Cardiovascular disease is a leading cause of death, and translational research is needed to understand better mechanisms whereby the left ventricle responds to injury. Mouse models of heart disease have provided valuable insights into mechanisms that occur during cardiac aging and in response to a variety of pathologies. The assessment of cardiovascular physiological responses to injury or insult is an important and necessary component of this research. With increasing consideration for rigor and reproducibility, the goal of this guidelines review is to provide best-practice information regarding how to measure accurately cardiac physiology in animal models. In this article, we define guidelines for the measurement of cardiac physiology in mice, as the most commonly used animal model in cardiovascular research.http://ajpheart.podbean.com/e/guidelines-for-measuring-cardiac-physiology-in-mice/.Listen to this article’s corresponding podcast at  The measurement of cardiac physiology is the foundation for assessing changes in anatomic and physiological features that occur within the myocardium during aging, in response to genetic alterations, and after a variety of experimentally induced pathologies. Cardiac physiology measurements also provide a means to examine the effects of therapeutic interventions.With increasing concerns over data rigor and reproducibility, best-practice information is needed regarding measurements of cardiac anatomy and physiology in experimental settings. The focus of this review is to provide comprehensive guidelines on how to assess cardiac physiology in mice. We will discuss the importance of having a complete and rigorous physiological assessment when evaluating a number of cardiac pathologies. We will clarify what needs to be measured in different cardiac pathologies and discuss parameters to establish consistency both within and among laboratories. This guidelines article is a good companion for the article “Guidelines for animal models of myocardial ischemia and infarction” .The sections in this article are divided by approach and include echocardiography, MRI, and hemodynamics measurements. Within each section, we discuss how each specific approach can be used to assess alterations in cardiac structure and function under different conditions, including studies of aging, cardiomyopathies such as postchemotherapy, diabetes, or sepsis, myocardial infarction (MI), and pressure overload cardiac hypertrophy induced by transverse aortic constriction (TAC), angiotensin II infusion, or isoproterenol infusion. Echocardiographic imaging is a widely used, noninvasive means to assess cardiac physiology and architecture in rodent models of heart disease and aging and allows for repeated assessment of heart function over the course of disease progression , 212–214Echocardiographic imaging uses high-frequency sound beams that penetrate the thoracic cavity and are reflected back to the ultrasound transducer when they reach an interface among moieties of different acoustic impedance, such as the myocardium, blood, valves, or vessel wall. This reverberated signal is then processed by the instrument software to produce a real-time image of the heart (or vessel). Echocardiography uses four main principal imaging formats: two-dimensional (2-D) brightness mode (B-mode), motion mode (M-mode), Doppler imaging, and three-dimensional (3-D) imaging. Unique challenges facing echocardiography in mice include the small heart size (5- to 8-mm length in an adult mouse) coupled with high heart rates . Recent technological developments include high-frequency transducers (up to 70 MHz) and enhanced imaging frame rates to provide high spatial and temporal resolutions to view structural and physiological changes in the left ventricle (LV). In addition, integration of respiration, heart rate, and ECG monitoring during ultrasound recordings allows for additional quality control  during recording. Echocardiography is now commonly used to measure different aspects of cardiac architecture  and physiology (systolic and diastolic) in rodents.Cardiac hypertrophy and dilated cardiomyopathy are generally associated with a uniform structural remodeling of the LV, and, as such, M-mode and B-mode imaging are suitable approaches to measure LV wall thickness  and LV chamber size. MI (permanent occlusion of the left anterior descending artery), on the other hand, is associated with nonuniform remodeling of the LV chamber due to the scar (infarct) formation that replaces a major fraction of the LV free wall (and sometimes the septum). In this scenario, M-mode imaging is limited in its assessment capacity; global changes in the structure of an infarcted, remodeled LV are better assessed using 2-D or even 3-D images. ECG-gated kilohertz visualization (EKV) is a 3-D reconstruction of the heart using imaging gated to the ECG . With EKThe first step in preparing for echocardiographic imaging is to decide what, if any, anesthetic to use. Some studies have reported that ultrasound recordings can be performed on conscious, carefully restrained mice to avoid an anesthesia-induced decrease in heart rate that can influence cardiac function . Mice caThe anesthetics that have been most commonly used for echocardiography in mice are isoflurane and ketamine-xylazine, while other anesthetics, such as tribromoethanol (Avertin), medetomidine, pentobarbital sodium, and ketamine, in combination with other anesthetics (including midazolam and fentanyl), have also been occasionally used in mice , 90. KetN-methyl-d-aspartate receptor antagonist, 100 mg/kg) and xylazine  has been previously and prevalently used as the anesthetic of choice for surgeries as well as for echocardiographic imaging. However, in the past two decades, numerous studies have demonstrated cardiodepressant effects of ketamine-xylazine, which have made this choice of anesthetic unacceptable for physiological measurements. This is mainly due to the cardiodepressant effects of xylazine, which can significantly reduce heart rate and LV function compared with isoflurane  and allows for assessment of cardiac chamber dimensions, cardiac physiology, and visualization of cardiac anatomic structures, such as papillary muscle and valves. In cine loops obtained from B-mode, the LV endocardium can be traced in diastole and systole to calculate cardiac ejection fraction (EF). Similarly, LV mass can be estimated by tracing the epicardium and endocardium in a midventricular parasternal short-axis view. B-mode also serves as an orientation guideline for regions of the heart that require further assessment by other imaging modes, such as M-mode or color Doppler imaging. Imaging of the right ventricle (RV) in the short-axis view in the mouse is challenging, due to interference from the sternum not allowing proper positioning of the probe for RV imaging; detailed protocols have been developed for using echocardiography to assess RV structure and physiology , 96, 122Among the currently available imaging modes, EKV provides maximum frame rate imaging with maximum resolution, allowing for increased temporal and spatial resolution imaging , 121. AsM-mode images are obtained by a rapid succession of B-mode scans along a single axis displayed over time. M-mode images appear as a continuous tracing, showing the motion of the myocardial walls as they contract during systole and relax during diastole. This mode provides a very high temporal resolution of LV wall motion to assess LV contractile patterns and chamber size. Parameters that can be obtained from M-mode imaging include LV internal diameter (LVID) at end systole (LVIDs) and end diastole (LVIDd), which can then be used to calculate fractional shortening (FS) as a measure of systolic function and cardiac contractility [FS = (LVIDd − LVIDs)/LVIDd × 100]. M-mode images can also be used to derive additional functional parameters such as calculated EF, cardiac output (CO), and stroke volume (SV) or structural parameters such as LV mass. Calculations of LV volumes and EF from M-mode, however, have a number of geometric assumptions that must be taken into account. In calculations derived from M-mode dimensions, the LV is assumed to be of a spherical (symmetric) rather than an oval (asymmetric) shape. This is not accurate and leads to even greater errors in pathological cases, such as post-MI remodeling. Similarly, while the calculated LV mass is often comparable with actual mass, the gravimetric measurement of LV mass remains the gold standard.This imaging mode uses the Doppler shift principle, reflected by the moving target, to determine blood flow velocity and direction, as evidenced by color differential. In the case of color Doppler, the moving target is blood cells ; in the case of tissue Doppler, the moving target is the myocardium. An increase in blood flow will be reflected as an increase in Doppler shift. In pulsed-wave Doppler, the transducer transmits and receives the sound waves, whereby the blood flow-velocity profile is determined from a precise location (determined by 2-D image guidance). Pulsed-wave Doppler can be used to measure transvalvular flow-velocity profiles, which are particularly useful in assessing cardiac diastolic function, including isovolumic relaxation time (IVRT), E wave and A wave ventricular filling velocities, and deceleration of the E wave. More details on accurate assessment of diastolic function are provided in later sections. Pulsed-wave Doppler can also measure systolic parameters, such as ejection time (ET), isovolumic contraction time (IVCT), and IVRT. These parameters provide information on the kinetics of LV systole (ET and IVCT) and cardiac diastole (IVRT). For instance, prolonged ET or IVCT may reflect a reduced rate of contraction, whereas an increase in IVRT often reflects impaired diastolic function.Color Doppler imaging uses a color-encoded map of flow velocity and direction superimposed on the 2-D image. Blood flowing toward the ultrasound transducer is identified in red (increase in frequency), blood flowing away from the transducer is depicted in blue (decrease in frequency), and blood flowing horizontally is not detected. Doppler evaluation of blood flow and velocity can also be obtained in any vascular bed. One of the possible applications of Doppler imaging to measure blood flow and velocity is in determining the severity of pressure overload in the TAC surgical model to induce cardiac hypertrophy , 136. PrTissue Doppler imaging is used to assess global and regional cardiac function. Mitral annulus measurements of motion velocity are used to assess E′, A′, and S waves (LV diastolic parameters of relaxation). Myocardial velocities can also be measured and strain (deformation) rates derived from these measures. Peak systolic myocardial strain rate is a relatively load-independent measure that can identify subtle changes in systolic function. One limitation of the Tissue Doppler imaging method is that it only measures velocities parallel to the beam; therefore, analyses of radial function are limited to the anterior and posterior walls, and the circumferential function is limited to the septal and lateral walls.M-mode and B-mode images represent a grayscale of amplitude in one and two dimensions. 