Remodelling of the LV was indicated between P8 and P21 when LV mass and cardiomyocyte size increased with no accompanying change in LV wall thickness. Whereas Doppler imaging showed the expected switch from LV filling driven by atrial contraction to filling by LV relaxation during post-natal week 1, systolic function was retained at the same level from P1 to P42. EKV ultrasound imaging also revealed loss of systolic function after induction of myocardial infarction at P1 and regain of function associated with regeneration of the myocardium by P21. EKV ultrasound imaging thus offers a rapid and convenient method for routine non-invasive characterisation of the neonatal mouse heart.The small size and high heart rate of the neonatal mouse heart makes structural and functional characterisation particularly challenging. Here, we describe application of electrocardiogram-gated kilohertz visualisation (EKV) ultrasound imaging with high spatio-temporal resolution to non-invasively characterise the post-natal mouse heart during normal growth and regeneration after injury. The 2-D images of the left ventricle (LV) acquired across the cardiac cycle from post-natal day 1 (P1) to P42 revealed significant changes in LV mass from P8 that coincided with a switch from hyperplastic to hypertrophic growth and correlated with  FurtherMagnetic resonance imaging can provide high-resolution 3-D images of mouse hearts from as early as postnatal day 0 (P0) , and thiThe primary aim of the present study was therefore to test the potential for EKV ultrasound imaging to detect structural changes during hyperplastic and hypertrophic post-natal heart growth and to identify contemporaneous changes in systolic and diastolic function. EKV imaging was also applied for detection of cardiac regeneration after neonatal myocardial infarction.All experiments were approved by and performed in accordance with the University of Edinburgh Animal Welfare and Ethical Review Body and the UK Home Office.ad libitum.All animals were C57 BL/6 J mice bred in house from stock originally obtained from Harlan  and aged post-natal day 1 (P1) to P42. Males were used for the normal growth study and both males and females for the neonatal cardiac injury study. Mice were kept under a 12-h light/12-h dark cycle mimicking circadian rhythm. Temperature of the environment was maintained at 21 ± 2°C and humidity at 50 ± 10%. Animals had access to chow diet and water 2  at concentrations: 5%  and 4%–5% . Mice were placed in a supine position on a heated ultrasound table (40°C). Adapters were used to deliver anaesthesia throughout the procedure for adequate effective delivery of anaesthesia  in medical Oesthesia a, 1b. Thesthesia a, 1b andImage acquisition was performed on a VisualSonics Vevo® 770 ultrasound biomicroscope . The probes used were: RMV704 for pups aged P2, P4 and P8  and RMV707 B for animals aged P21 and P42 . Cardiac structure and function were assessed using standard parasternal long axis (PLAX) images of the left ventricle (LV) in B-mode and M-mode. Functional measurements of the heart were acquired using mid-ventricular pulse wave Doppler from an apical 4-chamber view of the heart with the Doppler sample volume placed within the LV cavity below the aortic and mitral valves and aligned with the aortic valve. From this view, the ratio of the blood velocities at E (early peak diastolic flow) to A (late peak diastolic flow) was used to determine diastolic function and myocardial performance index (MPI) for global ventricular function  Fig. S1. Using tRepresentative videos 1–4 of each imaging mode can be found online.Fresh heart samples were washed in saline  then fixed in 10% formalin (Merck) for 24 h and subsequently placed in 70% ethanol (Merck) for at least 24 h before embedding in paraffin (Merck). Paraffin-embedded samples were cut into sequential 4 µm thick sections on superfrost slides . Blood samples were obtained from neonatal mice after decapitation and plasma isolated through centrifugation for later analysis.Slides were deparaffinised and rehydrated. Histologic analysis was performed on haematoxylin  and eosin  stained sections. For immunofluorescent staining, antigen retrieval was carried out in boiling sodium citrate buffer . Non-specific staining was blocked with 10% normal goat serum  and stained with isolectin B4  followed by streptavidin coupled Alexa Fluor 488  and Cyanin3 coupled anti–α smooth muscle actin  to identify endothelial and mural cells, or IB4 (1/100) followed by streptavidin coupled Alexa Fluor 488 (1/200) and rhodamine-coupled wheat germ agglutinin  to identify cardiomyocyte membranes and measure cardiomyocyte cross-sectional area (CMCSA). To identify proliferative cardiomyocytes, cell membranes were permeabilised (0.2% triton x-100) and slides incubated in blocking solution of 20% normal goat serum and 5% bovine serum albumin (Merck) in tris buffer saline (Merck), and then stained with mouse anti-cardiac troponin T  and rabbit anti-Ki67  in blocking solution with 0.1% Tween (Merck) followed by goat anti-mouse Alexa Fluor 488  and goat anti-rabbit Alexa Fluor 555 . Nuclei were stained with 1/1000 4′,6 diamino-2-phenylindole .+ve nuclei within cTnT+ve cardiomyocytes was performed within each region and normalised to its area. For vascular density, each vessel was counted and its diameter measured within each area. The number of αSMA+ve vessels was counted within the whole left ventricle. Analysis was performed using Adobe Photoshop CS6 .Pictures were taken using a Zeiss Axiovert200 microscope or a Zeiss Axio Scan.Z1 slide scanner at magnification × 40 . For measurement of CMCSA, four fields of view within the outer myocardium were obtained because this is where the cardiomyocytes lay perpendicular to the short axis view. Ten CMCSA were measured in each field of view. For measurement of cardiomyocyte proliferation, vascular density and vessel diameter, five regions only containing myocardium were drawn around and their areas measured. Counting of the number of Ki67Myocardial infarction was induced by ligation of the left anterior descending (LAD) coronary artery in P1 mice as described by Cardiac troponin I (cTnI) levels were measured in plasma samples obtained at day 1 after MI as an indicator of initial injury using a high sensitivity kit  following manufacturer's instructions.t-test was used for comparison of two groups. Comparison between more than two groups used a one-way analysis of variance with post hoc Bonferroni multi-comparison test, as indicated in the text. Significance level was set to p < 0.05.Statistical analysis was performed using GraphPad Prism 5 software . Data are expressed as mean ± standard error of the mean. Student's unpaired As shown in ex vivo measurements during early life, cardiac growth from P2 to P42 was studied in vivo by ultrasound and compared with ex vivo metrics. As shown in p < 0.0001). Ex vivo heart wet weight tended to increase from P2 but was only increased significantly between P21 and P42 , correlated with the timing of increased ultrasound-derived LV mass. The density of proliferative cardiomyocytes decreased rapidly to practically non-detectable levels during this period  and diastole (LVEDA) were both relatively stable until P4 but increased significantly from P8 onward . It was, however, unchanged between all other timepoints. The switch from atrial contraction  to ventricular relaxation  in driving left ventricular filling during diastole that occurs during the first day of neonatal life (p < 0.05) and remained at >1 thereafter. E wave deceleration  point to classic hypertrophic growth.The initial hyperplastic phase is followed by a switch to hypertrophic growth, which was confirmed here by a significant decrease in the density of Ki67 positive cardiomyocytes and increased cross-sectional area between P8, P21 and P42 agreeing with previously published data . Non-invLV systolic function was maintained, despite the considerable maturational changes within the LV, during the entire period studied. In contrast, diastolic function, detected by mid-ventricular Doppler waveforms, changed dramatically between P2 and P8, moving from a foetal pattern of LV filling predominantly through atrial contraction (A wave > E wave), to an adult pattern of LV filling predominantly as a result of ventricular relaxation (A wave < E wave), consistent with previous observations .Cardiac regeneration after injury at P1 in the neonatal mice is a widely used model to identify regenerative mechanisms that might be applied in the adult . Non-invin vivo information on structural and contemporaneous functional maturation from as early as P2. This enabled non-invasive detection of cardiac maturation in post-natal and juvenile mice that correlated with in vitro observations, as well as providing a means to detect functional changes associated with cardiac injury and regeneration. EKV high-resolution ultrasound imaging thus offers a practical 2-D in vivo tool to study the impact of genetic or other modification on the processes of neonatal cardiac growth and regeneration after injury.In summary, using EKV ultrasound imaging in neonatal mice we were able to collect


Xenopus tropicalis with our microangiography technique, hemoglobin contrast subtraction angiography (HCSA). To demonstrate the gene-teratogen-physiology relationship, we modeled human cardiomyopathy in tadpoles. First we depleted the sarcomeric protein myosin heavy chain 6 (myh6) expression using morpholino oligos. Next, we exposed developing embryos to the teratogen ethanol and in both conditions showed varying degrees of cardiac dysfunction. Our results demonstrate that HCSA can distinguish biomechanical phenotypes in the context of gene dysfunction or teratogen. This approach can be used to screen numerous candidate CHD genes or suspected teratogens for their effect on cardiac function.Congenital heart disease (CHD) is a significant cause of mortality in infants and adults. Currently human genomic analysis has identified a number of candidate genes in these patients. These genes span diverse categories of gene function suggesting that despite the similarity in cardiac lesion, the underlying pathophysiology may be different. In fact, patients with similar CHDs can have drastically different outcomes, including a dramatic decrease in myocardial function. To test these human candidate genes for their impact on myocardial function, we need efficient animals models of disease. For this purpose, we paired  Congenital heart disease (CHD) occurs in ~8 out of 1,000 live births and effects 1.3 million newborns per year worldwide  using morpholino oligonucleotides (MO) and, in a separate set of experiments, by exposing them to the known teratogen ethanol (EtOH).We previously demonstrated that hemoglobin contrast subtraction angiography (HCSA) can exploit the wavelength-sensitive absorption of hemoglobin as a molecular-specific source of endogenous flow contrast and can be applied to Xenopus suggesting a well-conserved disease mechanism  in accordance with NIH guidelines. Female and male mature Xenopus tropicalis were obtained from National Xenopus Resource.In vitro fertilization and microinjections were done as previously described  at one cell stage. Controls were injected with only tracer dye Alexa488. The advantage of MOs is that “gene dosage” can be