Global constructive work was significantly lower during RVP (1191 mmHg%) than during SVA and HBP  and did not differ between SVA and HBP (p = 0.075). Conclusions. 3D-EAM and MW evaluation showed that HBP was comparable to the physiological SVA in terms of activation time and cardiac performance. Compared to both SVA and HBP, RVP was associated with a worse activation timing and ventricular efficiency.Background. His bundle pacing (HBP) has emerged as an alternative site to right ventricular pacing (RVP) with encouraging outcomes. To date, no study has investigated the systematic approach of three-dimensional electroanatomic mapping (3D-EAM) to guide HBP implantation and to evaluate myocardial activation timing. Furthermore, studies reporting a comprehensive assessment of the ventricular function, using myocardial work (MW) evaluation are lacking. Objectives. (1) To evaluate the systematic use of the 3D-EAM as a guide to HBP; (2) to assess the electrical and mechanical activations with high-density mapping, comparing spontaneous ventricular activation (SVA), HBP and RVP; (3) to assess the myocardial function through speckle-tracking echocardiography (STE) and MW analysis in SVA, HBP and RVP. Methods. 3D-EAM was performed in consecutive patients undergoing HBP implantation with a low use of fluoroscopy. All patients were systematically evaluated with high-density mapping, MW and STE. Results. Fifteen patients were enrolled, of whom three had an implant failure (20%). RV activation time was not statistically different between SVA and HBP (103 vs. 104 ms,  The harmful effect of right ventricular pacing (RVP), both at mid- and long-term follow-up, lead to a continuous search for alternative pacing sites, among which His bundle pacing (HBP) emerged, showing encouraging results . HBP ideSeveral small observational studies have been published in the last 20 years, suggesting the interesting potential for HBP. In detail, when compared to apical pacing, HBP showed less ventricular dyssynchrony, less mitral regurgitation and a better left ventricular systolic function at standard and tissue Doppler echocardiography ,4,5,6. TTo date, no study has described the role of three-dimensional electro-anatomical mapping (3D-EAM) as a guide to HBP system implantation and in the evaluation of ventricular function. Furthermore, no study has provided a comprehensive assessment of ventricular function using contemporary echocardiographic functional imaging, namely changes in myocardial work parameters according to HBP stimulation.The aims of this study were: (i) to report on success rate and electrical parameters of HBP performed with systematic use of 3D-EAM, (ii) to evaluate electrical and mechanical ventricular activations comparing HBP, spontaneous rhythm and RVP by means of high-density mapping, (iii) to assess myocardial function through speckle-tracking echocardiography and myocardial work analysis.ClinicalTrials.gov (NCT05222672). The protocol was approved by the local ethics committee and informed consent was signed by all patients.The Electrical and Mechanical activation in PAcing The His bundle conduction sYstem (EMPATHY) study is a prospective, single center, cohort study, enrolling consecutive patients undergoing HBP at the Cardiology Unit of Azienda Ospedaliero-Universitaria di Ferrara, Italy. The study was registered on The inclusion criteria were: (1) class I or IIa indication for pacemaker implantation, according to European guidelines ; (2) ageThe primary endpoint of the study was to assess the success rate of HBP using 3D-EAM and to evaluate electrical and mechanical activation of ventricular myocardium and ventricular performance assessed with 3D-EAM and myocardial work (MW) during HBP, RVP and spontaneous rhythm.The index procedure was comprehensive of pacemaker implantation and simultaneous 3D-EAM. The right ventricle and the His bundle area were non-fluoroscopically mapped with a high-density catheter, inserted via the femoral vein. The pacing leads were inserted via the left cephalic or axillary vein, mapped in the 3D-EAM and inserted with the use of 3D-EAM and fluoroscopy. For His bundle pacing, an active fixation lead  was positioned, using a non-deflectable sheath . The position of the His bundle lead was confirmed with unipolar and bipolar intracardiac electrograms. Standard criteria were used to define selective and non-selective His capture . A backuHigh density 3D-EAM of the right ventricle was performed via the femoral vein at the time of pacemaker implantation, using Advisor HD Grid catheter and EnSite Precision mapping system  . At leasFollowing the procedure, all patients underwent an echocardiographic evaluation. Basic information, such as left ventricular (LV) volume (mL), LVEF (%), atrial volume (mL) and degree of valve diseases, were collected. Global longitudinal strain (GLS) and MW were analyzed. MW is a novel echocardiographic technique, based on the speckle tracking analysis, which estimates the left ventricular performance by area under pressure-strain loops curve, derived non-invasively from GLS and blood pressure ,17,18. AA twelve-leads ECG was performed and analyzed.3D-EAM, echocardiography and ECG evaluations were performed in each of the following conditions: spontaneous ventricular activation (SVA), HBP and RVP. HBP and RVP measurements were performed during pacing at a fixed rate in DDD mode with an optimized AV delay or in VVI mode, depending on whether patients were in sinus rhythm or atrial fibrillation. p values < 0.05 were considered statistically significant. The statistical analysis was performed using SPSS Statistics, version 25.0 .Continuous variables were expressed as mean ± standard deviation when normally distributed, as estimated using the Shapiro–Wilk test, or as median and interquartile range. Categorical variables were expressed as percentages. Differences between repeated measurements during SVA, HBP and RVP, were assessed using the ANOVA test or the Wilcoxon rank-sum test, respectively, for normally and non-normally distributed variables. Parametric and non-parametric multiple comparisons were tested with the Tukey and Bonferroni methods. Fifteen patients were enrolled in the study. The mean age was 76 ± 12 years and 13 were male (86%). The baseline clinical characteristics are summarized in Procedural data are shown in p = 0.969,) but was significantly higher in RVP (133 (120–147) ms, p = 0.011 vs. SVA and p = 0.001 vs. HBP). The QRS duration was significantly higher in RVP (168 ± 23 ms) than in SVA  and HBP  but did not differ between SVA and HBP (p = 0.929).3D-EAM, ECG and MW data are reported in GLS, GWI and GCW were all significantly higher during SVA or HBP than during RVP and did not differ between SVA and HBP . The GWWAt the one month follow-up, one patient died by a non-cardiac cause. The electrical parameters of the surviving patients are reported in The main finding of the current study is that HBP implantation guided by the 3D-EAM leads to right ventricular activation time and myocardial performance similar to spontaneous rhythm and definitely better than RVP . Previous studies reported rates of implant failure ranging between 12%–28% ,10. TherOur study showed that right ventricular activation time, assessed with 3D-EAM, is not different between SVA and HBP but is significantly lower in both these stimulation modalities, compared to the conventional RVP. This result is consistent with the hypothesis that HBP provides a “physiological” electrical activation of the ventricular myocardium . PreviouFor all the MW indexes considered, RVP resulted in worse performance, compared to SVA. Conversely, HBP was non different to SVA in terms of GWI and GCW. GWW and GWE were slightly lower, compared to SVA and HBP. Those findings indicate a worse left ventricular efficiency associated with RVP, in whom a major quote of myocardial energy is wasted. HBP had a lower impact over the myocardial efficiency, with GWI and GCW comparable to the physiological left ventricular contraction. However, GWW resulted higher in HBP than in SVA (even if not as much higher as during RVP), driving a slightly worse GWE. This might also be due to the small sample size, considering the small numerical difference between the two groups which instead becomes considerably consistent, in comparison to RVP, to the detriment of the latter.The echocardiographic MW is a function of pressure and strain, so it is not a direct measure of work but rather a surrogate index, while the invasive MW is expressed as pressure over volume, ultimately equivalent to the force times length. However, the echocardiographic MW is a robust index, validated against the invasive MW, of valuable significance in various clinical conditions, such as myocardial infarction, arterial hypertension, heart failure, cardiac resynchronization therapy and left bundle branch area pacing ,23,24,25It is the basis of the physiological pacing that QRS duration and morphology during HBP are nearly identical to spontaneous ventricular rhythm, particularly in case of selective His capture . PreviouWe observed an increase in HBP threshold at one month follow-up. Previous studies showed a significant increase in the His bundle capture threshold at 5-year follow-up, compared to implant measurements . Our stuOur cohort is relatively small, with only 15 patients, of whom 12 were successfully implanted. However, those numbers resulted sufficient to show a statistical significance. Previous studies exploring the hemodynamic and the performance of HBP enrolled comparable numbers of patients ,4,5,7,8.Only the RV activation time, and not the biventricular activation time, was collected. This limitation could not be overcome, since left ventricular mapping would have been adding a procedural risk for the patients, but having the activation time of the cardiac chamber where stimulation starts, combined with the indexes of the myocardial performance, is a good surrogate to explore the acute effects of physiologic stimulation.Electrophysiologic study with 3D-EAM and echocardiographic MW evaluation showed that HBP is comparable to physiological SVA, in terms of activation time and cardiac performance. Compared to both SVA and HBP, RVP was associated with worse right ventricular activation time and left ventricular efficiency.


