core with a T2* value <20 ms. Public registration: NCT02072850.Myocardial haemorrhage occurred in 7(23%), 13(43%), 11(33%), and 4(13%) patients at 4 - 12 hours, 3 days, 10 days and 7 months, consistent with a unimodal pattern. The corresponding amounts of myocardial haemorrhage (% LV mass) during the first 10 days post-MI were : 2.7, 7.0, 4.1; p < 0.001). Myocardial oedema (% LV mass) had a unimodal evolution in all patients (p=0.001). In patients without hemorrhage, infarct zone T2 values (ms) increased progressively during the first 10 days (62.1(2.9), 64.4(4.9), 65.9(5.3) (p < 0.001). Alternatively, in patients with myocardial haemorrhage, infarct zone T2 was reduced at day 3 (51.8 (4.6) ms) (p < 0.001), depicting a bimodal pattern.LV end-diastolic volume increased from baseline to 7 months in patients with myocardial haemorrhage (p=0.001), but not in patients without haemorrhage (p=0.377).The temporal evolutions of myocardial haemorrhage and oedema are unimodal, whereas infarct zone T2 (ms) has a bimodal pattern in haemorrhagic infarction. Myocardial haemorrhage is prognostically important. Further studies are warranted.


While most studies focus on cardiovascular morbidity following anesthesia and surgery in excessive obesity, it is unknown whether these intraoperative cardiovascular alterations also occur in milder forms of adiposity without type 2 diabetes and if insulin is a possible treatment to improve intraoperative myocardial performance. In this experimental study we investigated whether mild adiposity without metabolic alterations is already associated with cardiometabolic dysfunction during anesthesia, mechanical ventilation and surgery and whether these myocardial alterations can be neutralized by intraoperative insulin treatment.Mice were fed a western (WD) or control diet (CD) for 4 weeks. After metabolic profiling, mice underwent general anesthesia, mechanical ventilation and surgery. Cardiac function was determined with echocardiography and left-ventricular pressure–volume analysis. Myocardial perfusion was determined with contrast-enhanced echocardiography. WD-fed mice were subsequently treated with insulin by hyperinsulinemic euglycemic clamping followed by the same measurements of cardiac function and perfusion.Western-type diet feeding led to a 13 % increase in bodyweight, (p < 0.0001) and increased adipose tissue mass, without metabolic alterations. Despite this mild phenotype, WD-fed mice had decreased systolic and diastolic function  compared to CD-fed mice. Ventriculo-arterial coupling and myocardial perfusion were decreased by 48 % (p = 0.003) and 43 % (p = 0.03) respectively. Insulin treatment in WD-fed mice improved echo-derived systolic function , likely due to decreased afterload, but there was no effect on load-independent measures of systolic function or myocardial perfusion. However, there was a trend towards improved diastolic function after insulin treatment  in WD-fed mice.Mild adiposity without metabolic alterations already affected cardiac function and perfusion during anesthesia, mechanical ventilation and surgery in mice. Intraoperative insulin may be beneficial to reduce afterload and enhance intraoperative ventricular relaxation, but not to improve ventricular contractility or myocardial perfusion. Adiposity is a characteristic of about 50 % of patients undergoing anesthesia and surgery , and a rIn order to gain insight in the impact of mild adiposity on myocardial function during anesthesia and surgery, we investigated whether mild adiposity without metabolic alterations is already associated with intraoperative alterations in myocardial function in an experimental mouse model. We further hypothesized that mild adiposity is associated with cardiovascular alterations that can be restored by perioperative insulin treatment. Insulin has positive inotropic effects and it is known that high dose insulin improves cardiac function in animals with septic and hemorrhagic shock , 10 but Animal experiments were approved by the Institutional Animal Care and Use Committee of the VU University , and were conducted following the European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes and the ARRIVE guidelines on animal research  for calculation of microvascular blood volume A and the microvascular filling velocity ß, which corresponds to the capillary blood exchange rate. The estimate of myocardial perfusion was calculated as the product of A and ß.Custom-designed software was used for analysis of the estimate of myocardial perfusion  . For eaca), a measure for left ventricular afterload, were determined. From vena cava occlusion data, end-systolic elastance (Ees) was determined as the slope of the end-systolic pressure–volume relationship, a load-independent measure for cardiac contractility. The slope of the end-diastolic pressure–volume relationship, Beta, was determined, which is considered a load-independent determinant of diastolic function. The ratio Ees/Ea was determined as an estimate of ventriculo-arterial coupling, which describes adaptation of the LV in relation to the vasculature [After induction of anesthesia a subcostal thoracotomy was performed and a pressure–volume Millar catheter  was inserted in the LV via the apex. The Millar catheter continuously measures pressure and volume in the LV, and the volume signal was calibrated with stroke volume estimations that were obtained with echocardiography in the closed-chest situation. A ligature was placed under the inferior vena cava for transient preload reductions. Pressure–volume loops were measured in three series with vena cava occlusion-induced preload reduction. In a different group of mice, the same measurements were performed after hyperinsulinemic euglycemic clamping. Analysis of