titrated based on amount of MO injected providing fine dosage control. We used a translational-blocking start site morpholino oligo (MO)  with ring illuminator. Image acquisition setup: Zoom 6.2/Gain: 0/Depth 14 bit/LED 4,000 Lumens. Fifty RAW images acquired with 0.2 s intervals. High Speed color movie obtained with Motion Xtra N4-IDT, Inc. N4 Camera. For cardiac functional analysis, we embedded Stage 44–45 (post fertilization day 3 at 28°C) tadpoles in low melt agarose and positioned ventral surface exposed to the imaging plane . First, The graphical user interface allows the user to browse through the acquired images and select the frames corresponding to the maximal end-systole and end-diastole .tEDA), the total ventricular end-systolic area (tESA), percent change in the total ventricular area (Δ%tA = 100*(tEDA-tESA)/tEDA), end-diastolic blood area (EDBA), end-systolic blood area (ESBA), the stroke area (SA = EDBA-ESBA), and ejection fraction (EF = 100*SA/EDBA). We also derived a “myocardial fraction” metric where we estimated the myocardial area and referred to that as the myocardial mass index (MMI). To derive MMI, we assumed that during peak systole, where the myocardium is at its maximal contraction, most of the blood is ejected minimizing this confounding volume. We then subtracted the end-systolic blood area from the total ventricular end-systolic area assuming that the remainder of the segmented area would be a rough estimate of the myocardial mass at maximal contraction.Based on hemoglobin pixel counts and the total ventricular area delineated by manual segmentation, we estimated the total ventricular end-diastolic area (Tadpole raised and positioned in 1% agar as described above. Using microinjector (Harvard Apparatus PLI-100 Pico-Injector Microinjection System) Brilliant Blue FCF (Sigma-Aldrich) dye injected to the cardinal vein. Movie obtained with Redlake/IDT Y4 Lite grayscale camera.p-value is lower than 0.05.For comparison we utilized the Mann-Whitney test (non-parametric and not paired) and used a scatter plot with the bar showing the median and 95% confidence interval. We also included before-after graph including standard error of the mean. All significant differences between groups indicated in the figure legends. Significance was determined when the tEDA) (%tA) was significantly reduced in both morphants suggesting myocardial dysfunction , which is a surrogate for blood area. In end-diastole, due to their overall smaller cardiac size, 2 ng morphants filled with less blood whereas 1 ng morphants, given their normal cardiac size, filled with a similar amount of blood when compared to the controls  , whereasfunction . We dericontrols . Importacontrols . Therefocontrols . Then weESBA, a surrogate for blood volume at the end of systole, was significantly higher than controls  are essential to identify abnormal heart structures and heart function  in accordance with NIH guidelines. Female and male mature Xenopus tropicalis were obtained from National Xenopus Resource.ED, SJ, MK, and MC designed the study. ED and SJ acquired and analyzed the data. ED wrote the first draft of the article. SJ, MK, and MC contributed to the interpretation of the results and the writing of the manuscript. All authors have approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In this paper, we present the simulation of 5 different heart failures with the help of the Cardiovascular Simulation Toolbox (CVST) proposed by O. Barnea et al. at Tel-Aviv University. This is a modified version of the CVST, proposed by G.Ortiz; here, we show that the pathological failures can be covered by this tool. We varied the value of the tool blocks, included the results of the hemodynamic parameters and the P-V loop curves for each disease and compared them to the medical data to prove the effectiveness of the simulation. Based on these changes, we achieved an effective simulation of the following heart failures in the CVST: Diastolic Heart Failure (DHF), Systolic Heart Failure (SHF), Right Ventricle Heart Failure (RVHF), Low Output Heart Failure (LOHF) and High Output Heart Failure (HOHF). Circuits not only allow us to develop complex electronic systems, they also help us in the simulation and modeling of physical systems. The cardiovascular system is one the many examples which can be represented through an electric equivalent system. To set some examples: the heart operates like a hydraulic pump whose blood pressure output behaves like a variable tension source; the heart beats produce sudden shifts in the internal pressure, which makes the tissue in our heart expand as a circuit would react during its transitory phase; veins can be represented electrically as a serial line with complex impedance. Due to these circumstances, the circulatory human system can be represented and simulated by an equivalent electric system.®R2015a using the Cardiovascular Simulation Toolbox (CVST) tool which was originally created by O. Barnea [In this paper, the human heart is simulated alongside some other heart failures. These simulations were implemented in MATLAB/SimulinkSimulations of the human body can be useful for developing medical equipment, since complex devices such as VAD (Ventricular Assistance Device) or pacemakers could be better developed by taking in account this extra layer of information in their design stages. Tools, such as the one presented in this paper, could benefit the design process by predicting and estimating the human body behavior after a device has been implanted.Depending of the output in the ventricles: “High-Output” and “Low-Output”.Depending of their location: “Left-Sided Systolic,” “Left-Sided Diastolic” and “Right-Sided Right-Ventricle.”Heart failures are caused by a dysfunction of the heart, which denies an adequate blood flow and correct transport of oxygen and nutrients necessary to the metabolism of different tissues . They caHeart failures could also be explained in terms of their causes and effects. Since it was necessary to observe the effect of different diseases in the cardiovascular system, the model of a healthy condition  was modiHeart: Contains auricles, ventricles and valves.Measurements: Designed to obtain and visualize different parameters in the system.Veins: Contains power transmission-based circuits.Oxygen Transport: Contains blocks which calculate the oxygen concentration and the gas exchange between blood and the tissues.Other: Groups the other components that don’t fit the description of the previous categories, such as resistances and flow valves .The CVST-2 tool is a series of programmed blocks which together describes the behavior of the different parts of the cardiovascular system, inside them are a series of electrical connections of different active and passive components, signals and mathematical operations. This tool is divided in five categories:The complete model sketch of the cardiovascular system in a “healthy condition” can be appreciated in The “healthy condition” refers to the simulation obtained of a healthy person, by using the CVST-2 tool. In addition, this simulation was previously validated by comparing its results with standard medical values of a healthy person [Moreover, this tool prints the curves or functions of the different hemodynamic parameters shown in High-Output Heart Failure (HOHF): It happens when the body needs high levels of blood, due to that the heart beat faster than usual . Causes Low-Output Heart Failure (LOHF): It happens due to cardiac disorders that damages the adequate bombing function, due to diastolic and systolic dysfunctions. LOHF can produce damage to the valves, arrhythmia, vasoconstrictions and cyanotic and cold extremities. The cardiac output is normal but it tends to decrease when the body undergoes physical exertion .Systolic Heart Failure (SHF): It is the heart’s incapacity of bombing blood at its normal speed. The ejection fraction in the left ventricle plays an important role when diagnosing it, due to its significant diminution. This is a lethal sickness hence, deaths are very spontaneous . Some phDiastolic Heart Failure (DHF): It relates with the difficulty of filling one or both ventricles, as also, the camera of the ventricle does not accept the appropriate level of normal blood pressure. In this case, the quantity of blood that is bombed every beat in the left ventricle is normal . Some riRight-Ventricle Heart Failure (RVHF): It is a consequence from the damage resulted in the left side of the heart, the increase of blood pressure transfers to the lungs, thus going back to the right side of the heart. The blood accumulates in the veins, each time that the right ventricle loses pumping power. Some effects of RVHF are: inflammations in ankles and legs .The simulated heart failures presented in this article are the following:The results of different simulations with input values in Moreover, the graphs of P-V loops will be shown for a further and more extensive comprehension of the simulated conditions. This type of graph helps us describe the behavior of the heart such as its effectiveness to pump blood and the internal efforts, among other characteristics. It should be noted, that depending of each simulation the curve in the graph shows displacements in the horizontal axis, which represents the amount of blood in the chamber. Also, the increase or decrease in height represents the rise or fall of pressure; which is also useful to describe health conditions in patients. For the first two graphs, although the curve stays centered between the volumes of 80 mL and 180 mL; we can see that each one has a different height, which means that the simulations predict conditions of high and low pressure.Given the results shown in the previous section, we analyzed the data and compared each simulation with the general characteristics, as well as some parameters from different authors, to evaluate if the simulated condition is representative of each heart failure.HOHF: As shown in LOHF: In SHF: In the P-V loop curve shown in DHF: In RVHF: In Most heart failures produce damages such as the thickening of heart walls, diminution of the heart chamber’s contraction, reduction of the elastic tissues walls and increments of the heart valve’s resistance. These effects are meaningful in the simulation of heart failures, since those are a starting point in determining the input parameters values.The modifications for the simulation model variables are shown in The CVST-2 tool, not only provides an adequate simulation of the hemodynamic parameters of a healthy person but it also allows the simulation of the heart conditions due to different failures. Due to the ease of these parameter’s manipulation, we achieved, through simulation, the general behavior of five different heart failures. With this, we can provide a more precise description of the heart’s behavior to study in vitro the effect of adding different devices or components in the cardiovascular system, such as artificial cardiac pacemaker or a ventricular assist device. It should be also noted that this tool provides help for students in the biological area, as they can see and manipulate a heart’s condition in a simulation, instead of having to look for records of previous patients. Which gives this tool a great importance in development of medical devices as well for academic purposes.