This study aims to compare the differences between obstructed and unobstructed total anomalous pulmonary venous connection (TAPVC) using echocardiography, and to evaluate the clinical and echocardiographic parameters associated with pulmonary venous obstruction (PVO).We conducted a retrospective study of 70 patients with TAPVC between 2014 and 2019. The morphologic and hemodynamic echocardiographic parameters of patients were observed and measured, and the parameters between obstructed and unobstructed TAPVC were compared. The clinical and echocardiographic parameter differences between the two groups were used for ROC curve analysis.max ), peak E velocity of mitral valve, left ventricular fractional shortening, left ventricular ejection fraction, stroke volume and the incidence of patent ductus arteriosus, but there was no significant difference in birth weight. The first diagnosis age of obstructed TAPVC was earlier than unobstructed type. The ROC curve analysis for the first diagnosis age showed the sensitivity and specificity were 76.7%, 80% respectively. The ROC curve analysis for the PA Vmax showed the sensitivity and specificity were 88.5%, 67.6% respectively.Obstructed TAPVC was found in 30 (42.9%) of 70 patients. Between obstructed and unobstructed TAPVC, there were significant differences in atrial septal defect size, pulmonary artery maximum velocity (PA Vmax, peak E velocity of mitral valve, left ventricular fractional shortening, left ventricular ejection fraction, stroke volume, lead to earlier symptoms and earlier first diagnosis age. The first diagnosis age and PA Vmax were excellent values since they associated with PVO.Patients with TAPVC had a high incidence of PVO. The presence of PVO can affect the size of atrial septal defect and the closure of the ductus arteriosus, cause significant changes in PA V Obstructed TAPVC was found in 25% to 50% of patients with TAPVC, and represents a life-threatening neonatal emergency warranting immediate surgery.–5 PVO can alter hemodynamics of patients with TAPVC, and then affect the clinical presentation, physiology and prognosis. Thus, the presence of PVO is critical for the timing of surgery and surgical management.,7 At present, there are few comparative studies between obstructed and unobstructed TAPVC. The aims of this study were to compare the differences between obstructed and unobstructed TAPVC using echocardiography, and to evaluate the clinical and echocardiographic parameters associated with PVO.Total anomalous pulmonary venous connection (TAPVC) is an uncommon malformation of congenital heart disease in which all pulmonary veins connect directly to the systemic venous circulation, and not the left atrium (LA). It account for approximately 1% to 3% of congenital heart diseases.22.1 All patients with TAPVC were diagnosed for the first time after birth. Cases with functionally univentricular circulation, common atrium or pulmonary atresia were excluded. This retrospective study was approved by the institutional review board of Hunan Children's Hospital, and the requirement for informed consent was waived.Patients with TAPVC were consecutively collected in Hunan Children's Hospital from 2014 to 2019. A total of 70 patients with TAPVC were included in the study, including 30 obstructed and 40 unobstructed types, 47 males and 23 females, aged from 1 day to 5 years, and median age was 23 days. The discrimination of PVO is determined by CTA. CTA was reviewed by two experienced cardiac radiologist. PVO (obstructed TAPVC) was considered if the area of the draining veins was narrowed by more than 50% in this study. Drainage veins connecting to portal vein were also taken as an indicator of PVO, because obstruction results from the high resistance of portal venous flow needing to traverse through the liver parenchyma before returning to the heart.2.2Echocardiographic examinations were performed with PHILIPS EPIQ 7C ultrasound systems equipped with phased array probe (S8-3), including two-dimensional, pulsed wave and color Doppler examinations. All studies were performed by an experienced cardiac echocardiographer and reviewed by another pediatric cardiologist with more than ten years of experience in cardiac imaging. Echocardiographic parameters were measured according to the guidelines of the American Society of Echocardiography (ASE). The morphologic and hemodynamic echocardiographic parameters were recorded as the observation indicators. For parameters affected by age, the ratios were calculated to minimize the effect of age. We calculated the ratio of diameter of pulmonary artery/ascending aorta, right/left ventricular inner diameter and right /left ventricular wall thickness.2.3t tests were used to compare the differences between groups. Descriptive statistics for categorical variables were reported as frequency/percentage and were compared by using of the Chi-Square test (χ2). The ROC curve analysis was used to evaluate which variables associated with PVO. Values of P < .05 were considered statistically significant.Data were collected and analyzed with SPSS18. Normally distributed continuous variables were described as mean ± SD. Student 32 = 20.149, P < 0.001). The first diagnosis age of obstructed TAPVC was earlier than the unobstructed type, and patients with PVO were usually diagnosed during neonatal period . Eleven echocardiographic parameters were compared between obstructed and unobstructed TAPVC (Table max), peak E velocity of mitral valve (MV VE), left ventricular fractional shortening (LVFS), left ventricular ejection fraction (LVEF), stroke volume (SV) and the incidence of patent ductus arteriosus (PDA). These seven echocardiographic parameters with significant difference were used for ROC curve analysis. The results of ROC curve analysis for these parameters were showed in Table max  of 70 patients in this study. PVO occurred in 22(52.4%) of 42 supracardiac, 0 (0%) of 13 cardiac, 7 (87.5%) of 8 infracardiac, and 1 (14.3%) of 7 mixed types. There was significant difference of the incidence of PVO among the four anatomic types , the higher incidence of PVO. The infracardiac and cardiac types have the longest and shortest drainage vein respectively of four types. In this study, PVO occurred in 87.5% of infracardiac, 52.4% of supracardiac, but none of cardiac type (0%). In supracardiac, the most common sites of PVO were at the level of the vertical vein (VV), especially at the place where the VV step over the left pulmonary artery (PA) and bronchus, and the VV was often oppressed by them. In infracardiac, the drainage veins were usually connected to portal vein (PV), and obstruction resulted from the high resistance of PV flow needing to traverse through the liver parenchyma before returning to RA.,11,12TAPVC was classified into supracardiac, cardiac, infracardiac and mixed types according to the drainage site of the pulmonary veins. The incidence of PVO was highest in the infracardiac and lowest in the cardiac type.4.2 Our study demonstrated that the first diagnosis age of obstructed TAPVC was earlier than the unobstructed type, and patients with PVO were usually hospitalized during neonatal period. We believed that the presence of PVO led to earlier symptoms and thus to be discovered earlier.Our study showed the patients with TAPVC had normal birth weight, and there was no significant difference in birth weight between obstructed and unobstructed TAPVC. The reason was the unique nature of fetal hemodynamics allows the fetus with TAPVC to be well tolerated in utero. Pulmonary blood flow of the fetus was a small portion of the combined ventricular output, so the physical growth of the fetus will not be affected in utero. However, there was complete mixing of the pulmonary and systemic circulations in the right heart after birth. The patients will be cyanotic and may have difficulty feeding in the first weeks or months of life. If there was a PVO, it resulted in elevated pulmonary pressures and decreased systemic oxygen delivery, and severe respiratory distress and decompensation may ensue very early in the neonatal period. The patient's conditions can deteriorate rapidly and become life threatening unless the cause was promptly recognized and treated.4.3–16 All our patients presented ASD of various sizes except a case with common atrium, and unobstructed TAPVC had a larger ASD size than obstructed type. The first diagnosis age of unobstructed TAPVC was later than obstructed type, so a larger ASD size maybe resulted in later diagnosis age. PDA was the common concurrent abnormality with an incidence of 44.3% in this study. The direction of PDA flow was right to left or bidirectional shunt in 26 of 31 patients. We found that obstructed TAPVC had a higher incidence of PDA than unobstructed type, and the patients with PDA had a smaller ASD than that without PDA. The presence of PDA may relate to pulmonary pressure. Obstruction of drainage vein caused elevated pressure in pulmonary venous territory, elevated pressure in pulmonary capillary bed, pulmonary edema, pulmonary hypertension, and right heart failure with leftward shift of the interventricular septum and low systemic output. A PDA can alleviate the pulmonary hypertension and provide more blood flow for systemic circulation.For patients with TAPVC, a right-to-left intracardiac shunt is obligatory for survival, and it almost always occurs at atrial level through an ASD that is rarely restrictive. ASD size is one of the most important factors affecting the survival period. The presence of a large ASD allows some of the excessive venous return in RA to reach LA. Several cases of adult untreated TAPVC have been reported, even a few cases were diagnosed after 50 years of age, and they have very similar pathophysiology to a large ASD.4.4 and patients with TAPVC were often found having abnormal pulmonary artery flow velocity. Our study demonstrated that PA Vmax significantly higher in patients with unobstructed TAPVC than obstructed type. Obstructed type had a lower PA Vmax, which may be resulted from increased pulmonary vascular resistance and decreased compliance due to obstructed drainage veins. However, unobstructed type had an accelerated PA Vmax, we speculated that the increase of pulmonary circulation blood flow was not compatible with the expanding pulmonary artery itself, resulting in functional pulmonary artery stenosis, then led to an accelerated PA Vmax.Pulmonary arterial blood flow velocity was related to right ventricular function, pulmonary arterial pressure, blood flow and arterial diameter and so on. Right ventricular volume overload and pulmonary hypertension were common findings in patients with TAPVC,Enlargement of the right heart was a common feature to patients with TAPVC. The right ventricle was disproportionately larger than the left ventricle (LV) in most of our cases. The LA was frequently small and the LV was compressed by the dilated right ventricle. The ratios of the ratio of right /left ventricular inner diameter of obstructed and unobstructed TAPVC were larger than normal, but there was no significant difference between obstructed and unobstructed type. For patients with TAPVC, the blood of left heart was almost always obtained by an ASD, so the size of ASD could often affect the LV volume. The presence of PVO reduced the blood flow returning into the RA, the obligatory right-to-left shunt was also attenuated and the LV volume became small. The obstructed TAPVC had a smaller ASD than unobstructed type, which resulted in decreasing of SV in patients with obstructed TAPVC. Our study demonstrated that the obstructed TAPVC had a higher LVFS and LVEF