pressure volume loops was performed using PowerLab software . From steady state measurements, LV mean and end-systolic pressures as well as arterial elastance . Statistical differences between the western-type diet and the control group were tested using a Student Characteristics of mice fed a control or western diet for 4 weeks are shown in Table Hemodynamics as measured under stable, anesthetized conditions are described in Table es was 2.0 ± 0.5 versus 4.1 ± 2.4 mmHg/μL, p = 0.01) compared to CD-feeding. Afterload (Ea) did not differ between groups. Ventriculo-arterial coupling (Ees/Ea) was diminished in WD-fed mice compared to controls . Furthermore, WD-feeding increased diastolic Beta  compared to controls, which implies a stiffer ventricle. Myocardial perfusion was decreased by 43 % in WD-fed mice compared to CD-fed mice (p = 0.03).Cardiac function and perfusion parameters are described in Table a decreased from 1.8 ± 0.9 to 1.2 ± 0.4 mmHg/μL, p = 0.07) during insulin treatment. While systolic echocardiographic parameters improved slightly in WD-fed mice during insulin treatment , there was no improvement in end-systolic elastance (Ees was 1.6 ± 0.3 versus 2.0 ± 0.1 mmHg/μL at baseline) nor in ventriculo-arterial coupling. Furthermore, there was a trend towards decreased Beta during insulin treatment (−43 % from 0.07 ± 0.01 to 0.04 ± 0.01 mmHg/μL p = 0.05), indicating improved diastolic function. Finally, myocardial perfusion was unaffected by insulin treatment in WD-fed mice.Hemodynamics and cardiac responses to insulin treatment in WD-fed mice are described in Table In this study we demonstrated that a mild, early stage of diet-induced adiposity is already associated with decreased systolic and diastolic function, diminished ventriculo-arterial coupling and impaired myocardial perfusion during anesthesia, mechanical ventilation and surgery in mice. In this phenotype, intraoperative insulin treatment improved echo-derived systolic function, decreased afterload and showed a trend towards improved diastolic function. However, there was no effect on load-independent measurements of systolic function or myocardial perfusion. These combined findings suggest mild adiposity already compromises cardiac function during anesthetized and mechanically ventilated conditions, and that intraoperative insulin treatment may be applied to positively modulate loading conditions and ventricular relaxation, but not to influence cardiac contractility.In the present study we timed diet exposure to induce an early stage of adiposity without insulin resistance, so that the effect of early overweight conditions without confounding metabolic alterations could be studied. We demonstrated that intraoperative myocardial depression is already present in this early stage. Therefore, mildly adipose patients may be at increased risk for perioperative cardiac alterations, even when presenting in the early stage without metabolic alterations.In literature, conflicting results have been reported regarding the effect of diet-induced adiposity on systolic function. Some report decreased , 17, 18 Diastolic dysfunction is a consistent finding in diet-induced adiposity, and is the predominant cardiac feature in earlier stages of human obesity . The incCardiac function relies on adequate myocardial perfusion , for whiThe increasing prevalence of overweight and obese patients that undergo surgery under anesthesia and the myocardial depression demonstrated in the described mouse model warrant treatment strategies to optimize perioperative cardiac function. Insulin has been shown to improve cardiac function in the setting of acute myocardial infarction, ischemia and reperfusion injury, sepsis and hemorrhagic shock , 27, 28.In the present study, insulin treatment improved intraoperative fractional shortening, but not load-independent end-systolic elastance in mildly adipose mice. In combination with decreased afterload and end-systolic pressure during hyperinsulinemia, this effect is most likely due to peripheral vasodilation, which is in concordance with previous findings , 34, 35.Taken together, these results suggest that intraoperative insulin treatment does not improve systolic function or myocardial perfusion, but decreases afterload and may improve ventricular relaxation when administered intraoperatively to mildly adipose mice with cardiodepression. While decreased systemic vascular resistance and afterload may reduce cardiac work load, it may also cause hypotension which could negatively affect tissue perfusion. However, we did not observe a significant effect on blood pressure and myocardial perfusion in this study. Although we observed no effects on systolic function, the trend towards a beneficial effect on diastolic function that we observed may on itself be relevant in the perioperative period. Diastolic dysfunction is an important risk factor in the perioperative period, as hemodynamic changes such as arrhythmias and tachycardia may affect diastolic filling, and existing diastolic dysfunction can acutely decompensate in the perioperative period .In conclusion, mild adiposity is already associated with intraoperative myocardial depression in mice. Intraoperative insulin treatment improved echo-derived systolic function, decreased afterload and showed a trend towards improved diastolic function, but not load-independent measurements of systolic function or myocardial perfusion. These combined findings suggest that the early stage of adiposity without metabolic alterations already compromises cardiac function during anesthetized and mechanically ventilated conditions, and that intraoperative insulin treatment may be applied to modulate loading conditions and ventricular relaxation, but not to influence cardiac contractility.