3-D echocardiography in mice is based on reconstruction from multiple 2-D images. The images can be digitally stacked as a series of short- or long-axis views. Alternatively, a semi-automated 3-D acquisition image, obtained from varying transducer positions at the same points in the cardiac cycle (gating), measures LV chamber volume during end systole (LVESv) and end diastole (LVEDv), which are used to calculate EF [EF = (LVEDv − LVESv)/LVEDv × 100]. Whereas 2-D echocardiography is based on the symmetric LV shape and structure assumption, 3-D imaging avoids LV shape assumptions, a particularly useful feature in assessing LV dilation and dysfunction in a model of MI . It is iSpeckle tracking is a novel, non-Doppler-based technique used to detect myocardial displacement, wall motion velocity, and myocardial deformation indexes, such as strain  and strain rate (the rate of change in strain). Strain and strain rate detect early LV dysfunction before changes in EF occur . SimilarDisplacement can be measured along the radial and longitudinal axes as the distance traveled by the speckles from peak systole to peak diastole. In addition, strain and strain rate can be used to assess regional myocardial function. Radial strain  can be measured along the short or the long axis and is depicted as a positive curve during systole  and a negative curve during diastole . Circumferential strain is obtained from a short-axis view and represents the percent change in myocardial circumference, whereas longitudinal strain detects the percent change in LV length (from the apex to base). Time to peak analysis is another index measured by speckle tracking that is used to assess dyssynchronous contraction among different myocardial regions . In thisRegional strain per LV segment  can provide useful information in a post-MI model, since there is a clear regional difference in LV structural remodeling and function. As such, summation of all segments could mask regional differences. In hypertrophic or dilated cardiomyopathy associated with focal fibrosis, enhanced stiffness of a fibrotic segment reduces regional velocity, resulting in dyssynchrony. Therefore, speckle-track imaging can provide very useful information regarding the alterations within the myocardium that may be too subtle to be detected by conventional imaging modes. One important caveat with speckle tracking is that different ultrasound machines use their own proprietary software to acquire and track the speckles, resulting in a lack of standardization of strain and strain rate values. Care must be taken to acquire serial echocardiograms on the same equipment.3), which assumes the heart is a sphere. Volumes and EF derived from 2-D measurements assume a symmetrical LV geometry, which, of course, will not be the case in cardiac pathologies, such as MI. FS and EF are calculated based on LV chamber diameter and volume. Heart rate positively correlates with FS and EF, and, therefore, a drop (or rise) in heart rate, due to anesthetic, can lead to altered systolic function assessment. For instance, low heart rate associated with deep anesthesia is accompanied with LV dilation and overall cardiac depression. Therefore, the maintenance of a stable heart rate throughout the echocardiographic recording is particularly important, especially when assessing cardiac function in postinjury hearts that exhibit LV remodeling.Systole is the contraction phase of the heart that ensures normal ejection of blood from the chambers into the arteries to supply the body with oxygen. The most commonly used variables to evaluate systolic function are FS and EF, both provided as percentage values during systole compared with diastole. FS indicates the percentage change in LV chamber size and is an index of myocyte contraction, whereas EF indicates the percentage change in LV volumes and is an index of LV function. Other systolic physiology variables, such as SV and CO, can be calculated from measurements of LV wall thickness and chamber dimensions. The volumes and EF derived from M-mode are generally calculated using the cubed formula , followed by LV dilation and enlarged LV volume. Since the LV undergoes a uniform remodeling , M-mode imaging can be used to measure LV chamber diameter, from which FS can be calculated as FS = [(LVIDd − LVIDs)/LVIDd × 100].After MI or ischemia-reperfusion (I/R), there is nonuniform LV remodeling that includes thinning of the LV free wall and thickening of the septal nonischemic LV wall. Therefore, M-mode imaging in these cases provides an incomplete and sometimes false evaluation of LV remodeling and function. Additionally, M-mode could provide a biased view of the LV if the probe is not placed in the same location across all of the mice examined, particularly across control and MI groups. Therefore, it is our recommendation that M-mode measurements not be used as end points in this model. We recommend that images are acquired and analyzed according to American Society of Echocardiography guidelines for humans, tracing from leading edge to leading edge or trailing edge to trailing edge. While 2-D imaging provides clear views of wall motion abnormalities, several planes need to be imaged to delineate the extent and geometry of the abnormality. For this reason, small wall motion abnormalities can be missed. To circumvent this issue, 3-D imaging to evaluate LV volume (rather than LVID) and to calculate EF [EF = (LVEDv − LVESv)/LVEDv × 100] is superior and more accurate compared with FS measurements. LV volumes can be measured from several short-axis views using the Simpsons method , which rLV function post-MI or post-I/R can also be assessed by determination of the wall motion score index (WMSI) , which iAs in humans, an injection of contrast microbubbles can improve the definition of the endocardium. Additionally, the RV can be visualized. This approach, however, necessitates an intravenous injection. Care must be taken to inject a small volume of fluid (<20 µl) so that hemodynamic conditions are not disrupted by the injection.The Tei index or myocardial performance index provides an overall, combined assessment of both the systolic and diastolic function of the heart: (IVCT + IVRT)/ET. While the Tei index was originally and erroneously used to report diastolic dysfunction, it is an index of cardiac performance during a complete cardiac cycle (systole and diastole) . It has Diastole is the relaxation phase of the heart that ensures normal filling of the ventricles during rest and provides adequate blood volume to maintain normal CO. Diastolic dysfunction is defined as an impairment in active relaxation, passive stiffness, or the combination. Assessment of diastolic dysfunction in animal models of heart disease has received significantly more attention, since heart failure with preserved EF has become increasingly recognized in patients , 154. AsIt is important to note that the size of the mouse is a critical factor in selecting appropriate parameters to assess diastolic dysfunction accurately. A word of caution: a number of parameters, such as pulmonary venous flow and transmitral flow propagation velocity, which have been proven to be useful in patients, cannot be used in rodent models, due to the small size of the heart and fast heart rate in these animals, which restrict the spatial and temporal resolution beyond the detection limits of currently available technologies. Furthermore, the variability of these indexes among individual mice contributes to the difficulty and inaccuracy/inconsistency of diastolic assessment in this species.E/A) can be used as a measurement of diastolic dysfunction (if E/A < 1), however, not in isolation; as outlined by the new diastolic guidelines from the American Society of Echocardiography, E and A must be analyzed in the context of myocardial disease, annular tissue velocities, and LA size  and late or atrial filling (A wave), and provides information about the LV filling dynamics . The E w LA size .Mitral flow profile also provides information on DT and IVRT. DT is the time required for pressure equilibration between LV and LA and is measured as the time from the peak of the E wave to the baseline. IVRT is the time from closure of the aortic valve to the opening of the mitral valve. Increased IVRT represents prolonged LV relaxation. Although these measurements provide valuable information on LV filling kinetics, these parameters can be influenced by a number of factors, such as preload, arrhythmia, or very high heart rate as well as diseases that cause a hyperdynamic state. Furthermore, normal values of DT in mice are not well reported, and IVRT−a very short time interval−can be difficult to measure.LA size can be used as a marker for chronic elevation of LV filling pressure and is often used to assess diastolic dysfunction in humans , 139 andAssessment of cardiac physiology by echocardiography would not be complete without mentioning the possibility to assess ischemia and coronary reserve using stress echocardiography, Doppler-derived coronary reserve and myocardial perfusion using contrast echocardiography , 190. AdAmerican Journal of Physiology and (echocardiography or echocardiographic or ultrasound).” This search resulted in 437 articles, of which 52 articles were published between January 1, 2016, and present as well as 14 articles that were excluded as false positives . The remaining 38 articles were analyzed both for completeness of information provided and for quality assessment of the echocardiography values reported , provided results in tables so that we could obtain mean values and had results that the committee considered to be of high quality. These results were combined and are shown in MRI is a noninvasive, high-resolution imaging technique that can be used to assess myocardial anatomy, perfusion, wall motion and contractility, and physiology in mice , 192. MyDynamic imaging of the myocardium requires high ventricular blood-to-myocardium contrast, full coverage of the cardiac cycle, and high temporal and spatial resolution. For this reason, gradient echocardiography-based imaging techniques are used . MRI sysTo limit motion artifacts, it is essential to perform cardiac gating to acquire quality images. Images should be acquired over several cardiac cycles and simultaneously with an ECG for synchronization, a method commonly designated as prospective gating . ProspecWhile currently less widely available, more resource intensive, and with lower temporal resolution than echocardiography, advantages of using cardiac MRI in mouse models of heart failure include high accuracy and versatility , 167. CaCardiac MRI benefits from unrestricted spatial access to the myocardium, allowing long-axis imaging of two, three, or four chambers and continuous stacks of serial short-axis images for reproducible measurements of ventricular volumes and masses , 184. CuAssessment of LV diastolic physiology by MRI in mice is more challenging. Nevertheless, there have been a few successful reports. For example, in a mouse model of dilated cardiomyopathy, Chłopicki and colleagues used images of the midventricular short-axis plane at the level of the papillary muscle to measure filling rates derived from time-area curves , 180. Ot−1·min−1), providing a means to characterize the relationship between blood flow oxygen delivery and cardiac contraction. There are currently two cardiac MRI approaches to evaluate myocardial perfusion: 1) Gd-enhanced, first-pass perfusion after an intravenous bolus injection of an exogen contrast agent and 2) arterial spin labeling using the