than unobstructed type. The main reason may be that obstructed TAPVC need to increase cardiac output through strengthening the ventricular systole.4.5 The presence of PVO was significantly associated with an increased risk of death.,7 Therefore, an important part of preoperative diagnosis of TAPVC was to determine whether there was a PVO. Echocardiography can detect the PVO by measuring the blood velocity of the stenotic pulmonary vein. We tried to detect PVO by some familiar, easily obtained echocardiographic and clinical parameters. The first diagnosis age of obstructed TAPVC was earlier than the unobstructed type. The ROC curve analysis for the first diagnosis age showed the area under the curve was 0.805, and the sensitivity and specificity were 76.7%, 80% respectively at the optimal cut-off value of 0.64 (months). Therefore, we can make a preliminary judgment whether there was a PVO according to the first diagnosis age, which was the easiest parameter to obtain. If the first diagnosis age was less than 0.64 months, then a suspicion of PVO was strongly suggested, and further imaging examination was necessary. For both clinicians and echocardiographer, this was a convenient and quick way to understand the patient's conditions. Among echocardiographic parameters, the PA Vmax was also an excellent value in detecting PVO. It had 88.5% sensitivity and 67.6% specificity at the optimal cut-off value of 1.11m/s, and the area under the curve was 0.841. The other parameters appeared to be limited in its detection ability.TAPVC has an excellent outcome if detected early and corrected surgically in due time, but the prognosis is poor when TAPVC is associated with a PVO.4.6Some limitations should be addressed in this study. First, TAPVC is classified into multiple anatomical types, and the PVO positions of different types are different, which may affect the hemodynamics of patients with TAPVC. Due to the sample size of this study is small, there is no further study based on anatomical classification. Second, the degree of PVO has an impact on hemodynamics. Similarly, due to the small sample size, there is no further study based on the degree of PVO. Third, although we have tried our utmost to control the influence of age factors on parameters, it still could not be completely eliminated.5max, peak E velocity of mitral valve, LVFS, LVEF, SV, lead to earlier symptoms and earlier first diagnosis age. The first diagnosis age and PA Vmax were excellent values since they associated with PVO.Patients with TAPVC had a high incidence of PVO, especially in the infracardiac type; whereas, cardiac type was less likely to obstruct. The physical growth of the fetus with obstructed or unobstructed TAPVC will not be affected in utero. After birth, the presence of PVO in patients with TAPVC can affect the size of ASD and the closure of the ductus arteriosus, cause significant changes in PA VKe Jin: Conceived and designed the experiments. Yonghua Xiang: Analyzed the data and wrote the paper. Yinghui Peng, Qing Gan and Jun Qiu: Collected and analyzed the data. All authors have read and approved the manuscript.


External cardiac assist devices are based on a promising and simple concept for treating heart failure, but they are surprisingly difficult to design. Thus, a structured approach combining experiments with computer-based optimization is essential. The latter provides the motivation for the work presented in this paper.We present a computational modeling framework for realistic representation of the heart’s tissue structure, electrophysiology and actuation. The passive heart tissue is described by a nonlinear anisotropic material law, considering fiber and sheetlet directions. For muscle contraction, an orthotropic active-strain model is employed, initiated by a periodically propagating electrical potential. The model allows for boundary conditions at the epicardium accounting for external assist devices, and it is coupled to a circulation network providing appropriate pressure boundary conditions inside the ventricles.Simulated results from an unsupported healthy and a pathological heart model are presented and reproduce accurate deformations compared to phenomenological measurements. Moreover, cardiac output and ventricular pressure signals are in good agreement too. By investigating the impact of applying an exemplary external actuation to the pathological heart model, it shows that cardiac patches can restore a healthy blood flow.We demonstrate that the devised computational modeling framework is capable of predicting characteristic trends  of a healthy heart, and that it can be used to study pathological hearts and external activation thereof. Some patients receive a VAD only as a bridge to heart transplant, whereas for some patients it is their destination therapy. Over the years, many products have been invented; some work in a pulsatile manner, but most of them provide a more or less continuous flow. What all of the nowadays implanted devices have in common is that they remove blood from a heart chamber and deliver it into the ascending great vessels. Downsides of existing VADs are the surgical opening of anatomical structures of a closed system, direct contact with the blood stream and unnatural temporal actuation. To avoid these shortcomings, other concepts have been suggested, e.g. to use an inflating balloon in the right ventricle15 or the intrapericardial cavity,21 two contracting rings around the heart,33 inflatable diaphragms on the heart’s surface,48 curvature inverting devices,30 a twisting system7 and the criscone device.28Advanced heart failure is currently treated most successfully by heart transplantation. However, donor organ availability is very limited. Thus, over the past decades, ventricular assist devices (VADs) have become the standard alternative medical therapy.41 is considered. Similar as the surgeon’s palms, two opposed force patches periodically compress the heart and thus enhance the circulation. Before such devices can be used even for short term applications, such as during heart surgeries, numerous challenges need to be addressed. In addition to the difficulties in achieving desired flow rates and pressure differences, the consequences of attaching force patches directly on the epicardium are unclear. As illustrated in Fig. Here, an external mechanical actuation concept, inspired by open cardiac massage and previous work,14 is employed, and required fiber- and sheetlet directions are generated according to Refs. 44 and causes the cardiomyocytes to contract, is triggered by an electrical wave.3 Although similar frameworks have been published,50 activation has not been described by active strain nor has the effect of force patches been studied. Finally, in order to calculate blood pressure in the two ventricles, which is required for properly predicting deformations, the finite element model is coupled to a simplified hydraulic network accounting for pulmonary and systemic circulations.46 For the heart valves a novel pressure gradient dependent model is proposed.The main focus of this paper lies on the development of a computational framework suited to investigate external application of force patches while gaining a better understanding of cardiac mechanics. Investigating the impact of VADs on the heart function using experiments can be difficult, if not impossible, and expensive. On the other hand, computer simulations of the heart allow to study a variety of pathologies more easily. For example, one can use computational heart models reflecting coronary artery diseases, electrophysiological abnormalities or pressure-volume anomalies. Moreover, a computational model allows for optimization studies; objectives are e.g. cardiac output, overall contraction pattern, stress peaks or the right ventricle’s vulnerability. By adjusting force patches as functions of space and time, the desired flow rates and pressures can be imposed. The center piece of the computational framework presented in this paper is based on the finite element library LifeV, which implements a detailed model of the heart structure accounting for the highly anisotropic muscle, mechanical and electrical behavior. A Holzapfel–Ogden modelThe paper is organized as follows. In 51 and thus are ignored here. The resulting quasi-static boundary value problem readsLet 14 which leads toa, b, 5 The stress tensor is defined by the relation The myocardium is considered hyperelastic, and therefore its mechanical response can be fully characterized by a scalar-valued strain-energy function 43 Assuming the deformation gradient admits a multiplicative decomposition, Because numerical experiments have shown that the active-strain formulation is capable of reproducing appropriate contraction patterns, we follow such an approach.entclass1pt{minimac is the calcium concentration coming from electrophysiology, In Eq. , the act in Ref. . Thus, w in Ref. . The two3 In the reference domain V is the transmembrane potential, the vector Before any contraction of the heart muscle starts, the sinoatrial node (SA-node) initiates a wave of electrical depolarization propagating from the right atrium to the left atrium and to the atrioventricular node (AV-node). The AV-node delays the signal by approximately 0.12 s, before it propagates through the ventricular muscles. From the AV node, the electric signal travels through the fast cardiac conduction system to quickly activate the endorcardial surface in multiple locations and ensure a uniform ventricular contraction. To reproduce the signal after the AV-node, we use the monodomain equations combined with the minimal model for human myocardial action potential.52 Assuming the sheetlet field 45While DT-MRI data for reconstructing fiber fields are available, information on the collagen sheets is usually unavailable. Here, both fields are reconstructed using a rule-based approach. in Ref. , where i36 we neglect their contribution. Moreover, because in both ventricles the dynamic blood pressure is much smaller than the static pressure variations during a heart beat, we assumed a spatially constant pressure field.24The body circulation is represented by the circuit depicted in Fig. p at the nodes, from which the flow rates can be calculated. Lumped parameter models as used here obey Kirchhoff’s circuit laws and are by construction conservative. Thus, the sum of all flow rates i to its connected nodes j is zero, i.e.,R between two nodes i and j is the ratio of pressure difference C between a certain node i and the ground, from which one obtainsR and a diode D is in the vicinity of 0 (closed) or 1 (open). Then the respective Eqs. . Initial data and model parameters can be found in the Tables The overall framework has been implemented by using the parallel finite element library LifeV .32 Spatial discretization is the same as for activation and the mechanics. Ionic cell model  parameters are found in Ref. [Equation  is solveentclass1pt{minimaD is a function of the pressure difference across the heart valve. This implies that matrices k is the step number, The hydraulic circuit depicted in Fig. ing Eqs. –2.20), , 3.3\docD is set equal to one of them according to Eq. , , \documeg to Eq. . Equatiog to Eq.  is discrg to Eq.  and ; that is, in total on 192 cores. With 160 k elements it took 16.43 hours to simulate one heart beat of 800 ms.Validation of the whole framework can be done in different ways, for example by comparing contraction patterns from imaging data or by comparing with electrophysiological and flow measurements. However, the range of measurements among individuals is large and therefore our framework