Dobutamine stress echocardiography (DSE) services have traditionally been medically led. In some UK institutions, DSE lists are led by physiologists with medical support. In our tertiary cardiac centre at New Cross Hospital (NCH), the DSE service was established by a consultant echocardiographer. Following intensive training and assessment, the Trust approved drug administration by named senior cardiac physiologists. We believe this is the first report of a cardiac physiologist-managed DSE service, including physiologist drug administration. We have assessed the feasibility, safety and validity of this physiologist-led DSE service.Retrospective analysis of 333 patients undergoing stress echocardiogram for inducible reversible ischaemia, myocardial viability and valvular heart disease over 6 months. Patients’ case notes review after 18–24 months.Overall, 92% of all cases (306) were performed by physiologists. In 300 studies, dobutamine was administered. The majority of the referrals were for coronary artery disease (CAD) assessment (281). In 235 cases, the study was uncomplicated. Sixty-seven patients developed dobutamine-related side effects. In 16 cases, complications led to early termination of the study. In two cases, urgent medical review was needed. Of the 281 studies for CAD assessment, 239 were negative for ischaemia, 28 were positive and 14 inconclusive. In 5 out of 28 cases with echocardiogram, evidence of inducible ischaemia, coronary angiography revealed unobstructed coronary arteries.This study demonstrates the safety and effectiveness of this practice and provides potential for the expansion of the physiologists’ role and physiologist-led DSE services in other hospitals. Stress echocardiography (SE) is a well-established, reliable and safe method for assessment of ischaemic heart disease . FurtherCardiac physiologists are non-state registered members of the multidisciplinary ‘Heart Team’ . Many arCurrently, cardiac physiologists are not regulated by statute and therefore cannot be considered for exemptions under the medicines legislation . To aid Supplementary Table 1, see section on Supplementary data 2).Protocols were developed for drugs routinely given by the cardiac physiologist during the stress test within the dose range under the direct written instruction from an appropriate prescriber and for additional drugs, which may be needed in response to changes in the patient’s clinical condition. The agreed drug administration protocols were endorsed by the clinical lead for the Cardiology Directorate under the auspices of the Cardiology Governance Committee . The proConsecutive patients who underwent elective outpatient DSE for the assessment of CAD, the evaluation of myocardial viability or the significance of aortic valve stenosis during the period of 18th August 2015 to 17th February 2016 were included in this service review. The patients were referred by cardiologists, other speciality physicians or chest pain nurse specialists. At the time of data collection for this study, the National Institute for Health and Care Excellence (NICE) guidelines recommended SE as a non-invasive functional imaging investigation for diagnosing myocardial ischaemia in people with a moderate pre-test likelihood that chest pain was caused by angina (30–60%) and an uncertain diagnosis .Patient demographics, relevant medical history, cardiac medication, stress echocardiogram report, other functional non-invasive tests findings, including cardiac MRI, CT, coronary angiogram or myocardial perfusion scintigraphy and invasive coronary angiogram data were reviewed using hospital electronic databases retrospectively.The following data were collected from the DSE studies and reports: reason for the study, dobutamine-related complications, baseline left ventricle (LV) systolic function and evidence of reversible inducible ischaemia in patients referred for CAD assessment.In accordance with UK guidance from the National Research and Ethics Service, this study was registered with our National Health Service (NHS) Trust as a service evaluation for which local institutional approval was sought and obtained. Additionally, it was confirmed that patient consent and ethical approval were not required.A cardiac physiologist-led SE service was started in August 2015 in New Cross Hospital (NCH). Currently, the service complies with the updated regulations of setting up a stress echo service  with thePLDSE utilises two dobutamine stress protocols, the full dobutamine protocol for assessment of myocardial ischaemia (protocol A) and a low-dose protocol for the assessment of myocardial viability/LV contractile reserve in aortic stenosis (protocol B). These protocols are in accordance with the BSE procedure guidelines for the clinical application of SE. Atropine, when required to augment the heart rate response, is also helpful in reducing the likelihood of vagal reactions .Figure 1Imaging was performed using a standard protocol for rest and peak stress acquisition visualising the 16 American Heart Association LV myocardial segments . For aorIn addition, all the protocols allowed the use of contrast for LV opacification when imaging windows were suboptimal. Contrast helped to improve endocardial delineation when two or more continuous myocardial segments were not well visualised on standard harmonic imaging. Following the European Society of Cardiology recommendations, contrast was used to enhance detection of regional wall-motion abnormalities and could also be used to assess myocardial perfusion . In thisAbsolute contraindications for DSE include previous hypersensitivity/allergy to dobutamine, recent myocardial infarction, ongoing unstable angina, acute heart failure, LV thrombus, recent ventricular arrhythmias, uncontrolled supraventricular arrhythmias, high grade atrioventricular block, severe dynamic or fixed LV outflow tract obstruction, severe uncontrolled hypertension and active endocarditis or myopericarditis. A poor acoustic window makes any form of SE unfeasible to perform. However, this limitation of SE today should not exceed 5% of all referrals. With new transducer technology using harmonic imaging and the use of intravenous contrast agents for LV opacification, optimal endocardial border delineation is achievable in the vast majority of patients and should be available in every stress echocardiogram laboratory . AtropinBefore each study was undertaken, the patient was sent an appointment letter and a consent information leaflet explaining the procedure together with the potential risks and benefits. Consent was confirmed on the day of the test. The following risks were quoted: 1 in 2000 risk of life-threatening events including ventricular arrhythmias and myocardial infarction and 1 in 10,000 risk of death or allergic potentially life-threatening reaction to drugs and contrast. These rates derive from literature and echocardiography department experience .Visual assessment of endocardial excursion and wall thickening was used for analysis of stress echocardiograms. Function in each segment was graded at rest and with stress as normal, hyperdynamic, hypokinetic, akinetic, dyskinetic or aneurysmal. Images from low or intermediate stages of dobutamine infusion were compared with peak stress images to maximise the sensitivity for the detection of coronary disease . A normaMajor arrhythmic events were defined as life-threatening rhythmic complications  or complications that required hospital admission. Arrhythmic events which led to early termination of the test, but required no other action were not considered major events.Minor arrhythmic events were defined as the development of uniform or multiform premature ventricular beats, ventricular bigeminy or couplets, short episodes of self-terminating supraventricular tachycardia and non-sustained ventricular tachycardia.Severe hypotension was defined by an arterial pressure drop  ≥ 40 mmHg with symptoms.Non-cardiac side effects were defined as the development of headache, dizziness, nausea and vomiting.During the 6-month audit period, 333 patients attended the echocardiography department for an elective stress echocardiogram. Of these, 306 (91.9%) SEs were physiologist-led studies. In two cases, the study was not performed, one due to very limited apical echo windows and one because of the patient’s severe anxiety. As this article is about the effectiveness and safety of the PLDSE and because the overwhelming majority of the studies were performed by physiologists, the following data analysis and discussion focuses on the outcomes of the tests performed by the cardiac physiologist team.Dobutamine was the commonly used stressor in our hospital. Three hundred (98%) out of 306 tests were pharmacological stress echocardiograms. The majority of DSE requests were to investigate possible reversible inducible ischaemia due to CAD  in accordance with the NICE guidelines . The remThe average age of the patients enrolled in this service review was 60.8 years. The youngest patient was a 26-year-old woman and the oldest a 90-year-old man both referred for chest pain assessment. The majority of patients were male (57%). Sixty-five percent of the total were referred by cardiology consultants or registrars from the outpatient