intrinsic properties of water protons in blood as an endogenous tracer not requiring contrast injections , longer and more resource-intensive protocols, lower temporal resolution, signal-to-noise ratio limitations, and reduced availability see , 94, expInvasive hemodynamic measurements can refine the information on cardiac physiology provided by echocardiography. This approach is not routinely used in mice as a firstline method, however, because this approach is technically challenging and is a nonsurvival procedure precluding this from being a serial assessment, and the results can be difficult to interpret. A micromanometer-tip catheter is inserted into the LV chamber , where it can directly measure the changes in pressure (and volume when a conductance catheter is used) of the LV over time. Illustrations of pressure-volume loops and how they are altered in cardiac disease are shown in tmin) and the isovolumic relaxation constant (τ), although load dependent, are easier to interpret than echocardiographic mitral inflows in mice, which can be fused at high heart rates. RV pressure measurements are invaluable for a direct measure of pulmonary arterial systolic pressure. Pressure-volume loops are considered the gold standard for hemodynamic assessment of ventricular performance and are mostly obtained from the LV, although reports on RV performance have been made , are considered to be relatively load independent , Scisense , and RADI Medical Systems  showed that pressure measurements by all catheters were stable, with a drift of ±2 mmHg within the 0- to 300-mmHg range. Of the three, the Millar amplifier had the shortest delay (0.2 ms) compared with Scisense (3.2 ms) and RADI Medical Systems (10.6 ms) amplifiers . For a hIn addition, the Scisense catheter has the advantage of reporting the absolute LV volume without a need for calibration, while Millar pressure-volume catheters require volume calibration. This is achieved in the Scisense pressure-volume catheter, because when inserted into the LV, it measures the overall conductance as well as the parallel conductance coming from the surrounding myocardium (which changes during the cardiac cycle). Parallel conductance is automatically quantified and removed from the total conductance, thereby providing direct information on LV volume (blood volume in the LV chamber). With Millar pressure-volume catheters, the conductance catheter signal is proportional to volume (of blood in the LV) and must be appropriately calibrated to provide accurate absolute volume measurements. It must be emphasized that the calibration is a crucial and often technically difficult step in the use of conductance catheters. One step that we would suggest, in addition to the calibration proposed by the manufacturers , is to validate the conductance-derived volumes using the echocardiography-derived volumes.Similar to echocardiographic imaging, choice of anesthesia is important for reliable and reproducible assessment of hemodynamics. Isoflurane has become the anesthetic of choice in hemodynamic measurements in mice because of its minimal cardiosuppressant effects compared with ketamine-xylazine and pentobarbital sodium , althougLV catheterization can be performed by a closed- or open-chest approach. In the open-chest approach, the catheter is inserted into the LV (or RV) through the apex, whereas in the closed-chest approach, the catheter is inserted in the carotid artery and extended into the ascending aorta and LV. The closed-chest approach has a number of advantages: arterial blood pressure can be recorded from the carotid at the beginning or end of the procedure, intubation is not required, and animals can remain stable for a longer time, which is ideal for prolonged procedures, such as drug testing. This approach is also preferred for hemodynamic measurements post-MI, since the LV infarction often extends to the apex, and insertion of the catheter through the scarred myocardium can be problematic. Open-chest LV catheterization also has advantages, since proper placement of the catheter in the LV is easier to confirm and is a better approach if the carotid artery is severely atherosclerotic  or in cases of aortic valve calcification. In all cases, we would recommend the use of the 1-Fr catheter to ease the introduction of the catheter in the LV and to decrease the risk of obstruction of the LV cavity around the catheter with elevated and inaccurate systolic pressure recordings.tmax and dP/dtmin rise and decline can be derived from LV pressure traces (first derivative). LV τ can be calculated by the Weiss method, expressed as the regression of the pressure versus time logarithm, or by the Glantz method, expressed as the regression of dP/dt versus pressure , calibration is crucial to minimize error. All parameters are load dependent.dP/dpressure . τ increpressure . Systoliy-axis (pressure) and x-axis (volume).With the use of a conductance catheter, parallel changes in LV pressure and volume can be recorded over consecutive cardiac cycles. A number of parameters can be obtained from the conductance catheters, including SV (SV = EDV – ESV), EF (EF = SV/EDV), CO (SV × heart rate), and arterial elastance , where EDV is end-diastolic volume and ESV is end-systolic volume. Volume measurements rely on geometrica assumptions, which can make results difficult to interpret in asymmetrical volumes and for RV measurements . The preEes, is an index of end-systolic elastance, an index that provides information on contractile function . An increase in this slope will indicate increased myocardial stiffness or decreased compliance  can be determined. ESPVR represents the maximal pressure developed by the LV at any given volume and is a measure of cardiac contractility. The slope of ESPVR, also referred to as function . The degscussion . Ventricmpliance . Both Eey-axis) will be observed. In dilated cardiomyopathy, ESV and EDV increase, but LV pressure can remain unchanged; therefore, the ESPVR and EDPVR are shifted to the right. If dilated cardiomyopathy is associated with fibrosis and diastolic dysfunction, then an upward shift in the EDPVR will be observed. After MI or other instances of volume overload, ESV and EDV increase, end-systolic pressure decreases, and end-diastolic pressure increases; as a result, the pressure-volume loop will look smaller (shorter) with a rightward shift  is mandatory for reproducibility of all experimental approaches, and cardiac physiology experiments are no exception . The absThe ultimate validation is confirmation of results across individuals and across laboratories. As larger data sets are being acquired, consideration for how to harness big data and evaluate cardiac physiology results across laboratories should be given , 157. ThSupport from the following funding agencies is acknowledged by the authors: National Heart, Lung, and Blood Institute Grants HL-075360, HL-129823, HL-051971, and HL-131613; National Institute of General Medical Science Grants GM-104357 and GM-114833; American Heart Association Grant 14SDG18860050; Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development Grant 5I01BX000505; Heart and Stroke Foundation (Canada); and Canadian Institute of Health Research.The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the funding agencies listed. No conflicts of interest, financial or otherwise, are declared by the authors.M.L.L. conceived and designed research; M.L.L. prepared figures; M.L.L., Z.K., J.A.I.V., L.E.d.C.B., and M.S-C. drafted manuscript; M.L.L., Z.K., J.A.I.V., L.E.d.C.B., and M.S-C. edited and revised manuscript; M.L.L., Z.K., J.A.I.V., L.E.d.C.B., and M.S-C. approved final version of manuscript.


To calculate left ventricular (LV) global performance values in heart transplant (HT) recipients by three-dimensional speckle tracking imaging (3D-STI) and to observe the changes in LV global performance over time after HT and investigate the correlated factors.The 30 HT patients were divided into 2 groups according to postoperative time: 1 month postoperatively (HT-1) group and 6 months postoperatively (HT-2) group. Thirty healthy subjects were enrolled as control group. 3D-STI was performed to assess LV torsion, LV systolic dyssynchrony index (SDI), and LV global strain (GS). Global performance index (GPI) was calculated, and correlations factors with GPI were studied.Heart rate (HR), left atrium (LA), interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), and left ventricular mass (LVM) in both HT groups were higher than those in the control group. Compared with the control group, SDI was significantly higher in both HT groups, and SDI of the HT-1 group was much higher than that of HT-2 group. Compared with the control group, apical rotation (RoA), twist and torsion in the both HT groups decreased significantly. There were no significant differences in these values between the 2 HT groups; Basal rotation (RoB) showed no significantly difference among the 3 groups. GS in the both HT groups decreased significantly compared with the control group, and there were no significant differences in these values between the 2 HT groups. GPI of the both HT groups was significantly lower than that of the control group; however, GPI of HT-2 group was higher than that of HT-1 group. Multivariate stepwise regression analysis identified global left ventricular longitudinal peak systolic strain (GLS), the time length since surgery, left ventricular mass (LVM), and RoA as predictors of LV GPI. GLS was the most influential to GPI.The values of LV rotation, twist and SDI can be used to assess the LV systolic function and dyssynchrony. The GPI value based on 3D-STI may accurately reflect LV performance changes over time after HT. The GPI value has potential applications in clinical practice. GLS, the time length since surgery, LVM and RoA values can be the predictors of LV global performance, and as long as the left ventricular ejection fraction (LVEF) is preserved, the left ventricular global performance of HT recipients remains stable, and tends to improve over time after HT. Moreover, it is important to identify the early LV dysfunction of such HT patients who are clinically stable, which may provide a reference for clinical diagnosis and therapy.Heart transplant (HT) patients had a series of injury suffered from the operation, such as ischemia reperfusion, denervation, ischemic time before transplantation, long term use of immunosuppressive agents, and many other factors. After heart transplantation, to adapt to the postoperative environment, the heart must go through a series of adaptations to meet the needs of various physiological conditions.,2 Although previous investigations have addressed myocardial mechanics after heart transplantation, focusing either on the diagnosis of rejection or allograft vasculopathy, they have all used tissue Doppler imaging (TDI) or two-dimensional speckle tracking imaging (2D-STI) technology. However, TDI-derived parameters are angle-dependent and have frame-rate limitations.,4 2D-STI has been developed as an angle-independent echocardiographic modality to evaluate cardiac mechanical function. More recently, the three-dimensional speckle tracking imaging (3D-STI) has shown the potential advantage to overcome the limitations of 2D-STI for the assessment of LV global and regional systolic function.,7 The aim of this study was to investigate the usefulness of technology