shall reproduce common observations, e.g. by how much the distance between base and apex shortens, the wall thickens and the apex twists.1 The geometry is prepared for simulations according to Fig. www.gmsh.info). Three differently sized meshes with 160 k, 250 k and 500 k elements are deployed. While the solid mechanics solutions obtained with 160 k elements hardly differ from those obtained with higher resolution, the electrophysiological problem remains under-resolved with 160 k elements. However, at low resolution the coefficients Most heart geometry measurements are noisy and vary greatly in size. Thus, this framework uses idealized geometrical data, which are very detailed.p comes from coupling with the circulation. At the base, around the four heart valve openings, where the great vessels are attached to the heart, Robin boundary conditions, i.e., Insulation boundary conditions are applied to the electrical potential, the ionic model and the activation. Boundary conditions for the mechanics are set as follows. On both endocardial surfaces pressure boundary conditions, i.e., Before the actual simulation starts, the heart is preloaded with initial pressure values, that is, (see Eq. ), which V, the normalized calcium concentration c and the activation level 4 In addition, flow rate overshoots are visible as a result of the valve modeling and the phase of refilling through the mitral valve is rather short. On the right side of the figure, p-V loops of both ventricles are drawn. The total power output of the heart model is about 1.3 W, which is in good agreement with measurements.18Figure 39 Three phenomenological values, which are appropriate for validation of the ventricular contraction pattern, are the base-apex shortening, wall thickening and base-apex twist.In order to validate the contraction pattern of the heart model with phenomenological measurements, Fig. The plot on the left of Fig. We consider a pathological heart suffering from coronary heart disease. Thus, the myocardium’s ability to contract during systole is locally reduced, and Eq.  is adjusMyocardial infarction not only changes the contraction pattern, but also the cardiac output. Figure T are chosen such that the patch motion is synchronous to natural heart activation, i.e., Force patches see Fig.  are modeUnder these conditions, to regain a healthy stroke work, we need to impose a peak displacement of magnitude T and r and analyze their influence on the p-V loop. From the top of Fig. In this section we vary the four patch parameters mentclasspt{minimamentclasspt{minimaT in the temporal patch activation function, i.e., in Eq.  a dramatic reduction of the induced flow rates and significantly different deformations of the heart muscle. Computational results with external actuation using two opposed force patches applied on the epicardium of the diseased heart predict left ventricular pressure and volume changes which are in very good agreement with those of the healthy heart. The right ventricular pressure, however, rises above the desired peak value with this simple actuation scenario. Sensitivity studies with different patch sizes, peak displacements of the patches, peak displacement times, and different impact durations show that the right ventricular power output can be controlled. The gained knowledge can be used to adjust such patch configurations. It is emphasized that a healthy p-V-loop is not the only objective. For example, tissue stress and fatigue, as well as valve and papillary muscle deformation have to be taken into account. And of course it is crucial that the interface between patches and epicardium does not damage the tissue. However, in line with the focus of the paper, this study only serves to demonstrate the potential of the presented computational framework to perform optimization studies, and no attempt has been made yet to find a better combination of parameters, patch geometry and motion. Nevertheless, already the presented results are encouraging for future external VAD developments, and they demonstrate the usefulness of this computational model.35 and it is important to notice that the devised framework can be applied to investigate patient-specific or animal hearts, provided geometry, material properties and all other relevant parameters are available. Another limitation is the simplified flow model. Therefore it is not directly possible to take into account effects of damaged heart valves or the impact of force patches on them. At this point, a further shortcoming is the force patch boundary condition, which only accounts for the force component normal to the epicardium, i.e., tangential forces are ignored. Further, the problem that patches may slide off the slippery surface cannot be addressed, interactions between patches and coronary vessels are ignored, and no conclusions regarding long term tissue damage introduced by the force patches are possible. Also, at this point, independent actuation is implemented; in the future synchronization with the electrical pulses is envisioned.The main limitations of the modeling framework are uncertainties regarding geometry, distribution of material properties and of other parameters. They have been chosen based to the best of our knowledge relying on literature data. Especially among pathological hearts the variation is huge, and it is a separate challenge to retrieve complete descriptions. All presented simulation studies used the same basic heart geometry, and only parameters regarding patches and their actuation have been varied. Further sensitivity studies would be of interest and are planed in the future. There is a demand of personalizing the modeling of human pathophysiology,in vivo experiments, and on the other hand it allows for investigations which are not even possible in vivo. Due to its flexibility, the presented framework has the potential to become an integral part of patient-specific applications. Extraction of geometrical and material information, estimation of further parameters, and uncertainty assessment would be other components of such a much bigger framework.Despite several limitations, the framework is of significant value for future investigations and optimization of external VADs with force patches, as demonstrated by the computational studies in this paper. In addition, it can be used to study different disease scenarios and/or various assist device designs. On one hand, it can be expected that it will help to reduce the number of required Potential improvements of the presented computational framework include local modifications of the conductivity tensor in pathologic regions, a completely incompressible treatment of the elasticity by a mixed formulation approach, and atrial contraction by an additional compliance in the hydraulic circuit. Further, a resolved flow field in the two ventricles would be of interest in some cases, e.g. if heart valve functions become part of the investigations. And after all, there exists potential to improve the computational efficiency, which is of particular interest for parameter and optimization studies.in vivo experiments are planned. The intermediate goal is a device for emergency situations during open heart surgery.Regarding device development, further sensitivity studies would be of great interest, and optimization not only of patch location, patch displacement peak, displacement peak time and patch size, but also of patch shape and different actuation patterns. In addition to p-V curves, other objectives will be considered for optimization. These will include constraints for patch induced stress and deformation in the valve regions. Alongside computational studies, also ex- and


Fulminant myocarditis is a clinical syndrome associated with threatening dysrhythmia which temporary pacemaker can be used for life-saving support. As a method of physiological pacing, His bundle pacing (HBP) maintain better cardiac synchronization than traditional right ventricular (RV) pacing.It’s a severe case of fulminant myocarditis in a 41-year-old patient who presented for recurrent arrhythmias with hemodynamic instability. Temporary His bundle pacing combined with optimal medical therapy and extracorporeal membrane oxygenators (ECMO) supported him through his critical period of hospitalization.During 1-year follow up, the cardiac function recovery was obvious without any pacing related complications. Echocardiography showed better atrioventricular and intra-ventricular synchronization during HBP in DDD mode. This is the first reported case of temporary His-purkinje conduction system pacing used for severe fulminant myocarditis. Fulminant myocarditis is a clinical syndrome with severe symptoms of acute heart failure, cardiogenic shock, or life-threating rhythm disturbances which should be treated with full supportive care, using aggressive pharmacologic therapy and mechanical circulatory support . His-purA 41-year-old previously healthy male presented to our hospital after a week of fever. He had dyspnea and hypotension. He had no long-term medication. He did not smoke cigarettes, take alcohol or illicit drugs. Hypoxic on presentation, he required supplemental oxygen via nasal cannula. Heart rhythm was irregular but he did not have any murmur. Laboratory data on admission showed an alanine aminotransferase (ALT) level of 3904 U/L, creatine kinase (CK) level of 2463 U/L, creatine kinase-MB (CK-MB) level of 193 U/L, troponin I (cTnI) level of 42.38 ug/l, brain natriuretic peptide level of 734 pg/ml, and serum creatinine level of 111umol/l. The laboratory test of herpesvirus IgM antibody showed positive and the result of metagenome and target gene sequencing was negative. Chest radiograph showed obvious pulmonary congestion , cardiac output (CO), cardiac index (CI), central venous pressure (CVP) and invasive arterial pressure (IAP)  in three different pacing modes with HBP in DDD mode, RVSP in DDD mode and HBP in VVI mode at 1-year follow-up, with a washout period of 5 min between each pacing mode. In terms of left ventricular function, HBP with DDD mode showed better left ventricular (LV) synchrony evaluated by tissue Doppler imaging (TDI) and LV systolic function reflected by LVEF and CO than RVSP. RV systolic function with HBP evaluated by tricuspid annular plane systolic excursion (TAPSE) was better than that of RVSP. Finally, the intraventricular mechanical delay (IVMD) which was defined as the difference between the LV pre-ejection period  and RV pre-ejection period  was used to evaluate mechanical delay between the left and right ventricle, showed a significant difference between HBP and RVSP. RVSP had a worse IVMD compared to HBP. In addition, DDD pacing mode showed optimum atrioventricular synchronization with better morphology of mitral peak early diastolic velocity (E’), mitral peak late diastolic velocity (A’) and mitral E/A ratio Fig. .Fig. 2EcFulminant myocarditis is a clinical syndrome characterized by severe myocardial inflammation frequently associated with threatening dysrhythmia manifested as bradycardia, conduction block, ventricular tachycardia and ventricular fibrillation. ECMO use is commonly required for fulminant myocarditis patients with hemodynamic instability to support them through the acute phase of cardiogenic shock , 3. CondThe effectiveness , 6 and s“My heart failure symptoms resolved after optimal medical therapy and pacemaker implantation. My functional capacity returned to baseline at 1 year follow up. I’m tremendously grateful to the conduction system pacing team at the First affiliated hospital of Wenzhou university.” The patient talked about it at 1-year follow-up.