clinic 15% of the referrals came from chest pain specialist nurses from the rapid access angina clinic or following assessment of in-patients. In addition, a number of DSE requests came from the driver and vehicle licensing agency for assessment of the eligibility of the patient to hold a driver’s licence. A small number of referrals were from other clinicians as part of assessment before non-cardiac operations or organ transplant.Overall, 281 of the 300 DSEs were performed for the assessment of ischaemic heart disease or to rule out CAD. Of these, 239 studies were negative for reversible inducible ischaemia, 28 were positive and 14 inconclusive.Regarding the inconclusive tests, in two cases, the targeted heart rate for the individual patient was not achieved despite the maximum dose of dobutamine and the administration of atropine. Significant side effects related to dobutamine administration were observed in 11 cases, forcing early termination of the test. Only one patient’s DSE was cancelled due to very poor apical echocardiography images.Contrast for LV opacification was used in 267 DSEs (89%).Of the 28 patients who had a positive DSE for reversible inducible ischaemia, 26 underwent coronary angiography and 2 were treated medically for stable angina without any further invasive investigations. In 21 cases (80.8%), the angiogram confirmed the DSE findings with significant CAD in one, two or three vessels. In five cases (19.2%), the diagnostic angiogram revealed unobstructed epicardial coronary arteries.Eight of 239 patients (3.3%) with negative DSE for ischaemia, subsequently had a coronary angiogram, either because they were admitted with an acute coronary syndrome or presented with recurrent anginal symptoms, or an angiogram was performed before a valve operation. All eight showed severe coronary disease .Table 2The clear majority (231) of the patients who had a negative DSE for ischaemia were discharged back to their general practitioner (GP). In this group, none were referred for recurrent episodes of chest pain by their GP, nor attended the emergency department for typical cardiac chest pain. This group did not have any further invasive or non-invasive testing for the detection of CAD within the time period of 18–24 months after the performed DSE, as per the information derived by the clinical web portal of NCH. We cannot rule out attendances at other institutions.Overall, 235 DSE studies (78.6%) were uncomplicated with no recorded dobutamine or atropine side effects.A major arrhythmic event was observed in one patient (0.3%), a 39-year-old woman with no previous history of cardiac disease and limited mobility, referred for CAD assessment. She developed a severe vasovagal episode with profound bradycardia and junctional rhythm, which resolved with the administration of 600 µg of atropine. Her LV function was normal and the DSE was negative.Minor arrhythmic events, resulted in the early termination of DSE in five cases (1.7%). These dobutamine-induced arrhythmic complications included isolated ventricular ectopics, bigeminy, couplets, triplets or short runs of non-sustained ventricular tachycardia. These arrhythmias occurred in male patients with known ischaemic heart disease and in two cases severely impaired LV systolic function. In all cases, the arrhythmia terminated after the discontinuation of dobutamine infusion.Minor rhythmic complications were registered in 14.1% (42 patients). All minor arrhythmic complications were well tolerated.Dobutamine infusion provoked severe systolic blood pressure fall in 5 (1.7%) subjects, and this was usually at the higher dose of 40 µg/kg/min. One patient suffered from a severe vasovagal episode and significant blood pressure drop during cannulation.Non-cardiac side effects appeared in 7 (2.4%) subjects. In two of these episodes, the intensity of the symptoms prompted early termination of the dobutamine administration and target heart rate was not achieved, and thus the study was inconclusive.Two studies were terminated early because the patient became severely symptomatic with severe chest pain or shortness of breath, respectively. In one case, the patient developed dobutamine-induced hyperdynamic LV response, which led to LV systolic cavity obliteration and a large increase in LV outflow track gradient accompanied by a significant blood pressure drop.In two events, it was necessary for the cardiology registrar to intervene and support the physiologist team. Both of these incidences were due to severe and prolonged vasovagal episodes, which required fluid resuscitation.In this review, no deaths, cardiac rupture or myocardial infarction were registered.SE services have traditionally been led by cardiologists with physiologist and nurse support, particularly in the setting of dobutamine stress.To our knowledge, this is the first data analysis of the effectiveness and safety of an independent cardiac physiologist-managed DSE service, including the administration of intravenous drugs and the performance and reporting of the stress echo study. In this context, the cardiac physiologist has the responsibility not only to perform and interpret the findings of the study but also to deal with any complication that may arise in a timely, safe and effective manner. The development of highly trained and specialised cardiac physiologists and the emergence of the new consultant echocardiographer role , accommoThis paper is a service review, which focused on the unique and innovative UK-based cardiac physiologist-managed DSE service, including administration of intravenous medication as well as reporting the study. The agreement between PLDSE and invasive coronary angiography as a gold standard of accuracy was not assessed, so the precise diagnostic accuracy of the PLDSE could not be evaluated especially for the negative DSE studies (specificity).In addition, this is a retrospective analysis and event data were obtained from the clinical web portal of the Trust, so we do not have any data regarding cardiac events, which might have occurred in our patients who did not present to this Trust.The coronary angiographic cut-off for luminal diameter stenosis at which wall-thickening abnormalities occur is 58% for DSE . The repOur practice involves discussion and reporting of challenging cases at both the weekly echo multidisciplinary team (MDT) meeting and at the cardiothoracic MDT meeting. Feedback is also given by the intervention specialists for discrepancies noted between coronary angiogram and SE data. This is part of the ongoing learning and improving of service quality standards.In the interest of service quality, all the false-positive and false-negative cases in this study were discussed, and the images reviewed at a dedicated discrepancy MDT meeting. From the eight false-negative cases, minor amendments have been agreed in two reports regarding the assessment and grade of LV function on the baseline images, which were suboptimal despite using contrast and led to differences in opinion. It was confirmed that there was no evidence of reversible ischaemia. On one scan, following retrospective reassessment, evidence of reversible ischaemia was present.Regarding the five false-positive cases, after thorough review, the report changed in three cases to negative for inducible ischaemia. These three cases had been reported with inducible ischaemia localised at the basal inferior and basal infero-septal segments, which can be difficult areas to assess .As per the above-mentioned limitations of the study, we cannot estimate accurately the specificity of the PLDSE service. However, our results have demonstrated that the PLDSE service in our hospital has good predictive value for future cardiac events and, a normal wall-motion response to dobutamine stress was associated with a low incidence of cardiac events.Safety and tolerability of the DSE has been investigated in numerous studies , 27. DSEIn our study, no death, myocardial infarction, ventricular fibrillation or high conduction disturbances were observed. Almost all the incidences of dobutamine adverse effects, apart from two cases, were managed successfully by the physiologist team without the intervention of a physician.The current era of cost containment makes it challenging to dedicate physician time solely to the supervision of a time-consuming test such as DSE. In our hospital, the majority of DSE lists are led by physiologists. The innovative practice of independent cardiac physiologist-managed DSE services, without the support of a cardiologist or cardiac nurse for the administration of dobutamine/atropine, appears to be feasible, effective and safe. If this approach were to be adopted by other institutions in the UK, there is significant potential for physiologist-led SE services to improve access to and reduce waiting time for this highly effective diagnostic tool, whilst freeing up specialist medical and nursing staff for other duties. Cardiac physiologists involved in the service are now working towards obtaining the new formal BSE accreditation qualification in SE, which involves sitting an examination, collecting a log book of stress echo cases and by attending a practical exam assessment.The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.