Sepsis is a common condition encountered by emergency and critical care physicians, with significant costs, both economic and human. Myocardial dysfunction in sepsis is a well-recognized but poorly understood phenomenon. There is an extensive body of literature on this subject, yet results are conflicting and no objective definition of septic cardiomyopathy exists, representing a critical knowledge gap.In this article, we review the pathophysiology of septic cardiomyopathy, covering the effects of key inflammatory mediators on both the heart and the peripheral vasculature, highlighting the interconnectedness of these two systems. We focus on the extant literature on echocardiographic and laboratory assessment of the heart in sepsis, highlighting gaps therein and suggesting avenues for future research. Implications for treatment are briefly discussed.As a result of conflicting data, echocardiographic measures of left ventricular (systolic or diastolic) or right ventricular function cannot currently provide reliable prognostic information in patients with sepsis. Natriuretic peptides and cardiac troponins are of similarly unclear utility. Heterogeneous classification of illness, treatment variability, and lack of formal diagnostic criteria for septic cardiomyopathy contribute to the conflicting results. Development of formal diagnostic criteria, and use thereof in future studies, may help elucidate the link between cardiac performance and outcomes in patients with sepsis. Septic cardiomyopathy (SC) is often diagnosed when some acute perturbation in cardiac function exists in the setting of sepsis. At present, no formalized or consensus definition of SC exists, representing a critical knowledge gap. Complexity of the cardiovascular system, myriad methods of assessment, and variations in the pre-septic state of the heart make elucidation of a cause-and-effect relationship difficult.SC has been recognized for 40 years , 2 and mEarly studies utilized invasive assessment methods or radionuclide imaging , 9; whilEchocardiography, however, is widely available, non-invasive, and easily repeatable, making it an optimal modality for evaluation of SC. Measurement of serum cardiac biomarkers provides separate, but related, information about the state of the heart  and thusThe purpose of this article is to review the extant literature on SC, with a focus on the evaluation and prognostic implications of various echocardiographic and laboratory measures thereof.The pathophysiologic cascade of sepsis begins when the host immune system responds to an invading pathogen, resulting in activation of the innate immune response . This cuSeptic shock is often classified as a type of “distributive” shock—relative hypovolemia resulting from maldistribution of circulating volume due to peripheral vasodilation, glycocalyx dysfunction, and increased capillary permeability. It has also been described as a biphasic disorder with an early, hyperdynamic phase (high cardiac output (CO), low systemic vascular resistance (SVR), warm extremities) and a late, hypodynamic phase  , 6. CircWhile preload augmentation has long been a primary intervention for sepsis and can increase CO via the Frank-Starling mechanism, its ability to do so depends on the functional state of the heart. However, measures of preload, such as central venous pressure (CVP) and inferior vena cava (IVC) dimensions, provide limited information on underlying cardiac function. Even when volume responsiveness is suggested by low CVP, increased respiratory variation of IVC diameter, or other invasive methods, guidance of resuscitation based on these measures has not been found to improve outcomes –16.Changes in afterload also affect the ability of the heart to deliver blood to the peripheral tissues. Thus, a heart with poor intrinsic contractility may be able to increase CO when SVR is low—thereby giving the impression of normal function—when in fact systolic performance is impaired. This dysfunction may only become apparent when SVR returns to normal via natural (recovery from sepsis) or artificial means (vasopressor use). Boissier et al.  demonstrAn early hypothesis, based on animal models, was that SC was caused by global myocardial ischemia resulting from decreased coronary blood flow . SubsequDespite such pathology, a cardinal feature of SC is its apparent reversibility, with many studies reporting that patients’ cardiac function recovered fully to their pre-morbid