We read with great interest the single-centre study conducted by Jansson et al.  in 74 ICProspective TTE studies in consecutive COVID-19 patients are sparse due to the time and expertise required to perform serial examinations during a period of immense clinical burden. The authors should be commended for undertaking this impressive feat. However, their conclusion that RVD did not correlate with mortality or with AMI warrants further consideration.The timing of TTE within 72 h) preceded the peak incidence of AMI (denoted by peak HS-Tn levels) which occurred 1 week following ICU admission. It is, therefore, unsurprising that RVD did not associate with AMI, as the timing of the TTE was unlikely to be temporally related to AMI development. If the TTE was performed at the time of myocardial injury, then an association may well have been observed. For example, in a study of 172 ICU patients with COVID-19 who had TTE’s performed later on during ICU stay (median 7 days) in patients with a HS-Tn rise, RVD was associated with significantly higher HS-Tn levels [ h precedwith systolic impairment being the RV phenotype most strongly associated with mortality and having the highest HS-Tn levels [An interesting observation by Jansson et al. was that the peak of NT-ProBNP median 4 days) preceded the peak of HS-Tn (median 7 days). Indeed, we hypothesised that progressive RV dilation, although initially compensatory via the Frank–Starling mechanism, when severe, may eventually precipitate subendocardial ischaemia, RV systolic impairment and reduced RV forward flow , 3. Thisn levels , 3. None days predilation was the association with mortality and HS-Tn observed. Other RVD definitions that have associated with mortality in COVID-19 ICU patients also employ metrics of RV size [The lack of association between RVD and mortality/AMI in this study may, therefore, reflect how RVD was defined: as a composite of any 2 variables denoting either RV dilation (RV:LV end diastolic area (RV:LVEDA) > 0.6) or RV systolic impairment  < 35%, tricuspid annular plane systolic excursion < 17 mm, (TAPSE), free wall strain > − 20%, S prime < 6 cm/s). This definition is not validated, not recommended in any guidelines and has not been used in previous studies. Inspecting Table 2, patients defined as having ‘RVD’ by Jansson et al., had no difference in RV size (RV:LVEDA) or RV FAC compared to the non-RVD group. Without any difference in RV size, whether this cohort reflects ‘true’ RVD or not remains to be seen. For example, we found that RV systolic impairment alone was not associated with mortality or high HS-Tn levels. Only when it was combined with RV  RV size , 5. Thes RV size  (as defiClearly, selection bias may also play a role in the discrepant findings between this and other studies –5. Janssn=13 patients diagnosed with RVD.The final reason that RVD may not associate with mortality or AMI in this study is that the study is underpowered to detect this association, with only serial TTE examinations to describe the evolution of RVD across ICU stay. These studies must also employ validated definitions of RVD. Until this is done, it would be reticent to conclude that RVD does not associate with myocardial injury or mortality in COVID-19 or other critically ill cohorts, especially given the breadth of other literature suggesting that it does.Ultimately, the association of RVD with myocardial injury and mortality in critically ill COVID-19 patients is difficult to elucidate without large, prospective studies performing


The anterior mitral leaflet (AML) contributes to left ventricular (LV) function but is normally excised at the time of a bioprosthetic valve insertion. This study aimed to investigate methods of safely retaining the AML at the time of mitral valve replacement.Five adult sheep (57 ± 3.8 kg) each underwent 3 insertions of a bioprosthetic mitral valve (asymmetric interstrut sectors) alternating the wide and narrow interstrut distance under the AML. Each insertion was performed on normothermic beating-heart cardiopulmonary bypass, with full retention of the native valve. After each valve insertion, continuous measurements of LV and aortic pressures were recorded with echocardiographic assessment of mitral valve function. If LV outflow tract obstruction (LVOTO) was not seen on the resumption of normal cardiac output, a bolus of adrenaline was given to precipitate it.Thirteen of 15 valve insertions resulted in LVOTO caused by systolic anterior motion (SAM), independent of valve orientation. The wide interstrut distance subtending the AML was associated with a greater requirement for inotropic stress to precipitate an obstruction and was associated with late systolic rather than holosystolic obstruction.The predisposition to and nature of LVOTO due to SAM were associated with the bioprosthetic valve interstrut distance subtending the fully retained AML and may explain the survival differences in such patients. This model represents an effective method for research into prevention of LVOTO following mitral valve replacement with preservation of the native valve. Schematic representation of a normothermic beating-heart ovine model for the research into prevention of left ventricular outflow tract obstruction (LVOTO) using a bioprosthetic mitral valve, with full retention of the anterior mitral leaflet (AML). All episodes of LVOTO were due to systolic anterior motion. The wide interstrut distance subtending the AML was associated with a greater requirement for inotropic stress to precipitate an obstruction and was associated with late systolic rather than holosystolic obstruction. A wide bioprosthetic valve interstrut distance reduces the predisposition of a fully retained anterior mitral leaflet to cause outflow tract obstruction due to systolic anterior motion.The interstrut distance subtending the anterior mitral leaflet (AML) affects the nature of left ventricular outflow tract obstruction (LVOTO) due to systolic anterior motion of the AML. This model represents an effective method for the research into the prevention of LVOTO following mitral valve replacement with full preservation of the native valve.259 and 261.See Commentaries on pages ,5Left ventricular outflow tract (LVOT) obstruction (LVOTO) is an uncommon but serious complication of mitral valve surgery and transcatheter mitral valve replacement. LVOTO following surgical bioprosthetic mitral valve replacement can result from malpositioning of the prosthesis with a strut protruding into the LVOT or from systolic anterior motion (SAM) of the retained anterior mitral leaflet (AML).The objectives of this study were to develop an ovine model of LVOTO by a retained AML following bioprosthetic valve insertion and to assess the effect of interstrut distance on the predisposition to LVOTO. This model will allow research into methods to prevent LVOTO following bioprosthetic valve insertion and transcatheter mitral valve insertion when the AML is fully retained.Nine healthy adult Merino first-cross sheep  received humane care in accordance with the requirements of the Australian Code for the Care and Use of Laboratory Animals for Scientific Purposes 2013 (ISBN 1864965975). Animals underwent a minimum acclimatization period of 14 days, and the studies were performed at the Sydney Imaging Core Research facilities at The University of Sydney. This project was approved by the Animal Ethics Committee of The University of Sydney (Project 2017/1192). Sheep were deemed healthy  on physical examination findings before undergoing anesthesia for the procedure. Five sheep each underwent 3 valve insertions, and 4 sheep each underwent 3 sham procedures. All procedures were performed under a single anesthetic for each sheep and were terminated by euthanasia under anesthetic.2 pressure between 35 and 50 mm Hg and oxygen saturation >93% measured using pulse oximetry. Arterial blood gas, electrolyte analysis, blood lactate levels, and activated clotting times were measured periodically throughout the anesthesia to assess physiological status and ensure normal organ perfusion. A noradrenaline infusion  was administered to effect (0.1-1 μg/kg/hour intravenously) to support the maintenance of normotension.Sheep were premedicated intravenously with a combination of methadone  at a dose of 0.2 mg/kg and midazolam  at a dose of 0.4 mg/kg. Anesthesia was induced by administering propofol  intravenously to effect, to facilitate orotracheal intubation. Anesthesia was maintained with inspired 1% to 2% isoflurane  delivered in an air/oxygen mixture with a fraction of inspired oxygen between 50% and 90% and ketamine  at an intravenous infusion rate of 20 μg/kg/minute. Morphine injections  at 0.5 mg/kg intravenously were repeated every 4 hours. No neuromuscular blocking agents were used. Mechanical ventilation was initiated to maintain end tidal COEach sheep was placed in the right lateral recumbent position, and a left lateral thoracotomy was performed via the fifth intercostal space. The pericardium was opened, and the heart was supported in a pericardial cradle.A transit-time ultrasonic flow probe  was placed around the main pulmonary artery to measure cardiac output. A straight pressure sensor–tipped catheter  was placed into the aortic arch to monitor arterial pressure. A second straight pressure sensor–tipped catheter  was inserted transapically into the LV with the pressure sensor positioned below the aortic valve. Both catheters were calibrated using the Millar Pressure Volume Loop System (MPVS) control software before cardiopulmonary bypass (CPB), and both were connected to a data acquisition hardware device  for reliable data acquisition.All recording devices were linked to a data analysis software program , which allowed simultaneous recording of all signals. Two-dimensional epicardial and Doppler echocardiography  was used to rule out any cardiac anomaly before establishing CPB and to confirm the nature and severity of LVOTO when present. The LVOTO was graded as late systolic, holosystolic, or equivocal by the physician echocardiographer who was blinded to the valve orientation.CPB was established with right atrial and aortic arch cannulation without aortic cross-clamping. Normothermia was maintained with a perfusion pressure of 70 mm Hg and a flow rate similar to the pre-CPB cardiac output. No cardioplegia was used.The empty beating heart was partially filled and a left atriotomy was performed through the base of the atrial appendage where upon the mitral valve was immediately rendered incompetent by distraction of the posterior annulus away from the AML with a pump sucker. A suture was then inserted to snare the midportion of the AML to the anterior annulus  to rende° between the supporting strut posts  each underwent 3 valve insertions with a 31-mm Medtronic Mosaic porcine bioprosthetic valve . This valve prosthesis is asymmetric with respect to the leaflet sizes, with the largest leaflet occupying a sector with an angle of 135ut posts . LikewisFour sheep  underwent a sham heart valve insertion procedure in which a bioprosthetic valve was not inserted. The left atrium was opened, and the AML was rendered incompetent. The atrium remained opened for 20 minutes, which was the average time for bioprosthetic valve insertion in the study group. Then the left atrium was deaired and closed, and the suture immobilizing the AML was removed. No adrenaline was