Right ventricular function is a crucial factor of the prognosis of systemiclupus erythematosus (SLE).To evaluate the right ventricular function in SLE patients with differentdegrees of pulmonary hypertension (PH) by strain and strain rateimaging.A total of 102 SLE patients and 30 healthy volunteers were studied betweenOctober 2015 and May 2016. Patients were divided into three groups accordingto pulmonary artery systolic pressure (PASP) estimated by echocardiography:group control (A); PASP ≤ 30 mmHg ; PASP 30-50 mmHg; and PASP ≥ 50 mmHg . Longitudinal peak systolic strain (ε) andstrain rate (SR), including systolic strain rate (SRs), early diastolicstrain rate (SRe) and late diastolic strain rate (SRa) were measured in thebasal, middle and apical segments of the right ventricular free wall inparticipants by two-dimensional speckle tracking echocardiography (2D-STE)from the apical four-chamber view. A p < 0.05 was set for statisticalsignificance.The parameters of ε, SRs, SRe, and SRa were significantly decreased ingroups C and D compared with groups A and B. The ε of each segmentswas significantly lower in group D than in group C, while there were nodifferences in SRs, SRe and SRa between groups C and D.Strain and strain rate imaging could early detect the right ventriculardysfunction in SLE patients with PH, and provide important value forclinical therapy and prognosis of these patients. Moreover, right ventricular (RV) function is a crucial factorfor the prognosis of SLE patients.5 However, assessment of the rightventricle is limited due to its thin wall and complex anatomy - a triangular shapefrom the lateral view, and a crescent shape from section view.6 It has been documented thattwo-dimensional speckle tracking echocardiography (2D-STE) derived strain and strainrate imaging, a novel technique with less dependence on the angle andintra/inter-observer variability, could reliably and qualitatively detect earlysubclinical RV dysfunction.9 In this study, strain refers inparticular to the longitudinal peak systolic strain (ε), and represents thedegree of myocardial deformation. Strain rate (SR) is the shortening velocity of themyocardium, i.e., it represents the change in deformation overtime.10 SR includessystolic SR (SRs), early diastolic SR (SRe) and late diastolic strain rate (SRa),which reflect cardiac contraction during systole and diastole,respectively.11Although cardiac magnetic resonance and radionuclide angiography are considered goldstandards for the assessment of RV systolic function, echocardiography is stillwidely used for its simplicity, low price, and non-invasiveness.In this study, we aimed to assess the RV function through strain and SR by 2D-STE inSLE patients with PH estimated by echocardiography.12 Exclusioncriteria included left ventricular heart failure, congenital heart diseases,coronary heart disease, cardiomyopathy and valvular heart disease, pericardialeffusion, use of cardiotoxic drugs, history of hypertension, infectiousmyocarditis and pulmonary obstructive diseases. Eight patients with poor-qualityechocardiographic imaging and ten patients unwilling to participate in the studywere excluded.A total of 102 SLE patients  and 30 age-matched healthy volunteers as control group(Group A)  wereeligible to participate in this study. The study was conducted between October2015 and May 2016 in our hospital. The eligibility criteria of SLE diagnosis metthe 2012 Systemic Lupus International Collaborating Clinics (SLICC) standardcriteria.The selected patients were divided into three groups according to the PASPestimated by echocardiography: Group B included 37 patients with PASP ≤30 mmHg, which was considered as a non-PH group ; Group Cincluded 34 patients with 30 < PASP < 50 mmHg, considered as mild PHgroup, ; and Group D included 31 patients with PASP≥ 50 mmHg, which was considered as moderate to severe PH group .All subjects gave their written informed consent after receiving a detailedexplanation of the study protocol. The design proposal, methods of datacollection, and analysis of this study were approved by the ethics committee ofthe hospital.13 During ECG recording at astable frame rate in the left lateral position, the RV end-diastolic diameter(RVED) was obtained in the middle third of RV inflow, approximately halfwaybetween the maximal basal diameter and the apex, at the level of papillarymuscles at end-diastole in the RV-focused apical four-chamber view with leftventricle (LV) apex at the center of the scanning sector; the RV anterior wallthickness (RVAW) was obtained below the tricuspid annulus, at a distanceapproximating the length of the anterior tricuspid leaflet in its fully openposition and parallel to the RV free wall as seen from a subcostal four-chamberview. Both parameters were measured by a conventional, two-dimensional grayscaleechocardiography.13Tricuspid annulus plane systolic excursion (TAPSE) and peak systolic velocity oftricuspid annulus (S wave) were measured through the lateral portion of thetricuspid annulus by M-mode echocardiography and pulsed-wave tissue Dopplerimaging (TDI) in the apical four-chamber view, respectively. RV fractional areachange (RV FAC) was measured and calculated in the RV-focused apex four-chamberview: RV FAC (%) = 100 × (end-diastolic area [EDA] - end-systolic area[ESA]) / EDA.13Three-dimensional echocardiographic RV ejection fraction (3D RV EF) was alsomeasured: 3D RV EF (%) = 100 × (end-diastolic volume [EDV] - end-systolicvolume [ESV]) / EDV.13 Leftventricular ejection fraction (LVEF) was measured by Simpson’s biplane method.PASP was estimated according to the simplified Bernoulli equation: PASP =4×V2 (V = peak velocity of tricuspid regurgitation) +right atrial pressure (RAP). RAP was estimated through echocardiography based onthe diameter and respiratory variation in diameter of the inferior vena cava(IVC). A diameter of IVC < 2.1 cm that collapses > 50% with a sniffsuggests there is a normal RA pressure of 3 mmHg; while an IVC diameter > 2.1cm that collapses < 50% with a sniff or < 20% on quiet inspirationsuggests a high RAP of 15 mmHg; if the IVC diameter and collapse do not fit thisparadigm, an intermediate value of 8 mmHg would be used.14Two-dimensional echocardiographic examinations were carried out with a GE VingmedVivid 7  scanner equipped with a 1.7-3.4MHz transducer (M3S probe). After a 15-minute rest in the supine position in aquiet room at 23°C, blood pressure (BP) and heart rate (HR) of all patients weremeasured three times and the mean values were calculated. An electrocardiogram(ECG) was also recorded simultaneously. The measurements and calculated formulasof the parameters in our study followed the 2015 American Society ofEchocardiography and the European Association of Cardiovascular Imaging(ASE-EACVI) recommendations for chamber quantification.All images were digitally recorded in hard disks on offline analysis . Two-dimensional dynamic images were recordedfor the subsequent analyses. A frame rate of 40-80 frames/s acquisition wasused. All 2D-STE data were measured by averaging data of three heartbeats. Weselected the most stable cardiac cycle for generation of the strain curve. Aftermanually tracing the RV endocardium on apical four-chamber view, a region ofinterest (ROI) divided into six segments was automatically generated. Only RVfree wall segmental strain was analyzed. Using a single frame from end-systole,the RV free wall segments were manually mapped by marking the endocardial borderand the width of the myocardium. The parameters of ε and SRs, SRe and SRawere measured in RV free wall for basal, middle and apical segments,respectively, from the apical four-chamber view.The data were analyzed with SPSS 17.0 for Windows .Unpaired Student’s T-test was performed for continuous variables, which were allnormally distributed. Numeric variables are presented as the mean ±standard deviation (SD). One-way analysis of variance (ANOVA) was performed totest for statistically significant differences among the four groups. Continuousdata were compared between individual groups using the Student-Newman-Keulspost-test to test for statistically significant differences. All statisticaltests were two-sided, and p < 0.05 was set for statistical significance.Between the four groups, there were no significant differences in age, sex, bodymass index (BMI), body surface area (BSA), systolic blood pressure (SBP), anddiastolic blood pressure (DBP). Nevertheless, the HR in group D wassignificantly higher than that in the other three groups Seen in .There were no statistical differences in LVEF between the four groups. The RVAWand RVED were significantly higher in group D than in the other three groups,while TAPSE, RV FAC, pulsed Doppler S wave, and RV 3D EF were all significantlydecreased in group D compared with the other groups. However, there were nosignificant differences in RVAW, RVED, TAPSE, RV FAC, pulsed Doppler