of 3D-STI and the value of global performance index (GPI) in the evaluation of global LV myocardial performance. YU have found that GPI has a high sensitivity and specificity in the evaluation of the cardiac toxicity of chemotherapy drugs in children and is helpful for the early detection of hidden cardiac muscle damage. GPI is a reflection of the comprehensive index of LV spatial movement. It can reflect the overall LV longitudinal, radial, circumferential motion, and rotational motion. GPI also includes the coordination of the sequence of cardiac synchrony.It has been found that HT patients often have subnormal functional capacity, even in the absence of overt LV systolic failure or significant allograft vasculopathy.22.1The study was approved by the institutional research ethics committee at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China. All data used were anonymized. The subjects gave written informed consent. All procedures and data analysis were performed by the authors; specific contributions of all enlisted authors are provided.A total of 30 HT patients who underwent surgery were prospectively enrolled at Union Hospital in Wuhan, China, between November 2013 and June 2014, including 26 males and 4 females with a mean age of 56.93 ± 10.01 years. We followed the 30 patients and recorded the time since surgery, which was the basis for the creation of the 2 subgroups: 1 month postoperatively (HT-1 group) and 6 months postoperatively (HT-2 group). All patients were clinically stable at the time of enrolment. Exclusion criteria included: histologic evidence of acute rejection, reduced left ventricular ejection fraction (LVEF) <55%, significant coronary vasculopathy , significant valvular disease, and major cardiac events since baseline examination. We followed 30 patients along with the time after surgery.The control group consisted of 30 age-matched healthy volunteers, including 25 males and 5 females with a mean age of 57.71 ± 10.10 years. They had no history of cardiovascular disease with sinus rhythm. Other organic diseases were excluded by physical examination, biochemical tests, electrocardiograph, and echocardiography.Demographic variables, including age and sex, were collected at the time the echocardiographic studies were performed. Informed consent was obtained. Weight, height, and blood pressure measurements were also obtained in all subjects.When the regression analysis of GPI was performed, we also had another 62 heart transplant patients who had the surgery between December 2013 and February 2015. We got the value of global left ventricular longitudinal peak systolic strain (GLS), global left ventricular circumferential peak systolic strain (GCS), apical rotation (RoA), basal rotation (RoB), and twist and left ventricular mass (LVM) of each patient.2.2All subjects underwent complete transthoracic echocardiography (TTE) to determine cardiac structure, chamber size, and cardiac function according to the recommendations of the American Society of Echocardiography (ASE). A commercially available system  was used with S5–1 broadband phased-array transducers. Subsequently, all subjects underwent 3D echocardiography using the same system with an X5–1 transducer. Images were optimized to obtain the entire left ventricle in a full-volume apical 4-chamber view. Data sets were acquired using a 7-heart beat acquisition setting during a period of stable heart rate, defined as the heart rate not changing during the acquisition time and not varying by >2 beats/minute during the 30 seceonds immediately before acquisition. A minimum of 4 data sets were acquired for each subject, and the 3 highest quality data sets were selected for offline analysis. Data sets that missed a portion of the LV had indistinct endocardial borders or had stitch artifacts were excluded. Image acquisition was performed by the same investigator (DW) within a 30-minute time frame.2.3Cardiac chamber size includes heart rate (HR), left atrium (LA), interventricular septum thickness (IVST), left ventricular diastolic diameter (LVEDD), left ventricular posterior wall thickness (LVPWT), and LVM.2.4Offline 3D echocardiographic datasets analysis was performed using echocardiographic quantification . Measurements were made using the data set with the best image quality, which was selected by consensus of the 2 readers. The frame rate of the volumetric image was 15 to 24 frames/second.The following parameters of LV values analysis were evaluated: RoA, RoB, twist, torsion, SDI, GLS, global left ventricular peak systolic strain (GS), and GPI.By convention, counterclockwise LV rotation as viewed from the apex was expressed as a positive value, whereas a clockwise rotation was denoted as a negative value. LV twist was defined as the net difference between the basal and apical rotation angles LV torsion was calculated as the net LV twist normalized with respect to ventricular end diastolic (ED) longitudinal length between the LV apex and the mitral plane  The LV GPI, which takes into account the different aspects of LV mechanics, was calculated as GLS was averaged over the 16 segments. The SDI was calculated as the standard deviation of the 16 times to the highest peak segmental systolic 3D strain, as a percentage of the RR interval.The coordinates for rotation, twist, and torsion for each frame were exported to a spreadsheet .2.5P < .05 were considered statistically significant. Statistical analyses were performed using SPSS for Windows version 17.0 .All demographic, conventional echocardiographic, and 3D data are presented as numbers or percentages (mean ± SD). One-way analysis of variance was used to compare the data of the 3 groups. Multiple linear regression analysis was performed to determine the additional effect of the GPI of HT patients. 33.1P > .05). However, HR, LA, IVST, LVPWT, and LVM in both HT groups were higher than those in the control group (P < .05); and there were no significantly differences between the 2 HT groups in terms of HR, LA, IVSD, or LVPWT (P > .05)  Table .3.2P < .05); and SDI in the HT-1 group was much higher than in the HT-2 group (P < .05) ; there were no significant differences in these values between the 2 HT groups, and RoB showed no significantly difference among the three groups (P > .05) ; there were no significant differences in these values between the 2 HT groups (P > .05). Compared with the control group, GS in the both HT groups decreased significantly (P < .05); there were no significant differences in these values between the 2 HT groups (P > .05). Compared with the control group, SDI was significantly higher in both HT groups (P < .05), and SDI in the HT-1 group was much higher than in the HT-2 group (P < .05). GPI in the both HT groups was significantly lower than that in the control group (P < .05); however, GPI in HT-2 group was higher than that in the HT-1 group (P > .05)  Fig.  Table 3P < .05; Multivariate stepwise regression analysis identified GLS, the time since surgery, LVM, and RoA as predictors of LV GPI; of these, GLS was the most influential to GPI. As a result, the following equation was derived: The equation shows that GLS exerts the greatest influence on the GPI value Table .4,11 although others with a relatively stable clinical response and no obvious rejection will undergo a series of changes to meet the needs of the body and the changes of environment. The 3D-STI depends on the ability of the specking to track the movement of the heart muscle more accurately and objectively in the 3D space. 3D-STI can not only track the longitudinal, radial, and circumferential motion, but also the twist and rotational motion of the LV. Therefore, it can demonstrate the global systolic function of the LV more comprehensively.,13Early invasive examinations and many other research have demonstrated that LV function of the HT patients with obvious rejection is impaired,4.1Our research indicates that the HR of HT patients becomes higher than in healthy individuals. This change may be related to the denervation of the transplanted heart. HR is entirely reliant on the independently electrical activity of the sinoatrial node. The HR of healthy individuals is not only regulated by sinoatrial node, but is also controlled by the vagus and sympathetic nerves. The vagus nerve is mainly responsible for the negative regulation of the heart rate. Its effect is higher than the positive heart rate effect of sympathetic nerves. The denervation of the transplanted heart impairs the vagal response and therefore causes a significant increase in resting heart rate. In our research, the highest heart rate is as high as 94 to 106 beats/minute.Our research shows that the LA, IVST, LVPWT, and LVM of a HT patient are obviously higher than those of healthy individuals. The cases in our research all represent are all orthotopic heart transplantation, in which the left atrial posterior wall remains and coincides with the structure of the donor heart. During the operation, the reconstruction of a double atrium, namely, the separation of atrial and electrical activity, will all cause the expansion of double atria after surgery. Meanwhile, the operation itself and ischemia reperfusion will all cause edema of the myocardial cells. These changes caused by surgery will resolve or disappear with the passage of time. It is also important to note that the adaptive changes of the transplanted heart and long-term use of immunosuppressive agents could also cause the reconstruction of the transplanted heart, and cause an obvious increase in IVST, LVPWT, and LVM. These effects are considered adaptive changes of the transplanted heart.4.2 The influence of the effect of central nervous system vascular signals on cardiovascular system disappears, and the low blood volume and the mechanism of blood vessel relaxation activation of adrenal signal will be affected.Denervation is the most basic pathophysiological characteristics of the HT patients. Hemodynamics, endocrine, electrical physiology, responses to external stimuli, and pharmacological reactions of a transplanted heart are different from the normal heart when it has lost neural control. After denervation, the peripheral vascular resistance of a HT patient decreases. Central venous pressure soon decreases accordingly. The regulating axis among renin, angiotensin and aldosterone will be damaged, which might cause capacity overload, namely, the increase in preload of the heart. After denervation of the outgoing nerve, the capacity of catecholamines in transplanted cardiac muscle is quickly depleted. However, the contractile function of the transplanted heart was completely dependent on the end diastolic ventricular volume and the catecholamine in blood circulation, which maintain a normal increase in cardiac output.,15 reported research after 40 patients who had undergone the HT operations for 1 year. Tissue velocity imaging showed that the LV response was significantly lower than that of the normal heart. This finding is consistent with the results of our research and revealed that the LV systolic function of the transplanted heart had been obviously impaired, possibly through a series of injuries the patient might have suffered during the operation, such as ischemia reperfusion, cell rejection reactions after surgery, and long-term use of immunosuppressive agents. Specifically, ischemia reperfusion could lead to myocardial infarction