administered to these sheep.All procedures were performed by a senior cardiothoracic surgeon (H.S.P.) experienced in both human and ovine mitral valve surgery.max and contractility index (CI), where the CI is dP/dtmax/Pi (Pi = instantaneous LV pressure at the time of dP/dtmax). The CI was used to offset the effects of preload and afterload on dP/dtmax and to provide a better estimate of intrinsic LV contractility. When LVOTO occurred, it was resolved by resumption of CPB following echocardiographic assessment, whereupon replacement of the valve to the next rotation was performed. Therefore, the effects of LVOTO on contractility resulting from an episode of LVOTO were estimated from measurements taken after the subsequent valve insertion but before the onset of LVOTO from that insertion.For each valve insertion or sham procedure, contractility data representing data points were collected and averaged over 2 periods of 30 seconds each immediately before any LVOTO episode or adrenaline administration. LVOTO was defined by a peak instantaneous pressure gradient >30 mm Hg. LV contractility was assessed by the dP/dtK2 test. Normally distributed variables were described using mean and standard deviation. Intraclass correlation for repeated within subject measures was negligible, and thus differences in observed means were examined using a 2-sample t test. Nonparametric data were evaluated with the Wilcoxon rank-sum test. Repeated-measures analysis of variance was used to assess the effect of valve insertion number on measures of LV contractility. The effect of interstrut distance on the time to LVOT obstruction and the influence of LVOT duration on subsequent LV contractility were evaluated using mixed-effects linear regression. Models were fitted by backward stepwise selection and compared using the likelihood ratio test. The distribution of echocardiographic findings depending on the interstrut distance was calculated with Pearson's χ2 test. For all analyses, P < .05 was considered significant.All calculations were performed using Stata 13 . The normality of dependent variables was tested using the D'Agostino max and CI during LVOTO were secondary to the extreme afterload induced by the LVOTO. The dP/dtmax and CI increased from just before the onset of LVOTO to just after the onset by 48% and 23%, respectively.Thirteen of 15 valve insertions resulted in LVOTO. LVOTO was not demonstrated in the first sheep following the second and third valve insertions; therefore, 7 of 8 wide interstrut distances under the AML and 6 of 7 narrow interstrut distances resulted in LVOTO. Transapical epicardial echocardiography confirmed SAM of the AML as the cause of LVOTO in all episodes . The onsP = .0001) (P < .0001). LVOTO occurred spontaneously in 0 of 8 wide interstrut insertions and in 4 of 7 narrow interstrut insertions. The delay in onset of LVOTO resulted in an adrenalin bolus being given to induce LVOTO after 8 of 8 wide interstruts versus 3 of 7 narrow interstruts. The wide interstrut distance subtending the anterior leaflet was associated with a greater requirement for adrenaline boluses than the narrow interstrut distance to precipitate an obstruction   . To accoP = .04) . The seqP = .02)   and 2. Tmax and CI, LV contractility significantly deteriorated after each period of LVOTO  (P < .0001). However, neither the interstrut distance nor the nature of the obstruction significantly affected contractility.Based on dP/dtctively)  and 5. Tmax or CI across the 3 sham surgeries. Transapical epicardial echocardiography confirmed normal mitral valve function after each sham procedure.There was no significant difference in the dP/dt,Resection of the anterior leaflet chordae impairs the mitral valvular ventricular interaction, resulting in reduced LV contractility.A beating-heart ovine model was used to avoid the adverse consequences of cardioplegic myocardial ischemia. The mean arterial blood pressure during CPB was maintained around 70 mm Hg with a flow rate of approximately 70 mL/kg/minute or a flow rate similar to the pre-bypass baseline cardiac output. Normothermia was used to minimize metabolic disturbances. This model for mitral valve research has not been reported previously.To prevent air embolism, the mitral valve was rendered incompetent immediately after opening the left atrium. With the mitral valve incompetent and the left atrium open to atmospheric pressure, the empty LV cannot generate sufficient pressure to open the aortic valve against the pressurized aorta.,Because on-pump beating-heart surgery does not impair LV contractility, multiple open-heart interventions on CPB are possible without an extended recovery period.LVOTO was not induced after the second and third valve insertions in the first sheep. The LVOTO after the first valve insertion was holosystolic, and the duration of LVOTO was prolonged while echocardiographic assessment of LVOTO was performed for the first time in this project. Although the duration of LVOTO was associated with subsequent impairment of LV contractility, it was not possible to confirm that impaired LV contractility reduced the incidence of LVOTO. This is a likely limitation of the small numbers analyzed in this study.,,A Medtronic Mosaic bioprosthetic valve  was used to assess the effect of interstrut distance on the incidence of LVOTO. There was a benefit to having a wide interstrut distance subtending the AML in terms of reduced predisposition to LVOTO rather than incidence and also in terms of the nature of the LVOTO when it occurred (late systolic rather than holosystolic). The late systolic form of LVOTO that is typical in patients with hypertrophic obstructive cardiomyopathy might partly explain the variable tolerance of among patients. The late presentation with LVOTO 5 years following insertion of mitral bioprosthesis with full retention of the AML has been reported.,When LVOTO occurs following transcatheter mitral valve insertion, it should be determined whether SAM substantially contributes to the LVOTO or whether the obstruction is due to the prosthesis impinging in the outflow tract. There has been a suggestion in an ovine model that volume loading might aggravate the LVOTO on the basis that the mitral bioprosthesis causes a fixed diameter outflow tract, so that volume loading only increases the blood flow velocity and the tendency toward SAM.Variations in creating the animal models are unavoidable, but every effort was made to reduce the variation. All procedures were performed by a senior cardiothoracic surgeon (H.S.P.) experienced in both human and ovine mitral valve surgery. Data were acquired on a small number of animals, which could have led to type II statistical errors. However, an effort was made to reuse each animal 3 times to acquire 3 sets of data per animal and reduce interindividual variability.In this study, a bioprosthetic mitral prosthesis was used, which limits the extrapolation of our results to transcatheter mitral valve replacement, given the different design of the transcatheter valves. Assessment of holosystolic versus late systolic LVOTO was performed by a single observer and is to some extent subjective. However, this observer was blinded to the valve orientation and was experienced in ovine echocardiography. Moreover, the long-term effect of late systolic SAM and its impact of LV mechanoenergetics was not assessed in the model. Finally, none of the sheep had mitral regurgitation with attendant LV enlargement, which limits the comparison with clinical patients selected for transcatheter mitral valve replacement or mitral valve replacement.The bioprosthetic valve interstrut distance subtending the native AML influences both the predisposition to LVOTO and the systolic duration of LVOTO when it occurs. The model of bioprosthetic insertion on a normothermic beating heart presented in this study is an effective model for research into prevention of LVOTO following mitral valve replacement with preservation of the entire native mitral valve and allows multiple interventions sequentially in each animal during a single study.The authors reported no conflicts of interest.Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.The


Mitral valve prolapse (MVP) has changeable auscultatory features regarding the onset and amplitude with physiologic and pharmacologic maneuvers. We report a case of MVP in which not only the onset and amplitude of systolic murmurs but also the endpoint of systolic murmurs were dynamically altered according to preload. An asymptomatic 61-year-old man presented with a grade 3 crescendo murmur best heard at the apex, which started in the mid-systole without a click, and lasted up to the second sound. A diagnosis of moderate to severe mitral regurgitation due to MVP of P2 scallop was confirmed by echocardiography. At his regular follow-up visit, changes in cardiac auscultation were recognized although the patient was still asymptomatic. A grade 2, high-pitched crescendo murmur, which was softer than the previous findings, started immediately after the first sound and ended approximately 100 ms before the second sound on phonocardiography. On echocardiography, the severity of mitral regurgitation was abated in comparison with the previous findings, and mitral regurgitation abruptly ended in mid-systole but continued to the end of systole during increased preload due to an elevation of the legs. The present case highlights the importance of careful auscultation to estimate hemodynamic conditions in patients with MVP. Mitral valve prolapse (MVP) has unique auscultatory features characterized by mid-systolic clicks, frequently followed by late systolic murmurs ,2. It isAn asymptomatic 61-year-old man was referred to our hospital for heart murmurs after a medical check-up. He had no notable medical history and did not take medication. He stopped smoking at the age of 48 years, drank occasionally, and had no known allergies. The patient reported that there was no family history of cardiovascular diseases. His vital signs and physical examination were normal except for a grade 3 crescendo murmur best heard at the apex, which started in the mid-systole without a click and lasted up to the second sound Figure . The lab2 .Echocardiography showed moderate to severe mitral regurgitation due to MVP of the P2 scallop Figures , 2B. No 2). Furthermore, the heart rates during echocardiography were faster than the first examination by 8-10 bpm, although no treatment including diuretics was initiated. Of note, mitral regurgitation abruptly ended in mid-systole in the supine position but continued to the end of systole during increased preload due to an elevation of the legs . Decreased left ventricular end-diastolic volume as well as decreased left atrial volume index may also support the speculation. However, attention should be paid to the relation between regurgitation signals and murmurs since echocardiography can detect more sensitively minute changes in frequency range than vibrations in the audible frequency range . AuscultMVP is known to show changes in auscultatory features, e.g., earlier or later onset of the murmurs, with physiologic and pharmacologic maneuvers. The present case highlights the importance of careful auscultation, not only with regard to the onset timing but also with regard to the end timing of systolic murmurs, to estimate the hemodynamic conditions in patients with MVP.