S wave, andRV 3D EF between groups A, B and C Seen in .The average of the longitudinal strain and SR of each segment in the basal,middle, and apical regions of the RV free wall was calculated in each groupSeen in .We found that there were no significant differences in all the parameters betweengroups A and B. On the other hand, in groups C and D, ε, SRs, SRe and SRaof each segment were significantly decreased compared with groups A and B. Theparameter ε of each segment in group D was also significantly lower thanthat in group C, although there were no significant differences in SRs, SRe andSRa of each segment between groups C and D.15 and that 2D-STE-derived strain and strain rate imagingcould precisely reflect deformation of RV myocardium, and detect the subclinical RVdysfunction.16 Thereby,evaluation of RV function in SLE patients with PH is important for establishingtreatment strategy, prevent clinical RV dysfunction and RV failure, and increase thesurvival rate of SLE patients with PH. To our knowledge, this has not been studiedbefore.It has been previously demonstrated that RV function is a decisive factor for theseverity and prognosis of SLE patients with PH,20 It also indicatesthat the degree of deformation of group D was decreased.In the present study, we found that there were no significant differences in age,sex, BMI, BSA, SBP, and DBP between the four groups. Nevertheless, the HR in group Dwas significantly higher than that in the other three groups. It has been reportedthat HR could affect ε, and the increased HR was related to reduced ε,which represents the degree of deformation.21 PH is acommon and devastating complication of SLE characterized by progressively increasedpulmonary vascular resistance (PVR) and PASP.22 Its mechanism is very complex and closely related toinflammation and the immune system.24The function of the RV is to maintain the normal blood flow of pulmonary circulation,which mainly depends on three factors: preload, contraction, andafterload.25 As PASP further increases, the impaired RV myocardiumundergoes hypoxia, which causes enlarged RV volume, tricuspid valve insufficiency,and increased RV preload. This progresses to increased right atrial diameter andexacerbated myocardial impairment, leading to RV remodeling and decompensation,reduced RV contraction, and finally clinical RV dysfunction.26 Based on conventional data, group D experienced clinical RVdysfunction. Decreased TAPSE, RV FAC and pulsed Doppler S wave also implied a badprognosis, and decreased RV 3D EF even triggered the RV failure of patients in groupD, while the RV function in group C was still normal.In this study, we found that RVAW and RVED were significantly higher in group D thanthose in the other three groups, while TAPSE, RV FAC, pulsed Doppler S wave, and RV3D EF were all significantly decreased in group D compared with the other groups.However, there were no significant differences in RVAW, RVED, TAPSE, RV FAC, pulsedDoppler S wave, and RV 3D EF between groups A, B and C. It demonstrates that thestructure of the RV was remodeled in group D, and the RV myocardial systolicfunction was also impaired. We argue that long-standing increases in PASP in SLEpatients with PH cause increased RV afterload, decreased pulmonary vascularcompliance, and compensatory increases in RV contractility. Structurally, theseresults in expansion of the right ventricle and increased RV wall thickness formaintenance of RV function.27 Thismeans that the degrees of RV deformation in groups C and D were significantly lowercompared with groups A and B, and significantly lower in group D than in group C.This implies that the RV function of both groups C and D was impaired, and this wasmore severe in group D. This is in accordance with the findings of Pirat etal.,28 The discrepancy ofε and SR between groups C and D in this study might be related to thesignificant differences in HR and PASP in these groups. While SR has been shown tobe independent of load, HR and other factors, an increased HR and altered loadchanges have been associated with reduced ε.20 Theimpaired RV function of group C (mild PH group) was detected early by 2D-STE-derivedstrain and SR imaging compared with the conventional echocardiography.In this prospective study, based on the 2D-STE data, we found that ε, SRs, SReand SRa of each segment were significantly decreased in groups C and D compared withgroups A and B, while there were no significant differences in these parametersbetween groups A and B. The parameter ε of each segment in group D was alsosignificantly lower than that in group C, although there were no significantdifferences in SRs, SRe and SRa of each segment between groups C and D. As mentionedbefore, ε represents the degree of deformation, and SR represents ventricularcontractility.There were several limitations of this study. First, PH was not determined viaright heart catheterization, but estimated by echocardiography. Second, RV wasnot assessed by cardiac magnetic resonance for the sake of comparison. However,these might not be a limitation of this study, because it aimed to evaluate andcompare the RV function of SLE patients with different degrees of PH estimatedby 2D-STE-derived strain and SR imaging. Third, clinical data of SLE patients,such as antiphospholipid antibodies were not collected. Also, estimation of PHby 2D-STE may be influenced by factors, such as patient’s breathing pattern.Finally, some participants such as obese patients may not be able to use thismethod, because it requires high-resolution image quality.In conclusion, 2D-STE-derived strain and SR imaging could early detect the RVdysfunction in SLE patients with PH, especially in those with mild PH. This has animportant value in guiding early therapy in clinical settings, improving theprognosis, and increasing the quality of life of SLE patients with PH.


Routine ambulatory echocardiographic estimates of left ventricular (LV) filling pressures are not cost-effective and are occasionally fraught with anatomic, physiologic as well as logistical limitations. The use of implantable hemodynamic devices such as CardioMEMS Heart Failure (HF) System has been shown to reduce HF-related readmission rates by remote monitoring of LV filling pressures. Little is known about the correlation between CardioMEMS and echocardiography-derived estimates of central hemodynamics.  We performed a prospective, single-center study enrolling seventeen participants with New York Heart Association functional class II-III HF and preimplanted CardioMEMS sensor. Simultaneous CardioMEMS readings and a limited echocardiogram were performed at individual clinic visits. Estimated left atrial pressure (LAP) by echocardiogram was calculated by the Nagueh formula. Linear regression was used as a measure of agreement. Variability between methods was evaluated by Bland–Altman analysis. r2=0.798, p ≤ 0.001).  Mean age was 74 ± 9 years; 59% (10/17) were males. LV systolic dysfunction was present in 76% (13/17) of subjects. Mean PAdP was 18 ± 4 mmHg and 19 ± 5 mmHg for CardioMEMS and echocardiographic-derived estimates, respectively, with a significant correlation between both methods ( Our study illustrates a direct linear correlation between PAdP measured by CardioMEMS and simultaneous measurement of LV filling pressures derived by echocardiography. Congestive heart failure (CHF) impacts more than six million Americans. It is the admission diagnosis for more than one million hospitalizations annually and also accounts for the highest readmission rates , 2. The E/e' or Nagueh formula may not be the best method to calculate the LAP or pulmonary capillary wedge pressure (PCWP). In such instances, other diastology parameters such as isovolumetric relaxation time (IVRT) or IVRT/TE-e' ratio are utilized to measure LAP. Furthermore, serial ambulatory evaluations by echocardiography are not only impractical but are also not cost-effective. Pressure-guided therapy is a novel strategy in the management of CHF which allows clinicians to proactively manage patients before they decompensate and require hospitalization. The CardioMEMS Heart Failure (HF) System is the only FDA approved implantable hemodynamic device, and provides real-time pulmonary artery (PA) hemodynamic data. Earlier investigations have reported a correlation between the standard PA-catheter measurements and echocardiography-derived estimates of pulmonary artery systolic pressure (PAsP) with CardioMEMS data [Increase in left atrial pressure (LAP) occurs earlier prior to any symptoms in the hemodynamic cascade of events that eventually leads to heart failure exacerbation . EchocarEMS data . We aimeWe prospectively enrolled seventeen patients with a history of CHF and preimplanted CardioMEMS HF device. Patients with presence of mitral prosthesis, severe mitral annular calcification, and permanent atrial fibrillation were excluded. Simultaneous