and apoptosis. The aforementioned factors will all cause the decreasing of the LV strain of the transplanted heart.Our research shows that there is no significant difference in LVEF between HT patients and healthy individuals. The strain of the entire left ventricle is significantly lower than in normal hearts. K Haydar et al4.3The effective pumping blood of the normal human heart is mainly relying on the rhythmically synchronized contraction and relaxation of the ventricular wall. The LV systolic and diastolic function can be affected by the decreases in the ventricular wall motion, which will cause changes in the hemodynamics. Other researches have shown that there are advantages in quantitatively evaluating the LV function and the coordination and synchronization of LV myocardial contraction of a HT using 3D-STI. SDI can be used as an effective index for evaluating LV systolic synchrony in HT patients. Even the mass activity of the implanted heart will increase of swing, which will also cause a decrease of synchronism. Atrial anastomosis maintains the sinoatrial nodes of the recipient heart. This condition will cause the transplanted heart to have 2 sinoatrial nodes at the same time. This separation of the atrial electrical activity and the contrast in electric activities will cause nonsynchronous mechanical activity to varying degrees. The synchrony of LA contraction will cause a decrease in the coordination and synchronization of LV wall passive relaxation. The SDI of the 6-months postoperative group was smaller than that of the 1-months postoperative group. This difference indicated that the LV synchrony of HT patients 6 months after surgery becomes better than that of patients 1 month after surgery. This difference reinforces that the operation itself and ischemia reperfusion also influence the synchronization of transplanted hearts. With the prolongation of postoperative time, the synchronization of the myocardium will improve because of the partial recovery of LV myocardial from damage.Our research shows that the left ventricular 16-segment volume-time curve is smoothing and makes corresponding curves. The time when the curve reaches the LV end systolic volume (curve trough), that is, the trough of the 16-segment volume-time curve is more concentrated. The LV 16-segment volume- time curves of 1-months and 6-months postsurgery groups are messy and have poor consistency. The troughs of the 16-segment curves are discrete, especially in the 1-months postoperative group. The SDI of the HT increases significantly compared with the normal groups. Because the recipient heart is often significantly expanded after implantation of the transplanted heart to the location where the recipient heart had been removed, the implanted heart may require a location change.4.4 Larger spatial location changes will occur when the transplanted heart has been implanted in the body and its activity increases significantly. These factors will all influence the torsion and rotation of the heart itself.The spatial movement of the heart is very complex. Ventricular wall motion mainly includes inward contraction of the myocardium, with rotation of the heart along the axis and the level of the heart and stretching, twisting, and other local movement. Therefore, we can evaluate the LV systolic and diastolic function base on LV torsion. The torsional motion of the heart refers to the rotational motion around the LV short axis center as the imaginary circle. From the apex to the bottom of the heart, we can observe that the apex rotates counterclockwise when contracting; however, the bottom of the heart rotates clockwise. This action forms the torsional motion of the left ventricle along the long axis. This type of torsional motion plays an important role in the LV systolic and diastolic function. Any pathological condition, such as aortic stenosis and coronary artery disease, may affect LV torsion and rotational motion, such as aortic stenosis and coronary artery disease.,23 The direction and size of the LV torsion depend on the cross-wall stress of the LV myocardium and the mechanical advantages of myocardial fibers of the epicardium compared with that of the endocardium. Research shows that the myocardial torsion angle and the cross-wall stress gradually decrease from the apex to the base at the time of the contraction. Our research demonstrates that the LV apical rotation and LV torsion of HT patient are significantly lower than those in healthy individuals. Because the LV torsion is very sensitive to sympathetic nerve stimulation, the denervation of the transplanted heart will seriously influence the LV torsion.,26 Ischemia, hypoxia, and the transplant procedure will all cause different degrees of injury to the myocardium, resulting in damage to the LV twist and rotation function. After HT, caused by a variety of factors including ischemia reperfusion injury, allograft vasculopathy immune injury and long-term immunosuppression, the left ventricle will be remodeled, the myocardium of the left ventricle will be damaged and the function of LV torsion will deteriorate. The decrease in LV torsion and rotation in HT patients may be related to the fact that the transplanted heart has no limitation of pericardium because the pericardium plays a supporting and maintaining role in the twisting and rotating motion of the heart. Our research shows that the LV apical rotation of HT patients is significantly lower than in healthy individuals; there is no significant difference between normal and transplanted hearts regarding the LV rotation angle of the basal part. For normal hearts, the LV apex is relatively free. Its range of motion increases significantly compared with the basal part of the left ventricle. The LV apex is dominant in the torsional and systolic function of the left ventricle; thus, the decrease in LV apical torsion is more obvious than that of the basal part.The LV myocardium is a myocardial band which is formed in a spiral fashion. Contraction and relaxation of the left ventricle result in the LV systolic torsion similar to twisting a towel and the diastolic untwisting.4.5Our research shows that the LVM of the transplanted heart is significantly higher than in healthy individuals. Detecting abnormal changes in the LV mechanics of HT patients would provide a useful reference for clinical determination of the damage of LV systolic function. With greater postoperative time, the ischemic reperfusion injury suffered in surgery, the cell rejection reaction after surgery, and the long-term use of immunosuppressive agents and any other factors will all interact. There will be some changes in the LV strain, torsion rotation and synchrony of the transplanted heart. Our research analyzes the LV strain, introduces the LV twist and synchrony and measure the GPI based on 3D-STI. It shows that the LV GPI of HT patients is lower than that in healthy individuals. This change is related to decreases in LV strain, rotation, torsion, and synchrony. Furthermore, the GPI of 6 months after surgery shows an increasing trend compared with the 1 month after surgery, although the difference is not statistically significant, which may be related to the short postoperative time of the patients we included and the small number of patients. Our research shows that the LV GPI of HT patients is lower than that in healthy individuals. This difference can more comprehensively reflect the different degrees of damage to LV function in HT patients whose LVEF value is “normal.” Furthermore, we used multiple linear stepwise regression in our study to find the factors that may affect the overall function index of the left ventricle. Multivariate stepwise regression analysis identified GLS, the time length since surgery, LVM, and RoA as predictors of LV GPI. GLS was the most influential to GPI. At the same time, this finding also indicates that the overall function of the left ventricle gradually improves with time after surgery, possibly related to resolution of edema myocardial cells. Early temporarily impaired cardiac function can be gradually restored. With the extension of partial nerve regeneration after surgery, the related functions of neural regulation can be partially recovered.The main patients in our research are relatively stable clinical heart transplant patients whose LVEF values are in normal ranges and who have no obvious signs of rejection. GPI parameters overall reflect the function of the left ventricle in these patients in terms of left ventricular strain, torsion and synchronization. This parameter can provide a reference for clinical diagnosis. The left ventricular global performance of HT recipients remains stable and tends to improve over time after HT, which can be a certain basis for the future monitoring of transplant rejection, coronary artery disease and other serious complications4.6Limitations of our research include the follow-up time that was too short to reflect the change of the function of HT patients after surgery. The frame rate SD-STI was low, which could influence on speckle tracking ability. Furthermore, the number of patients in our research was too small. Future studies assessing left ventricular performance in HT over time after surgery is needed as it looks promising.


To assess the changes of mitral valve (MV) in ischemic mitral regurgitation (IMR) using Mitral Valve Quantification (MVQ) program.We examined 46 patients (18 women) with IMR aged 45-86 and a control group of 33 healthy individuals (14 women) aged 18-88. Following parameters were assessed: Area of minimal surface spanning annulus (A3), annulus height (h), tenting height (Th), exposed area of anterior (AL), posterior (PL) and both leaflets (BL), ejection fraction of the left ventricle (LV EF), regurgitation volume (RV) and BL/A3, AL/A3, PL/A3 ratios. The normal range of BL/A3 ratio was defined as the average ± 2SD of control group. The study group was separated into subgroup 1 with BL/A3 ratio within normal values and subgroup 2 with pathological BL/A3 ratio. Corresponding parameters of IMR group were compared to the controls and both subgroups were compared to each other using Student t-test.In IMR group, as compared to the controls, A3, AL, PL, BL as well as BL/A3, AL/A3, PL/A3 ratios and Th were significantly increased, conversely, h and LV EF was significantly decreased. In the subgroup 2 as compared to the subgroup 1 there was significant increase of Th, BL, AL and PL, while EF LV was significantly decreased. There was no significant difference between these subgroups in A3, h and RV.In ischemic MV remodeling two stages were identified without relation to the severity of IMR. The first stage was mainly influenced by the LV dilatation while LV remodeling was more important in the second stage. The main feature of mitral regurgitation in ischemic heart disease (IHD) is its functional nature without structural abnormalities of the mitral valve. The underlying mechanism of ischemic mitral regurgitation is remodeling of the left ventricle (LV) and of the mitral valve itself as a part of the ventricle . The remRT 3D echocardiography is a new modality capable of exact assessment of mitral valve . Mitral The aim of the study was to assess the changes of mitral annulus and leaflets in ischemic mitral regurgitation.We examined 46 consecutive patients (18 women) referred for heart surgery with IHD and ischemic mitral