The development of the latest generation of durable left ventricular assist devices (LVAD) drastically decreased adverse events such as pump thrombosis or disabling strokes. However, time-related complications such as aortic insufficiency (AI) continue to impair outcomes following durable LVAD implantation, especially in the context of long-term therapy. Up to one-quarter of patients with durable LVAD develop moderate or severe AI at 1 year and its incidence increases with the duration of support. The continuous regurgitant flow within the left ventricle can compromise left ventricular unloading, increase filling pressures, decrease forward flow and can thus lead to organ hypoperfusion and heart failure. This review aims to give an overview of the epidemiology, pathophysiology, and clinical consequences of AI in patients with durable LVAD. Durable left ventricular assist device (LVAD) therapy is indicated in selected patients with advanced heart failure refractory to guideline-directed medical treatment to improve survival and quality of life. Improvement of the technology with the latest generation of pump  and the modifications in the cardiac allocation system in the United States contributed to significantly change the landscape of indications and outcomes in patients with durable LVAD . Most paApproximately 5% of patients who were evaluated for a LVAD or heart transplantation suffered from moderate or severe AI  6–8). I–8. I6–8)Progression of AI severity, in patients with pre-existing AI at the time of LVAD implant, has been reported in several publications –13. Patide novo AI on LVAD support (n = 25) or a HeartMate-II (n = 53) between 2004 and 2008, Cowger et al. found that 11% of these patients presented with moderate to severe AI at 6 months, 26% at 1 year and 51% at 18 months , absence of aortic valve opening, smaller body surface area and longer LVAD support duration , 19, 21. females . Surgica females . It has  females , 24. Bec females , 19. TanLeft ventricular assist device support can lead to AV fusion . The preStasis develops on the ventricular surface of the valve when the AV remains closed and thus promotes thrombus formation and organization, which furthers leaflet fusion , 29, 30.The mechanisms of AI are multifactorial. The absence of aortic valve (AV) opening is one of the strongest factors associated with AI. Durable LVAD promote LV unloading by pumping the blood from the LV directly into the aorta, which decreases LV pressures. The transvalvular gradient is defined as the difference in pressure between the aortic root and the LV. With an LVAD, the transvalvular gradient is increased due to the unloaded LV and the elevation of the pressure in the aorta by the continuous flow from the outflow graft . This coAs described by John et al., normal valve biomechanics are dependent on the distensibility of the sinus tissue and the pressure cycle in the aortic root, pressure pulsatility and vortex generation . The retLeft ventricular assist device support can also contribute to the development of aortic root dilation and can thus participate to AI. The underlying mechanism used for aortic root dilation in LVAD patients seems to be the increased aortic wall sheer stress caused by the turbulence induced by the device , 31, 32.First, it is important to evaluate whether there is opening of the AV or not, using the M-mode in the parasternal long axis view, over 10 cardiac cycles . Then, CTherefore, new methods have been described for the evaluation of AI in LVAD patients: diastolic flow acceleration and the systolic-to-diastolic (S/D) velocity ratio of the outflow cannula .2  and pulmonary capillary wedge pressure (PCWP)] while maintaining the same cardiac index (CI) . With tiThe right ventricle (RV) remains the Achilles heel of this technology. Right-sided failure can occur after LVAD implantation, when a vulnerable RV faces a sudden rise in cardiac output provided by the LVAD, and is unable to accommodate to this increased preload. In addition, altered RV contractility secondary to the withdrawal of inotropes or to the loss of septal contraction may contribute . AggressThe presence of AI can further compromise RV function, indirectly through its impact on increased LV filling pressures and reduced effective pre-load. First, higher pulmonary wedge pressures lead to a passive rise in pulmonary artery pressures and consequently higher RV afterload . In addiIn patients with significant pulmonary hypertension before LVAD implantation, it may not totally resolve post-operatively despite LV unloading by the device, thereby leaving some residual and variable degree of increased RV afterload . These pp = 0.006) and 28.6% vs. 22.8% (p = 0.05), respectively   and a shorter 6-min walk distance  (p = 0.001)  . The sur < 0.01) . SimilarThe impact of AI on post-transplant outcomes in patients supported with LVAD is not known. Although the duration of LVAD support is not associated with post-transplantation outcomes, it is reasonable to postulate that increased pulmonary pressures might lead to higher rates of primary graft failure secondary to pulmonary hypertension, . RVAD orOne of the aims of medical management is to relieve congestive symptoms with diuretics and improve filling pressures with vasodilators . In addiTargeting pump speeds in the lower range may be helpful to promote AV opening and ultimately reduce the risk of developing AI. This strategy could facilitate intermittent aortic valve opening, reduce AV malcoaptation and fusion and thus prevent AI development , 18. ThiOn the other hand, when congestive symptoms are present and refractory to medical therapy, patients should undergo an echocardiography guided ramp study, as well as right heart catheterization. Increasing the pump speed will initially promote LV unloading and a decrease in LV end-diastolic pressure (LVEDP). However, this will then start a vicious cycle of complete aortic valve closure leading to increased AI due to a rise in the TVP, ultimately raising the LVEDP , 36, 44.2, with, ideally, intermittent AV opening and minimal mitral insufficiency  are the RPM that best achieve hemodynamic optimization, defined as a PCWP <18 mm Hg, CVP <12 mm Hg and a CI >2.2 L/min/mficiency .When aggressive medical and pump parameters optimization fails to improve symptoms, surgical and percutaneous aortic valve interventions might be considered. The detailed description of those techniques is addressed in another article of this collection. Improvement in functional status has been observed , 47. Surde novo AI development and its hemodynamic impact on the LV and RV during LVAD support. Further research studies are needed to better characterize the severity of AI, to better understand its impact on patients transplanted, and to prevent its development.In conclusion, the incidence of AI increases with longer support durations. Development of AI in patients supported with a durable LVAD compromises the benefit of the therapy. There is still a lack of consensus on the effect that AI has on mortality, but several studies report that AI increases heart failure related hospitalizations and contributes to the deterioration in functional status. Multiple strategies exist to minimize EC was responsible for the literature review, drafting the manuscript, and the creation of the figure and table. P-EN supervised the work and provided direction. P-EN, AD, MC, YL, and WB reviewed the manuscript and provided feedback. All authors contributed to the article and approved the submitted version.