state , 20, 24.A summary of the echocardiographic parameters that have been used in the evaluation of SC, and their limitations, is listed in Table Systolic dysfunction, as measured by left ventricular ejection fraction (LVEF), was one of the first described parameters to assess for SC. Parker et al., in 1984  and furtStrain imaging is a novel technique based on regional myocardial deformation. The most frequently used strain parameter is global longitudinal strain (GLS), which represents the mean longitudinal strain value from each segment of the LV .Most commonly, GLS is calculated using speckle-tracking echocardiography (STE) . STE is Strain imaging has the ability to detect subtle changes in LV systolic function prior to decline in LVEF . A meta-p < 0.001), and 0.89 , respectively.Conversely, Orde et al.  found thSystolic function can also be assessed using tissue Doppler imaging (TDI)-derived velocity of the mitral annulus or by mitral annular plane systolic excursion (MAPSE). Peak systolic velocity of the mitral annulus, denoted S′, has been shown to have prognostic value in a variety of cardiovascular illnesses  and is rThe evidence with regard to the utility of these variables in septic patients is conflicting. Weng et al.  found a In the absence of infiltrative or restrictive cardiac disease, diastole is the main determinant of LV compliance . While ie’), with lower values corresponding to worse diastolic function [E) to early diastolic mitral annular velocity (E/e’) has been found to correlate with left-atrial pressure—a surrogate for pulmonary capillary wedge pressure [The preferred method for evaluation of diastolic function is TDI-derived velocity of the mitral annuls during early diastole . A 2017 update [Prognostic ability of urvivors –56; two urvivors . A 2015 urvivors  of 636 p7 update , of 15077 update  found in7 update , this la7 update , 43, 49.Lanspa et al.  found beDysfunction of the right ventricle (RV) contributes to morbidity and mortality in a variety of conditions, including heart failure and pulmonary hypertension , 62. Trip ≤ 0.05); these results are promising but require validation.Reported prevalence of RV dysfunction in sepsis varies, from 31 to 83% . As withAbnormal cardiac biomarkers, primarily troponin and natriuretic peptides (NPs), are another potential indicator of myocardial dysfunction that provide unique but related information about the heart . TroponiContemporary troponin assays  have been studied in septic patients, with concentrations generally rising with increasing disease severity; short-term non-survivors often have greater elevations than survivors , 69, butr = 0.35) [B-type NP (BNP), which is released in response to wall stress, reflects myocardial loading conditions and provides indirect functional information—as the heart moves towards the unfavorable portion of the Frank-Starling curve, wall stress, and BNP, rise , 74. As  = 0.35) , and a t = 0.35) . Dilatio = 0.35) , 55, 76, = 0.35) . Sturges = 0.35)  found thSome of this variability may be due to the fact that cardiac biomarker concentrations above the reference range are common in sepsis, with prevalence as high as 84% for cTnT , 98% forCurrently, no treatment recommendations exist that specifically address the presence of SC. Patients with SC may be at greater risk for excessive fluid resuscitation and more likely to require inotropic support, as hypoperfusion would less likely be corrected by IVF administration alone. However, data comparing use of vasopressors, inotropes, and other treatments in patients with and without SC are scant and subject to extensive confounding. Where treatment data are stratified by presence or absence of SC , 52, 78,Positive inotropic agents have the same putative benefits of vasopressors—increasing CO, thereby improving oxygen delivery to the peripheral tissues. Recommendations to titrate therapy to central venous oxygen saturation > 65% are of uncertain utility, as a normal value does not necessarily indicate adequate resuscitation . FurtherSC is a multi-factorial process that involves complex interactions between host and pathogen factors, and a full understanding of the disease process remains elusive. Prognostic implications of echocardiographic and biomarker findings are precluded by conflicting data from extant literature. Formal diagnostic criteria for SC do not exist; development of these, and studies based thereon, should be priorities for future research.