regurgitation. They were aged 45-86 years (67 average). These patients had no structural abnormalities of the mitral valve; instead the regurgitation was due to the remodelling of the left ventricle with subsequent dilatation of the mitral annulus and changes in leaflets motion and coaptation.We also investigated a control group of 33 healthy individuals (14 women) aged 18-88 years (56 average). These healthy controls were referred for TEE to exclude patent foramen ovale because of previous embolization to the central nervous system. The normal controls had no valve defect, no ventricular hypertrophy, and their left ventricular function was within normal limits. All were in sinus rhythm.Transesophageal echocardiography was performed in all study subjects using 3D matrix transducer (X7-2T) on Philips iE33 system . Both live (zoom) and full volume acquisition were performed in all individuals. Full volume data were preferred for MVQ model construction because of wider angle of acquisition and higher frame rate in this mode. In patients with atrial fibrillation, live data were used for analysis. End-systolic model of mitral valve was created using MVQ program (version 7.1) within commercially available Q-lab software (Philips). The basis for the model construction is the 3D data set. In a series of 2D sections obtained from the 3D data the echocardiographer defines the annulus and commissures and traces the leaflets. The MVQ program then generates the valve model. A number of parameters of the mitral valve can then be quantified according to the selected preset.We assessed following parameters:1. Parameters defining mitral annulus: Area of minimal surface spanning annulus (A3) , mitral 2. Parameters expressing the relation between the annulus and the leaflets: Tenting height (Th), exposed area of both leaflets (BL) , exposed3. Other parameters: Ejection fraction (EF) of LV using Teichholz formula (2D) and regurgitation volume (RV) using hemiellipsoidal PISA method.Corresponding parameters of patients with IHD were compared to healthy controls using Student t-test.The normal range of BL/A3 ratio was defined as the average ± 2SD of control group. According to the BL/A3 value the study group was divided into 2 subgroups: In patients of subgroup 1 the BL/A3 ratio was within normal values while in patients of subgroup 2, BL/A3 ratio was higher than normal values. Corresponding parameters of both subgroups were compared to each other and to the control group as well, using Student t-test.Control group of 33 healthy individuals (14 women) aged 18-88 years (average 56) had an average ejection fraction of 58.2%. All individuals were in sinus rhythm. Six were treated for hypertension but were normotensive following treatment. In the group with ischemic heart disease there were 46 study subjects (18 women) aged 45-86 years (average 67) with average ejection fraction of 39.8%. Thirty three (71.7%) were treated for hypertension and 12 (26.1%) had atrial fibrillation.The measured parameters of the mitral valve in patients with IHD and healthy controls  expressed as the average ± 2SD are shown in the In patients with ischemic heart disease, as compared to healthy individuals, LV EF was significantly depressed, area of minimal surface spanning annulus, exposed areas of leaflets as well as BL/A3, AL/A3, PL/A3 ratios were significantly increased. Mitral annulus height was lower in ischemic mitral regurgitant lesions and conversely, tenting height was higher than in healthy controls.Group of patients with IHD was divided into two subgroups according to BL/A3 ratio. In patients of subgroup 1 in whom the BL/A3 ratio was within normal values, there were 19 individuals (7 women). In patients of subgroup 2, BL/A3 ratio was higher than normal values and this subgroup comprised 27 study subjects (11 women). Followed parameters of both subgroups, compared to the controls, are shown in the Both subgroups of patients with ischemic mitral regurgitation as compared to healthy individuals had significantly larger area of mitral annulus as well as exposed areas of both leaflets. Tenting height in both subgroups of IHD was higher and conversely LV EF was lower than in normal individuals. Mitral annulus height was significantly decreased only in subgroup 2 while in subgroup 1 this parameter did not significantly differ from controls.The comparison of followed parameters of both ischemic subgroups to each other can be seen in the In the subgroup of patients with pathological BL/A3 ratio, there was significant increase of tenting height and exposed areas of both leaflets, whereas their LV EF was significantly decreased. There was no significant difference between the ischemic subgroups in the annulus height and area of mitral annulus and in regurgitant volume.Ischemic mitral regurgitation still remains a challenge-both its assessment and decision making concerning adequate heart surgery. Some pathophysiological mechanisms contributing to the ischemic mitral regurgitation are well described in the literature. Remodeling of the left ventricle together with its dilatation leads to atypical position of papillary muscles in relation to the mitral leaflets. Restrictive movement of the leaflets with increase of tenting height and the decrease of coaptation length and area are the consequences of the remodeling process . 2D echoIn our study we evaluated mitral valve as a complex consisting of mitral annulus and leaflets. We analyzed both components separately and also the relations between them. In 2D echocardiography tenting height is generally accepted parameter reflecting the stage of LV remodelling. Area of minimal surface spanning annulus represents the real three-dimensional (nonplanar) area of mitral annulus. The value of this parameter, as well as the value of mitral annulus height, is mainly influenced by dilatation of the left ventricle . The exposed area of both mitral leaflets is the part of the valve visible from the left atrium. Mathematically it can be defined as the area of the mitral valve with exclusion of the area of coaptation. Its size is influenced by the dilatation of mitral annulus, but also by abnormally deeper position of the leaflets due to the atypical position of papillary muscles in IHD. It changes also relations between closing and tethering forces of mitral valve. For this reason the coaptation area of mitral leaflets in IHD is decreased whereas the exposed area of leaflets increases. Evaluation of LV EF and regurgitation volume in our study represent assessment of consequences of functional changes of the mitral valve.In our study group we found in patients with ischemic mitral regurgitation flattening of the annulus  and increase of the mitral annulus area  together with the increase of tenting height. These findings correlated well with the data in the literature , 4-9and Among the patients with IHD two subgroups were differentiated according to the BL/A3 ratio-those with normal value (subgroup 1) and those with pathological value of this parameter (subgroup 2). All followed parameters with exception of the annulus height in both subgroups differed significantly from the healthy controls . As compAs for the functional consequences of the remodelling process, there was no significant difference between the subgroups in regurgitation volume at rest. In literature the correlation of severity of ischemic mitral regurgitation with dilatation of the LV but not with LV EF is described, but all authors admit the effect of LV remodelling too -14. HoweIn the future the evaluation of the stage of mitral valve remodelling may be useful in decision making about the valve surgery. It will be necessary to enlarge the study group, to assess the changes of RV in both subgroups during physical stress or to define some new parameters of mitral valve with good correlation to the regurgitant volume or treatment outcome. In this respect especially the evaluation of changes of subvalvular portion of the LV (chordae and papillary muscles) may help in decision making in mitral valve surgery .RT 3D echocardiography with MVQ program provides new parameters for assessment of the mitral valve in IHD. Using these parameters in patients with ischemic mitral regurgitation two stages of remodelling process of the LV  can be identified. The changes of the mitral valve in the first stage are caused mainly by LV dilatation, while the LV remodelling is responsible for the second stage. The severity of ischemic mitral regurgitation doesn’t simply correlate with the remodelling stage.The main limitation is relatively small study group. A larger number of study subjects  will refine the values of assessed parameters.Patients were examined only at rest, the potential changes of the regurgitation volume during physical stress was not assessed.Patients with mild (insignificant) ischemic mitral regurgitation were not included into the study, the range of regurgitant volume was relatively narrow.Due to the limited resolution of RT 3D TEE , the subvalvar apparatus of the mitral valve was not assessed.


Degenerative Mitral Valve Regurgitation (DMR) is a severe form of mitral valve disease for which the survival rate is poor if left untreated. Defining the optimal timing for surgery is challenging in spite of advances in diagnostic imaging. No sensitive measure of left ventricular dysfunction from CMR have yet been reported since the ejection fraction (EF) is usually preserved in DMR patients. However, to assess LV function, standard analysis of the Cine images only focuses on two time-points of the cardiac cycle (end-diastole and end-systole), discarding more than 80 % of the available data. Available cardiac analysis software now allows the analysis of the entire cardiac cycle in a reasonable time, leading therefore to a full LV volume curve over time. The aim of this study is to assess the sensitivity of two indices extracted from the LV volume curve: the peak ejection rate and the peak filling rate.http://segment.heiberg.se) by 3 trained analysts. Several indices were extracted from the full LV volume curve: the ejection fraction, the maximum and minimum amplitude of the flow (derivative of the volume with respect to time) also referred to as the peak ejection rate (during systole) |min(dV/dt)| and peak filling rate (during diastole) |max(dV/dt)|. Statistical 2-sample t-test was performed on these 3 indices to measure their sensitivity between the patient group and the control group.30 patients with clinically identified DMR disease  were recruited as well as 10 controls without known heart disease . Both groups were scanned on a Siemens Trio 3T MRI. In addition to the localizer, breath-hold CINE steady state free precession (SSFP) short axis sequences were acquired (slice thickness 8 mm with 20% gap). Global LV function was quantified blindly using Segment v1.9 R3556 (As shown in Figure This study confirms the physiological understanding of DMR. The LV empties rapidly preferably into the low impedance left atrium rather than the high pressure aorta. The ejection fraction being preserved, the LV relaxation must also be faster. In addition, this study shows that two indices currently not measured in CMR could be predictors for degenerative mitral valve regurgitation severity. With now available analysis software, the peak filling rate and the peak ejection rate could easily be measured in a routine clinical environment.