CardioMEMS readings and a limited echocardiogram were performed at individual clinic visits to evaluate the agreement between PAdP and PAsP via CardioMEMS and echocardiography-derived estimates of LAP. The study was approved by the local institutional review board. All subjects provided an informed consent.e' and lateral e' annulus was pulsed from an apical four chamber view. A sniff test was also performed at the time of evaluating the inferior vena cava (IVC) for estimation of right atrial pressure (RAP) [VTR) as follows: PAsP = 4(VTR)2 + RAP. Mitral inflow velocity (E) and septal and lateral annular (e') velocities were averaged to calculate the E/e' ratio. Estimated LAP was then calculated by taking the ratio of E/e' and applying the Nagueh formula (LAP = 1.24 × (E/e') + 1.9) [Subjects were brought in for a routine clinic visit. After initial clinical assessment for volume status, a limited echocardiogram was performed by one technician using a Philips Sonos 5500 with a 3.2 MHz transducer , and three CardioMEMS readings were obtained and averaged. The limited echocardiogram included a parasternal long axis, right ventricular inflow and outflow, apical four chambers, and subcostal views for the inferior vena cava. All the four valves were pulsed to evaluate for stenotic and regurgitant lesions. Mitral inflow velocities were obtained from an apical four chamber view using the pulse wave Doppler. The sample volume was placed 1–3 mm between the mitral leaflet tips during diastole. The inflow velocities were measured at end-expiration with a sweep speed of 100 m/s. The tissue Doppler at the medial re (RAP) . PAsP wa) + 1.9) . Right hN (%) for categorical variables; continuous variables are presented as mean ± SD. Linear regression analysis was used for the comparison of PA pressures obtained with CardioMEMS and echocardiographic-derived measurements. Variability between the methods was expressed relative to the average PA pressures plus 2 SDs by Bland–Altman analysis. Significance was determined as a p value < 0.05.All statistical analyses were performed using IBM SPSS, version 21.0. Summary statistics are presented as p=0.015) with no significant difference between estimated PAsP readings . Linear regression and agreement plots for PAdP and PAsP from CardioMEMS and echocardiogram as a function of average measurements are shown in Figures r2=0.798, p ≤ 0.001) and PAsP  measurements between both methods. Using Bland–Altman analytic methods, the bias for the echocardiographic estimates of the PAdP and PAsP was −0.12 mmHg and 0.49 mmHg with 95% limits of agreement ranging from +3.37 to −3.62 mmHg and +3.91 to −2.93 mmHg, respectively. Doppler echocardiography was inaccurate (defined as being greater than ±5 mmHg of the CardioMEMS measurement) in <1% (1/17) of cases for both PAdP and PAsP with PAdP being overestimated by 7 mmHg and PAsP underestimated by 6 mmHg by echocardiography in the aforementioned instances.Baseline demographic, anthropomorphic, and clinical history are presented in Acute decompensated heart failure (ADHF) is associated with abnormal hemodynamics especially left ventricular filling pressure and cardiac output. While invasive hemodynamic monitoring using a pulmonary artery catheter in ADHF provides useful objective data, its clinical use has largely fallen out of favor in uncomplicated cases and is not recommended for routine hemodynamic monitoring in ADHF . EchocarE/e' is the most feasible and reproducible method for the estimation of filling pressures and predictive of normal or abnormal filling pressures when the ratio is <8 or >15, respectively [E/e' may be an unreliable way to predict LV filling pressures in certain clinical settings. For instance, those with long-standing HFrEF who have undergone left ventricular remolding may already have LV dilation and functional mitral regurgitation. The functional mitral regurgitation leads to an increase in transmitral inflow, the peak E velocity increases on the mitral inflow, and there is a reduction in the systolic to diastolic (S/D) ratio in the pulmonary venous flow [E/e' shows a poor correlation with intracardiac filling pressures especially with large LV volumes because of significant mitral regurgitation and wide QRS leading to abnormal septal motion [E/e' is not the best indicator of LAP estimation [The use of ectively , 15. E/eous flow . In patil motion . Furthertimation . FinallyVTR as a surrogate marker for LAP in the absence of pulmonary vascular or parenchymal disease [VTR signal from which the peak pressure can be estimated. A poor quality or noncoaxial signal can frequently underestimate the estimated PAsP. This occurs more than frequently in patients with severe lung disease where PAsP estimation should be avoided in the absence of a good VTR envelope [VTR Doppler signal assume that there is no pulmonary valve stenosis and may be inaccurate in the presence of RV systolic dysfunction. Furthermore, RAP is often overestimated if IVC measurement is used, leading to overestimation of PAsP [Recognizing the potential limitations of transmitral Doppler velocities for assessment of LAP, the current American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines for assessment of diastolic dysfunction recommend utilization of PAsP derived from  disease . Again, envelope . Chronicenvelope . Calcula of PAsP .p < 0.0001) [Serial echocardiographic assessments provide little incremental prognostic information over clinical presentation or biomarkers in patients with ADHF . In curr 0.0001) .r2=0.96 and 0.88 at baseline, r2=0.90 and 0.48 follow-up, p ≤ 0.01), with a mean difference of 6.2 ± 4.5 and −1.6 ± 6.8 mmHg, respectively. PAsP measurements between CardioMEMS and echocardiographic-derived estimate also had a significant correlation  with a mean difference of −2.6 ± 11 mmHg. Echocardiography determination of PAdP in their study was only feasible in 2 patients due to technical reasons and hence was not reported.There is only limited data on simultaneous assessment of PA pressures derived from the CardioMEMS device and echocardiographic estimates. Verdejo et al. performed serial assessments in 12 subjects to assess correlation between wireless PA pressure monitoring using CardioMEMS with Swan–Ganz catheter and echocardiographic PA pressure measurements . CardioMVTR signal and evidence of enlarged right atrium, signifying chronic elevation in right-sided filling pressures. In addition, there was presence of baseline DPG in 2 subjects signifying presence of mixed pulmonary hypertension. While Verdejo et al. could not reliably report echocardiography-derived PAdP, our study specifically aimed to look at its comparison with the CardioMEMS data. While there are currently no guidelines available for DPG correction for an accurate assessment of derived LAP, we used an acceptable DPG cutoff of 7 mmHg. All 17 subjects had reliable Doppler data for accurate assessment of estimated LAP with significant correlation seen between both methods.Our study, for the first time, reports simultaneous hemodynamic readings from CardioMEMS and echocardiography-derived estimates of both PAsP and PAdP as a surrogate marker for LAP. Similar to the findings by Verdejo et al., there was a significant correlation between all CardioMEMS and Swan–Ganz catheter PA pressure readings at the time of implant amongst the enrolled patients on retrospective review of all tracings (data not presented). Of note, there were very few patients who had normal LV filling pressures because the cohort included patients with baseline NYHA class III heart failure who qualified for CardioMEMS implantation . LikewisCongestive heart failure is a syndrome that impacts millions of Americans on a daily basis and its management continues to evolve so that more patients are symptom-free, heart-failure hospitalization decreases, and socioeconomic burden associated with the management of heart failure is reduced. Chronic heart failure management is transitioning from symptom-guided therapy to pressure-guided therapy because the hemodynamic changes occur well in advance. The CardioMEMS HF system is the only FDA-approved device that has shown to reduce hospital readmission for heart failure. PAdP has now been established as the best guide for monitoring and titration of medications in ambulatory HF patients. Our study, for the first time, illustrates a direct linear correlation between PAdP measured by the CardioMEMS HF system and simultaneous measurement of echocardiography-derived estimated of LAP. While echocardiography remains as an invaluable tool in our clinical practice, one must be aware of the nuances associated with Doppler-derived estimates of filling pressures. CardioMEMS, in appropriately selected patients, is a valuable tool in a cardiologist's armamentarium to accurately monitor and optimize filling pressures in patients with CHF and reduce the risk of hospitalization.