A total of 64 atrial fibrillation patients admitted to our hospital from April 2020 to December 2021 were prospectively selected as the case group and 61 healthy subjects who received physical examination during the same period were selected as the control group. Serum MIP-1α level was determined by a double-antibody sandwich enzyme-linked immunosorbent assay. Serum MIP-1α expression levels were compared between the case and the control groups. The case group was divided into high-level and low-level groups according to the serum MIP-1α median. Simultaneously, the sociodemographic data, clinical data, and left atrial remodeling indexes of the patients were collected in the case group. The Pearson correlation analysis was applied to analyze the correlation between the serum MIP-1α level and the risk of left atrial remodeling in patients with atrial fibrillation. The serum MIP-1α level was significantly higher in the case group than that in the control group (P < 0.05), high-level group , and low-level group . There were significant differences in the anteroposterior diameter, upper and lower diameter, left and right diameter of the left atrium, left atrial volume, volume index, left atrial global ejection fraction, and sphericity between the low-level and high-level groups (P < 0.05). The Pearson correlation analysis showed that serum MIP-1α level was positively correlated with the left atrial anteroposterior diameter (r = 0.745), left atrial left and right diameter (r = 0.759), left atrial upper and lower diameter (r = 0.810), left atrial volume (r = 0.837), left atrial volume index (r = 0.813), and left atrial sphericity (r = 0.785) but negatively correlated with the left atrial global ejection fraction (r = -0.731) (P < 0.05). The expression level of serum MIP-1α is high in atrial fibrillation patients and is associated with the risk of left atrial remodeling.The aim of this study is to investigate the expression level of macrophage inflammatory protein-1 The ectopic impulse theory of atrial fibrillation, the single-loop reentry theory, and the multiwavelet reentry theory are cornerstones for understanding the mechanisms of the occurrence and maintenance of atrial fibrillation, which increase the risk of ischemic stroke, systemic embolism, heart failure, and mortality . Electriα (MIP-1α), a chemokine secreted by fibroblasts and macrophages, is involved in inflammatory responses and exerts a crucial effect on the pathogenesis of the cardiovascular disease [α is involved in the induction of autoimmune myocarditis, which leads to the development of heart failure and increases the risk of dilated cardiomyopathy. A study [α expression. These studies all indicate that MIP-1α may have an impact on the atrial structure, but the relationship between the two is not clarified. To further clarify whether MIP-1α is associated with left atrial remodeling, this study investigated the MIP-1α level and its correlation with the risk of left atrial remodeling to provide new biomarkers for the prevention and treatment of left atrial remodeling in atrial fibrillation patients.There is mounting evidence  that inf disease . A previ disease  has show A study  on circaα level was measured by a double-antibody sandwich enzyme-linked immunosorbent assay. The serum MIP-1α expression level was compared between the case and the control groups. The case group was assigned to high-level and low-level groups according to the serum MIP-1α median. Simultaneously, the sociodemographic data, clinical data, and left atrial remodeling indexes of the patients were collected in the case group. The correlation between serum MIP-1α levels and the risk of left atrial remodeling in atrial fibrillation patients was analyzed by the Pearson correlation analysis.After approval by the hospital ethics committee, 64 atrial fibrillation patients admitted to our hospital between April 2020 and December 2021 were prospectively enrolled in this study. Inclusion criteria were as follows: (1) meeting the diagnostic criteria of atrial fibrillation , and 12-Information on the sex, age, body mass index, comorbidities , smoking history, duration of atrial fibrillation, type of atrial fibrillation , CHA2DS2-VASC score (congestive heart failure/left ventricular dysfunction (C), hypertension (H), diabetes (D), vascular disease (V), age of 65–74 years (A), sex  (Sc) 1 point, age of ≥75 years (A) is 2 points), and cardiac function classification were collected.α levels Five mL of fasting venous blood were harvested from patients of the case and control groups in the morning and maintained in a place without stirring at room temperature for 2–4 h. The blood was centrifuged at 3000 r/min for 30 min to separate and obtain serum. An automatic biochemical analyzer  was employed to detect serum MIP-1α levels using a double-antibody sandwich enzyme-linked immunosorbent assay. Briefly, the standard and samples to be tested were added to the corresponding wells, followed by incubation with the detector antibody labeled with horseradish peroxidase. The plate was covered with a sealing film and incubated in a 37°C water bath for 60 min. The reaction solution was discarded and the plate was patted dry after washing, followed by incubation with the corresponding substrate at 37°C in the dark for 15 minutes. Finally, 50 μL termination solution was added, and within 15 minutes, OD values at a wavelength of 450 nm were obtained using a microplate reader .MIP-1Color Doppler ultrasonography  was applied for cardiac examination. The patient was lying on the left side or in a supine position, breathing calmly. The left atrial diameter was measured in the parasternal left ventricular long-axis aortic root section. The left ventricular end-systolic and end-diastolic volumes were measured by recording the real-time motion trajectory of the mitral valve annulus at the apical four-chamber, two-chamber, and apical left heart long-axis views. After acquiring the apical four-chamber image in two-dimensional imaging mode, the left three-dimensional volume data were transmitted to the workstation. The rotary cutting method is adopted on the quantitative software of the processing workstation to obtain three mutually orthogonal reference planes of the left atrium and to record the left atrial volume and the left atrial volume index  + 0.0124 × weight (kg) − 0.0099).All patients underwent left atrial CT angiography: 64-slice gemstone energy spectral CT  was used with the following scanning parameters: tube voltage: 120 kV; tube current: 350–750 mA; slice thickness: 0.625 mm; pitch: 0.26; slice spacing: 0.625 mm; and tube rotation time: 0.35 s/circle. The patients were scanned from head to foot in the supine position. ECG signal frequency and heart rate of the patients were monitored by three ECG leads. The scanning range was from the aortic arch to the diaphragm and the left atrial images were collected. The scanned images were sent to the ADW4.4 workstation for image processing. Cardiac software was utilized to analyze the left atrial function and measure the anteroposterior diameter, upper and lower diameter, and the left and right diameter of the left atrium , and the left atrial ejection fraction and left atrial sphericity were automatically calculated.The training was unified and a unified investigation plan was determined. The inclusion and exclusion criteria were strictly implemented to ensure the objectivity and accuracy of the research data. Data were double-entered into Epidata software to ensure that all data were correct.n (%). The differences between groups were compared utilizing the χ2 test. Continuous variables that met the normal distribution were expressed as the mean ± SD and compared with the independent samples t-test. GraphPad Prism was applied to compare serum MIP-1α levels between the case and control groups. The Pearson correlation analysis was employed to analyze the correlation between the serum MIP-1α level and the risk of left atrial remodeling in atrial fibrillation patients. R software was used to draw a heatmap. At the α = 0.05 level, a value of P < 0.05 was considered statistically significant.Data were analyzed using SPSS 22.0 software. Count data were expressed as α level was significantly higher in the case group than that in the control group (P < 0.05) as shown in The serum MIP-1P > 0.05) as shown in The differences in age, sex, cardiac function classification, atrial fibrillation course, and type of atrial fibrillation were not statistically significant between the high-level and low-level groups (P < 0.05) as shown in Significant differences in the anteroposterior diameter, upper and lower diameter, left and right diameter of the left atrium, left atrial volume, volume index, left atrial global ejection fraction, and sphericity were detected between the low-level and high-level groups , left and right diameter (r = 0.759), left atrial upper and lower diameter (r = 0.810), left atrial volume (r = 0.837), left atrial volume index (r = 0.813), and left atrial sphericity (r = 0.785) but negatively correlated with the left atrial global ejection fraction  as shown in The Pearson correlation analysis results showed that serum MIP-1α, also known as CCL3, is a cytokine belonging to the CC chemokine family, known for its role in leukocyte activation and migration to inflammatory areas. In arrhythmic cardiomyopathy [α level and its correlation with the risk of left atrial remodeling may provide a new direction for the diagnosis and treatment of atrial fibrillation.Although the pathogenesis of atrial fibrillation is still unclear, it is known that atrial structural remodeling plays an important role in the occurrence and development of atrial fibrillation. In an animal model study  and a clmyopathy , chemokiα affects key factors in the migration and maintenance of relevant immune cells into infected tissues or the tumor microenvironment. When CD4 is released, CCL3+ T cells interact with dendritic cells, and CD8+ T cells expressing CCR5 were recruited to enter specific locations to activate and proliferate in living organisms. In recent years, with the deepening of the research, the MIP-1α effect on the tumor microenvironment has gradually transferred to cardiovascular diseases. MIP-1α can be utilized to predict clinical outcomes in patients with atherosclerotic cardiovascular disease, myocardial ischemia, and heart failure [α levels were higher in patients with atrial fibrillation, indicating that MIP-1α was highly expressed in atrial fibrillation patients. Inflammatory response and oxidative stress exist in the occurrence of atrial fibrillation. Sustained inflammatory response and excessive oxidative stress can activate NF-KB and release MIP-1α. High MIP-1α levels can promote the electrical and structural remodeling of the heart. Therefore, MIP-1α is highly expressed in atrial fibrillation patients.In the tumor microenvironment , MIP-1α  failure . In card failure , the CCRα, have been implicated in atrial fibrosis and episodes of atrial fibrillation [α, which may induce leukocyte activation and migration to inflammatory areas and participate in the repair process. It was found in MIP-1α-induced experimental autoimmune myocarditis [α plays a key role in myocardial fibrosis. Another study has confirmed that [α can induce monocytes to produce matrix metalloproteinase 9 and TGF-β expression, while MMP-9 and TGF-β accelerate the progression of atrial fibrillation by increasing the degree of atrial fibrosis and participate in the left atrial remodeling in atrial fibrillation patients. These studies indicate that the MIP-1α level may be involved in the left atrial remodeling in atrial fibrillation patients. The results from the present study displayed that the anteroposterior diameter, upper and lower diameter, left and right diameter of the left atrium, left atrial volume, volume index, and sphericity were higher but the left atrial global ejection fraction was lower in the high-level group than those in the low-level group. Further correlation analysis results revealed that MIP-1α levels were negatively correlated with the left atrial global ejection fraction but positively correlated with the remaining left atrial remodeling indexes, indicating that MIP-1α can remarkably predict left atrial remodeling in patients with atrial fibrillation. This is associated with the fact that elevated MIP-1α levels can promote the activation and migration of leukocytes to inflammatory areas, leading to left atrial remodeling.Left atrial enlargement is considered a marker of atrial remodeling and typically occurs in response to left atrial pressure and volume overload in patients with atrial fibrillation. A previous study  has demoillation . In termillation  suggestecarditis  that MIPmed that  MIP-1α cα expression levels are high in patients with atrial fibrillation, and MIP-1α levels are associated with the risk of left atrial remodeling. This study has certain limitations. First, the serum MIP-1α expression level was not dynamically analyzed, and the correlation between dynamic serum MIP-1α level and the risk of left atrial remodeling could not be observed. Second, due to the limitation of objective conditions such as sample size, only the left atrial remodeling indicators were analyzed in patients with atrial fibrillation, and the electrical remodeling of the left atrium was not considered. Further investigations are needed and will make up for the abovementioned shortcomings.In conclusion, serum MIP-1