Chronic stimulation of the right ventricle with pacemaker is associated withventricular dyssynchrony and loss of contractility, even in subjects withoutprevious dysfunction. In these patients, there is a debate of which pacingsite is less associated with loss of ventricular function.To compare pacemaker-induced dyssynchrony among different pacing sites inright ventricular stimulation.Cross-sectional study of outpatients with right ventricle stimulation higherthan 80% and preserved left ventricular ejection fraction. Pacing leadposition  was assessed through chestX-rays. Every patient underwent echocardiogram to evaluate for dyssynchronyaccording to CARE-HF criteria: aortic pre-ejection time, interventriculardelay and septum/posterior wall delay on M mode.P=0.04) was found. No difference inQRS width among the positions could be noted. Intraventricular delay waslower in apical patients against mid septal (34.4±17.2vs. 54.3±19.1 P<0.05) - nodifference with those electrode on the free wall. No difference was noted inthe pre-aortic ejection time (P=0.9).Forty patients were included. Fifty-two percent had apical electrodeposition, 42% mid septum and 6% free wall. Mean QRS time 148.97±15.52milliseconds. A weak correlation between the mean QRS width and pre-aorticejection time (r=0.32; Apical pacing showed a lower interventricular conduction delay when comparedto medial septum site. Our findings suggest that apical pacing dyssynchronyis not ubiquitous, as previously thought, and that it should remain anoption for lead placement. However, data on long-term follow-up revealedpotentially harmful effects of chronic RV apical stimulation-5. The mechanisms involved in such effects include myofibrillarderangement and intraventricular and interventricular dyssynchrony, which may leadto loss of contractile function.The clinical consequence of such changes manifest through worsening of leftventricular ejection fraction (LVEF) and, in some cases, heart failure (HF)symptoms. Once LVEF starts to fall, it leads to deterioration in quality of life, toan increase in atrial fibrillation burden and to a tendency to a highermortality-11. The DAVID trial showed that RV pacing is poorly tolerated bypatients and may cause heart failure. The BLOCK-HF study showed that apical RV stimulationassociates with poor outcomes in patients with atrioventricular block and mild tomoderate HF.Apical pacing of the right ventricle (RV) has been the preferred site for pacemakerlead positioning.However, these studies were limited by a relatively small sample size andheterogeneity of both the selected population and of the methods used for monitoringfor LV function. As such, theideal pacing site for patients requiring RV-only pacing, if existent, remains amatter for debate.Recent studies suggest that non-apical pacing sites may reduce dyssynchrony andconsequently preserve LVEF in patientswith different RV pacing sites.In this study, LVEF and ventricular synchrony criteria were compared This was a cross-sectional study conducted at the pacemaker clinic of our institutionbetween June and November 2015. Patients aged 18 years or older were eligible ifthey had a RV pacing percentage above 80 and a LVEF above 50%. Exclusion criteriawere: atrial fibrillation (AF), New York Heart Association (NYHA) HF symptoms classIII our IV, moderate to severe valvular disease, epicardial electrode, biventricularpacemaker and HF hospitalization before pacemaker implant. All participants signedthe consent form. Study protocol was approved by local ethics committee.During the index visit, clinical data and current medication use were assessed.Clinical data collected were the reason for pacemaker implant, pacemaker programmode, RV pacing percentage, height, weight, resting heart rate (HR), NYHA HFfunctional class status and the presence of comorbidities such as hypertension,diabetes mellitus (DM), coronary artery disease (CAD), dyslipidemia and smokingstatus. Relevant medications assessed were diuretics, angiotensin enzyme converter(ACE) inhibitors, beta-blockers, calcium channel blockers and amiodarone., which was divided into 3 categories: RV apex,middle RV septum and RV free wall.All patients underwent 12-lead electrocardiography (ECG) examination, chest X-ray andtransthoracic echocardiography. ECG finding collected was largest QRS duration ofthe 12 leads. X-ray was used to assess RV lead position. All the analyses were performedafter, at least, three months from the date of implantation. The followingmeasurements of dyssynchrony and ventricular function were analyzed:Echocardiography was performed using Vivid E9 machine  and EchoPACsoftware . Single and two-dimensional images were obtained, as wereDoppler velocities and pulsed and continuous Doppler tissue imagingDriving delay between the interventricular septum and posterior wall in Mmode (cutoff ≥ 130 ms);Difference between pre-ejection times the for the left and rightventricles (interventricular delay) and the pulsed Doppler (cutoff≥ 40 ms);Measure the pre-ejection time LV (aortic) the pulsed Doppler (cutoff≥ 140 ms);Measurements of systolic and diastolic left ventricular volume and leftatrial volume in the biplane method;Left ventricular ejection fraction calculation using the Simpson biplanemethod;Ratio E/e ' by Doppler analysis of transmitral and pulsed Dopplerflow.https://www.medcalc.org;2008). Continuous variables were expressed as mean and standard deviation ormedian and interquartile range. Categorical variables were presented as absoluteand percentage number.The collected data were stored in Excel spreadsheets and analyzed using thesoftwares SPSS version 23.0  and MedCalc version 8.2  was used. The data were transformed intorank to analyze the differences between the obtained values and the standarderror. A A total of 40 patients were included for this analysis. Other two patients able toparticipate were excluded because they did not have a post-implant chest X-rayrecorded on our electronic chart. The majority (55%) of patients were male and theirmean age was 69 years . The mosRegarding echocardiographic evaluation, a mean LVEF of 63% was found. QRS measurementduring echocardiogram ranged from 77.96 to 109.4 ms, averaging 93.68 ms on lead DII.As for dyssynchrony parameters, the pre-aortic ejection time was slightly prolongedwith a mean of 141 ms, and the interventricular delay measurement was also extended,averaging 43 ms .P=0.044) ((P<0.001) , andno difference was found when compared to those with RVFW pacing (P=0.9)  in42% and RV free wall (RVFW) in the remaining 6%. No differences in QRS durationbetween the 3 groups could be noted  and 2. MP=0.044)  andhad P=0.044) . NYHA avP<0.001) . IntraveW pacing . Pre-aor (P=0.9) .In this study, left ventricular function and myocardial synchrony were compared amongdifferent right ventricular pacing sites. Our main finding was that RV apical pacingwas related to a lower degree of interventricular dyssynchrony when compared toseptal pacing . Further-23. It has been shown that apical pacing potentially leads toelectrical dyssynchrony, and that it changes the physiological apex-to-basecontraction to an alternate pattern. Theoretically, RVMS pacing could create a fasterdepolarization wavefront, since it is in close proximity with the normal conductionsystem. However, there are still no conclusive data to prove that these changestranslate into clinical outcomes.Our findings are in contrast with several previous studies that have suggested thatRVMS might provide better results when compared to RVA pacing. It should benoted, however, that those patients had a lower percentage of RV pacing whencompared to subjects in our study (50-60% vs. > 80%). A secondstudy has shown that septal pacing relates to improvement in 6-minute walktest, even though theapical position presented the same result. On the other hand, another study inelderly patients has shown that even though apical pacing was related with worseningof LVEF, this finding did not translate into heart failure symptoms. Recent review suggests thatunfavorable clinical outcomes are associated not only with the stimulation site, butalso with other pre-existing condition as CAD and systolic dysfunction where thecompensatory mechanisms of dyssynchrony has been exhausted.One of such studies showed that septal pacing not only did not correlate with LVEFworsening, but also had fewer atrial arrhythmias during the follow-upperiod. In this review, 14 randomized clinical trialanalyzed population ranging from 12 to 122 people, followup periods of 3 to 90months, different evaluation methods (echocardiography and nuclear imaging) anddifferent cutoff points for ventricular function as selection criteria; some of themhad LVEF as low as 27%. Inclusion of patients with AF and very broad definitionsamong the control and study groups by percentage of stimulation below and above 10%,respectively, contribute even more to the heterogeneity of the results, whoseclinical translation is still uncertain.The heterogeneity both of dyssynchrony criteria and of patient selection across thesestudies interferes with extrapolations and hampers pooled-data analysis. In fact, ametaanalysis on this subject has highlighted the diversity of study populations andinclusion criteria concluding that non-apical pacing sites were non-inferior toapical ones, with a statistical tendency to be betterNot evaluating RV outflow tract (RVOT) pacing is a potential limitation of our study.Even though there are several studies that have suggested this pacing site as a goodalternative to RVA, our institution does not place leads in that position routinely.Intraventricular flow was not evaluated either, which has been shown to markedlychange in RVA pacing. However, since the clinical meaning of such measurement is yetunknown, CARE-HF dyssynchrony criteria was chosen to be used in our study, hopefullyto allow study comparisons and pooled-data analysis.In this study, RVA pacing showed a lower interventricular conduction delay whencompared to RVMS pacing. Our findings suggest that RVA pacing dyssynchrony is notubiquitous as previously thought, and that it should remain an option for leadplacement.


Transpulmonary thermodilution is recommended in the treatment of critically ill patients presenting with complex shock. However, so far it has not been validated in hemodynamically stable patients with heart disease.n = 11), moderate-to-severe aortic valve stenosis , or dilated cardiomyopathy .We assessed the validity of cardiac output, global end-diastolic volume index (GEDVI), an established marker of preload thought to reflect the volume of all four heart chambers, global ejection fraction (GEF) and cardiac function index (CFI) as variables of cardiac function, and extravascular lung water index (EVLWI) as indicator of pulmonary edema in 29 patients undergoing elective left and right heart catheterization including left ventricular angiography with stable coronary heart disease and normal cardiac function . Left ventricular end-diastolic volume was normal in controls and AS, but significantly higher in DCM . GEDVI did not differentiate between patients with normal and patients with enlarged left ventricular end-diastolic volume . No difference in GEF and CFI was found between patients with normal and patients with reduced left ventricular ejection fraction. Patients with AS but not DCM had higher EVLWI than controls , while there was only a trend in pulmonary artery occlusion pressure .Cardiac output was similar in controls, AS, and DCM, with good correlation between transpulmonary thermodilution and pulmonary artery catheter using the Fick method (Cardiac output measurement by transpulmonary thermodilution is unaffected by differences in ventricular size and outflow obstruction. However, GEDVI did not identify markedly enlarged left ventricular end-diastolic volumes, and neither GEF nor CFI reflected the increased heart chamber volumes and markedly impaired left ventricular function in patients with DCM. In contrast, EVLWI is probably a sensitive marker of subclinical pulmonary edema particularly in patients with elevated left-ventricular-filling pressure irrespective of differences in left ventricular function. Transpulmonary thermodilution is recommended in the management of critically ill patients presenting with complex shock , 2, enabBased on these data, the use of transpulmonary thermodilution is generalized across a broad population of critically ill patients, even though the validity of parameters derived from transpulmonary thermodilution remains largely unknown in the setting of cardiac disease. Even though GEDVI is thought to reflect the volume of all four heart chambers , 8–10, iIn order to fill this important gap, the aim of the present study was to assess the validity of transpulmonary thermodilution-derived flow and volumetric parameters in hemodynamically stable cardiac patients with suspected but stable coronary heart disease (controls), aortic valve stenosis (AS), and dilated cardiomyopathy (DCM) during elective left and right heart catheterization including left ventricular angiography. Our hypothesis was that (I) transpulmonary thermodilution measurement of blood flow is unaffected by differences in ventricular size and outflow obstruction, (II) GEDVI permits the distinction between patients with normal and enlarged left ventricular volumes, (III) GEF and CFI are lower in patients with reduced left ventricular systolic function, and (IV) EVLWI is elevated in patients with left ventricular systolic and diastolic dysfunction.All protocols and procedures conformed to the Declaration of Helsinki and were approved by the local ethics committee (EK-1649). Informed consent for the study protocol and all procedures has been obtained from all patients prior to inclusion. The placement of a pulmonary artery catheter in addition to left heart catheterization has been declared as a study specific intervention in the control group and was clinically mandated in patients with AS and DCM.E/e′ < 15) /predicted body weight), and pulmonary vascular permeability index (PVPI = EVLW/PBV). In addition, left ventricular stroke work index was calculated using Ppao measured by the pulmonary artery catheter (LVSWI = SV/predicted body surface area × [sPlv − Ppao] × 0.0136). ITTV, PTV, ITBV, and PBV, since they are not reproduced in the PiCCO2 monitor’s digital output, were reverse-calculated from GEDVI and EVLWI as saved by the monitor. The mean of the three-to-five transpulmonary thermodilution measurements is reported for all parameters.After measurement of Pra, the tip of the Swan-Ganz catheter was carefully positioned at the intersection between the inferior vena cava and the right atrium using fluoroscopy. Transpulmonary thermodilution was then performed using a PiCCO thermodilution catheter inserted through the arterial access sheath and connected to a PiCCO2 monitor . Three boli of 20 ml of cold saline tempered to 5 °C were rapidly injected, and in case of an error of >10% in cardiac output between the three measurements, another two measurements were taken. Measurements resulting in a peak temperature difference during the thermodilution bolus of <0.15 °C were discarded. Data from the PiCCO2 monitor were recorded digitally through the system’s USB interface. Parameters directly derived from the thermodilution curve by the monitor’s software included cardiac output (Q), intrathoracic thermal volume (ITTV), and pulmonary thermal volume (PTV), as well as the estimation of intrathoracic blood volume (ITBV) and pulmonary blood volume (PBV). Parameters calculated therefrom included stroke volume (SV), global end-diastolic volume index (GEDVI = [ITTV – PTV]/predicted body surface area), global ejection fraction (GEF = SV/[GEDV/4]), cardiac function index (CFI = Q/GEDV × 10E/e′) was assessed using pulsed wave and tissue Doppler imaging in order to quantify left ventricular diastolic function. Moderate and severe diastolic dysfunction were considered present given an E/e′ ratio of 8–15 and >15, respectively [E/e′ ratio was omitted in patients with moderate-to-severe mitral regurgitation [2, respectively [−2 in females and males, respectively [Echocardiography examinations were performed transthoracically using a stationary device with tissue Doppler imaging capability . The left ventricular end-diastolic and end-systolic volume and LV-EF were measured using the biplane disk summation technique , in addiectively . Interprgitation . Right vgitation . Moderatectively . DCM wasectively , 18. Allp < 0.05 was considered statistically significant. For all statistical analysis, a fully scripted and reproducible data management pathway was created within the R environment for statistical computing, version 3.2.2 [Comparisons of measurements between the control, AS, and DCM groups were performed using independent measures one-way analysis of variance (ANOVA), with group membership as the main factor. Pairwise analysis was performed using pairwise two-sample tests with Benjamini and Hochberg’s correction algorithm  applied.on 3.2.2 . Graphicon 3.2.2 . Values −1. Echocardiography indicated severe AS in 4/10 (40%) patients in the AS group and moderate AS in the remaining six. Overall, the mean aortic valve area was 1.0 mm2, and the mean pressure gradient was 26 mmHg in the AS group . Three patients in the DCM group suffered from moderate-to-severe secondary mitral regurgitation, as opposed to none in the AS and control groups. Patients in the DCM group also presented with only slightly increased right ventricular longitudinal diameter as compared to the AS and control groups, with similar right ventricular transversal diameters. Right ventricular function and Pra were normal in all groups. No patients presented with moderate-to-severe tricuspid regurgitation. Pulmonary vascular resistance was normal in all groups.Twenty-nine patients were included, 10 with AS, 8 with DCM, and 11 in the control group. Patients with AS were older than those with DCM and controls . Bland–Altman analysis revealed a bias of 0.9 l min−1 with a precision 0.8 l min−1 (level of agreement −0.7 to 2.6 l min−1) and mean percentage error of 33%  or CFI  as measured by transpulmonary thermodilution. In contrast, LVSWI was significantly lower in DCM patients when compared to the other two groups . No difference was found in GEDVI between all three groups .Patients in the DCM group were well differentiated from the AS and control groups in left ventricular angiography by their larger LV-EDV , while no linear relationship was found between EVLWI and Ppao .All ten of the patients in the AS group presented with normal LV-EF but moderate-to-severe diastolic dysfunction. In the DCM group, all patients presented with significantly depressed LV-EF, but only 6 of 8 (75%) with moderate-to-severe diastolic dysfunction. As selected by the inclusion criteria, in the control group none of the patients presented with severe diastolic dysfunction, but in 5/11 45%) moderate diastolic dysfunction was present. Overall 5% moderaThe present study, using state-of-the art invasive reference hemodynamic measurements, demonstrates that (I) transpulmonary thermodilution measurement of blood flow is unaffected by differences in ventricular size and outflow obstruction. However, (II) GEDVI as measured by transpulmonary thermodilution does not differentiate between patients with a normal-sized left ventricle and those with a left ventricle enlarged by DCM. This finding may not contradict GEDVI’s role as a preload indicator, but it might require a revision of its understanding as the volume of the four heart chambers. Furthermore, in our hemodynamically stable patients, (III) both transpulmonary thermodilution-derived cardiac function parameters, GEF and CFI, failed to detect impaired LV-EF in DCM patients. In addition, we found that (IV) EVLWI is a sensitive marker for the detection of subclinical pulmonary edema in patients with impaired diastolic and systolic cardiac function.Blood flow measurements by thermodilution are a specialized case of the indicator dilution principle based on a slightly modified Stewart–Hamilton formula . The theIn analogy to flow measurements by transpulmonary indicator dilution, volumetric measurements have been developed using dye dilution. Some of these findings have later been translated to the use of a thermal indicator. Early findings suggest that the volume in-between the injection and detection sites minus the largest volume chamber in the series may describe the combined volume of all four heart chambers , 32, tem−1 in septic and 2.7 l min−1 in acute heart failure patients, whereas GEDVI was not different between groups (907 ml in sepsis and 995 ml in acute heart failure). In contrast, in our hemodynamically stable patients with no significant differences in cardiac output, stroke volume, and GEDVI, CFI and GEF did not reveal markedly depressed LV-EF of the DCM patients. However, calculating LVSWI—which takes into account besides stroke volume also the difference between mean Pa and Ppao—significant differences were found between the DCM group and the other two. Thus, our data suggest that CFI and GEF values are surrogate markers of global cardiac function but not LV-EF, hence cardiac contractility. In euvolemic hemodynamically stable patients monitored with a pulmonary artery catheter, calculation of LVSWI may be more suitable for the assessment of cardiac power, as Ppao values reflect myocardial systolic and diastolic function.The CFI has been conceived as a parameter reflecting cardiac performance independently of changes in intrathoracic pressure, myocardial compliance, and vascular tone . GEF is Due to thermodynamic as well as hemodynamic interactions within the pulmonary capillary network, the signal derived from transpulmonary thermodilution also contains information about extravascular lung water that can be extracted by referencing it with a concomitantly performed inert dye dilution . EVLWI iThe present study was designed to compare transpulmonary thermodilution measurements to left ventricular angiography and pulmonary artery catheterization in hemodynamically stable patients with cardiac disease. Our data only encompass one point in time, and the examinations were not repeated during the course of treatment. Thus, no conclusions can be made regarding the dynamic response of the examined parameters to interventions. Additionally, even though left ventricular angiography is the accepted gold standard used to determine ventricular end-systolic and end-diastolic volumes, there are several technical limitations. A similar disk summation algorithm  is appliCardiac output measurement by transpulmonary thermodilution is unaffected by outflow obstruction in aortic valve stenosis and large differences in left ventricular end-diastolic volume as present in dilated cardiomyopathy. However, in our study, GEDVI did not identify markedly enlarged left ventricular end-diastolic volumes in patients with dilated cardiomyopathy. In addition, neither GEF nor CFI reflected markedly reduced left ventricular ejection fraction in the same patient population. Thus, in hemodynamically stable cardiac patients, transpulmonary thermodilution has clear limitations and needs to be interpreted with caution. In contrast, EVLWI is probably a sensitive marker of subclinical pulmonary edema, particularly in patients with aortic valve stenosis presenting with elevated left ventricular filling pressure, irrespective of differences in left ventricular function.