Pediatric hematopoietic stem cell transplantation (HSCT) recipients are at increased risk of cardiovascular disease later in life. As HSCT survival has significantly improved, with a growing number of HSCT indications, tailored screening strategies for HSCT-related late effects are warranted. Little is known regarding the value of cardiovascular magnetic resonance (CMR) for early identification of high-risk patients after HSCT, before symptomatic cardiovascular disease manifests. This study aimed to assess CMR-derived left ventricular (LV) systolic and diastolic function, aortic stiffness and myocardial tissue characteristics in young adults who received HSCT during childhood.1H-CMRS), respectively.Sixteen patients (22.1 ± 1.5 years) treated with HSCT during childhood and 16 healthy controls (22.1 ± 1.8 years) underwent 3 T CMR. LV systolic and diastolic function were measured as LV ejection fraction (LVEF), the ratio of transmitral early and late peak filling rate (E/A), the estimated LV filling pressure (E/Ea) and global longitudinal and circumferential systolic strain and diastolic strain rates, using balanced steady-state free precession cine CMR and 2D velocity-encoded CMR over the mitral valve. Aortic stiffness, myocardial fibrosis and steatosis were assessed with 2D velocity-encoded CMR, native T1 mapping and proton CMR spectroscopy (P = 0.004) was higher, LVEF  and global longitudinal strain (GLS)  tended to be lower, while aortic pulse wave velocity , native T1  and myocardial triglyceride content  were comparable. There were no differences between patients and controls in E/A  and diastolic strain rates.In the patient compared to the control group, E/Ea  and LV systolic function (LVEF and GLS) tended to be reduced as compared to healthy controls, whereas no concomitant differences were found in aortic stiffness and myocardial tissue characteristics. When using CMR, assessment of LV diastolic function in particular is important for early detection of patients at risk of HSCT-related cardiovascular disease, which may warrant closer surveillance. Hematopoietic stem cell transplantation (HSCT) recipients are exposed to several pre-transplant and/or HSCT-related therapies which may increase the risk of cardiovascular disease , 2. As HAccording to current guidelines , pediatrPre-transplant or HSCT-related cardiotoxic exposures may cause endothelial damage leading to increased aortic stiffness and myocyte cell death with reactive interstitial fibrosis , 2. In aWe hypothesize that, when using CMR, subclinical deteriorations in LV function, aortic stiffness and/or myocardial tissue characteristics can be detected in young adults who received HSCT during childhood. Therefore, CMR may be suitable for early identification of patients at increased risk of developing HSCT-related cardiovascular disease. Accordingly, the aim of this study is to assess CMR-derived LV systolic and diastolic function, aortic stiffness and myocardial fibrosis and steatosis in young adults who have received pediatric HSCT and to compare these measures with those in healthy controls in the same age range.The patient group consisted of young adults (18 to 25 years old), who received HSCT for malignant or non-malignant disease during childhood. Patients were recruited from the outpatient clinic for screening and treatment of late effects of childhood cancer and/or HSCT of the Internal Medicine Department . Healthy controls were recruited by local advertising in Leiden University, the Netherlands. The control group was in the same age range as the patients and was sex-matched. Laboratory measures in the patient group were performed based on clinical indication and were typically measured within 1 year prior or after CMR examination. No blood samples were drawn in the healthy control group.1H-CMRS) to measure the myocardial triglyceride content. For standardization of the measurement of myocardial triglyceride content, all participants were asked to fast for 6 h and the CMR examinations were scheduled at fixed times (evenings). No CMR contrast material was used.The study participants underwent 3 T CMR , with a dStream Torso anterior coil and a FlexCoverage posterior coil in the table top, resulting in up to 32 coil elements for signal reception. The protocol consisted of standard electrocardiographic (ECG)-triggered two-, three- and four-chamber and short-axis cine balanced steady-state free precession (bSSFP) CMR and ECG-gated gradient-echo 2D velocity-encoded CMR over the mitral valve to quantify LV structure, systolic and diastolic function; 2D velocity-encoded CMR transecting the aortic arch and abdominal aorta to derive aortic stiffness; cardiac native T1 mapping to assess diffuse fibrosis and proton cardiovascular magnetic resonance spectroscopy (2 (long-axis) and 400 × 352 mm2 (short-axis), acquired voxel size 2.0 × 1.6 mm2 (long-axis) and 1.5 × 1.5 mm2 (short-axis), slice thickness 8 mm, echo/repetition time (TE/TR) 1.5/3.0 ms, flip angle 45°, number of phases 30 (long-axis) and 35 (short-axis). For short-axis bSSFP cine, the complete LV was imaged, using 14–16 slices, depending on the size of the LV, with 2 slices per breath-hold. Free-breathing through-plane 2D velocity-encoded (venc 100 cm/s) CMR was acquired perpendicular to the mitral valve, with FOV 350 × 350 mm2, acquired voxel size 2.5 × 2.5mm2, slice thickness 8 mm, flip angle 10°, TE/TR 2.9/4.6 ms, number of phases 40.For the bSSFP cines, typical field-of-view (FOV) was 350 × 350 mm2, slice thickness 8 mm, acquired voxel 2.8 × 2.8 mm2, flip angle 20°, TE/TR 2.5/4.4 ms, temporal resolution 10 ms.Aortic pulse wave velocity (PWV) was quantified as a measure of aortic stiffness. For aortic PWV, first, a double-oblique sagittal scout view of the aorta was obtained. Then, two free-breathing through-plane 2D velocity-encoded CMR scans were acquired, one transecting the ascending aorta (venc 150 cm/s) and one transecting the abdominal aorta, above the aortic bifurcation (VENC 100 cm/s). Typical imaging parameters were: FOV 350 × 282 mm2, slice thickness 8 mm, acquired voxel size 2.1 × 2.1 mm2, flip angle 20°, TE/TR 1.1/2.3 ms, SENSitivity Encoding (SENSE) factor 2. 1H-MRS was performed as described previously [3 was placed in the interventricular septum. For the acquisition with and without water suppression, 48 and 6 signal averages were obtained, respectively. ECG-triggering was used to acquire 1H-CMRS at 200 ms after the R-wave, and a respiratory navigator, tracking the lung-liver interface, for acquisition at end-expiration. A high permittivity pad was placed on the chest for improved signal-to-noise ratio.Native T1 mapping was acquired in the mid-ventricular short-axis slice, with breath-holding, using the 5s(3s)3s modified Look-Locker inversion recovery (MOLLI) scheme. Typical imaging parameters were: FOV 350 × 300 mmeviously . In summ1H-CMRS. The image analysis was blinded to patient or healthy control status.CMR data were analyzed using MASS Research Software V2016-EXP  for LV structure and function and aortic PWV, custom-made software for further analysis of the aortic velocity-time curves [For LV mass and volumes, the endocardial and epicardial LV borders were manually outlined in the end-diastolic and end-systolic phase, with exclusion of the LV papillary muscles. For the feature tracking based strain calculations, the manually annotated endocardial LV borders were automatically tracked throughout the cardiac cycle. Global longitudinal strain (GLS), global longitudinal peak systolic strain rate (GLSR-S) and global longitudinal early peak diastolic strain rate (GLSR-E) were calculated based on the two-, three- and four-chamber cine images. Global circumferential strain (GCS), global circumferential peak systolic strain rate (GCSR-S) and global circumferential early peak diastolic strain rate (GCSR-E) were extracted from the mid-ventricular short-axis cine slice Fig. . The ratAortic PWV was calculated by dividing the distance between ascending and abdominal aorta by the transit time of the onset of the systolic velocity wave front Fig. , as descP < 0.05 and all tests were two-sided. Additionally, we performed a post-hoc power analysis .Statistical analyses were performed in SPSS 23 . Normal distribution was checked using the Shapiro-Wilk test. Differences between groups were tested for statistical significance using the Student’s t-test or the Mann-Whitney U test for normally and non-normally distributed variables, respectively. Patients with prior HSCT vs. controls were compared and additional analyses were performed for patients with HSCT for malignancies vs. controls. Levels for statistical significance were set at 1H-CMRS data were not analyzed due to insufficient quality. Also, in one patient 2D velocity-encoded CMR over the mitral valve was not acquired due to imaging time constraints. Height and body surface area (BSA) in the patient group were lower compared to the healthy control group. The anthropometric characteristics are presented in Table In total, sixteen patients  men) and sixteen healthy controls  men) were included and analyzed. In one patient, 2) for HSCT conditioning. Five patients had a ferritin level above 250 μmol/L. In two of them, cardiac T2* was assessed upon clinical indication. In both, the T2* values were not suggestive of myocardial iron deposition. Clinical and biochemical patients characteristics are presented in Tables In ten patients, HSCT was indicated for a malignant disorder. Seven patients were treated with anthracyclines prior to HSCT, eight received total body irradiation  and fourteen were given high-dose cyclophosphamide (> 1 g/mP = 0.004), while the E/A ratio  and diastolic strain rates were comparable. There was a trend towards a lower LV ejection fraction (LVEF)  and lower GLS , whereas GCS was preserved . Stroke volume  but also cardiac output  and cardiac index  were lower. In contrast, aortic PWV , LV concentricity , native T1  and myocardial triglyceride content  were comparable. CMR results are presented in Table Patients as compared to the healthy controls had a higher E/Ea ratio . Additionally, LVEF , GLS  and GCSR-S  were lower. For the HSCT recipients treated for malignancies, aortic PWV was: 4.39 ± 0.18 m/s (P = 0.36 vs. controls), LV concentricity: 0.63 ± 0.10 g/mL (P = 0.73), native T1: 1208 ± 36 ms (P = 0.138) and myocardial triglyceride content: 0.53 ± 0.21 (P = 0.69).When comparing the subgroup with HSCT for malignancies with controls, the higher E/Ea persisted , myocardial triglyceride content of 0.69% or higher (+ 0.19%) and native T1 of 1268 ms or higher (+ 39 ms). These differences in aortic PWV, myocardial triglyceride content and native T1 are comparable to approximately 3, 20 and 35 years of normal aging, respectively –25.Our study showed that young adults with a history of pediatric HSCT, as compared to healthy controls in the same age range, have subclinical impairments in LV diastolic function and tend to have a lower LV systolic function, whereas aortic stiffness and myocardial tissue characteristics are comparable. Our results indicate that CMR-derived LV diastolic parameters, rather than aortic PWV, cardiac native T1 or myocardial triglyceride content, may be early markers of cardiovascular deterioration after HSCT.The estimated LV filling pressure was found to be increased after childhood HSCT, which is indicative of reduced LV diastolic function. When LV myocardial relaxation progressively deteriorates, LV filling pressure becomes increased to compensate for the impaired LV diastolic filling . AccordiIn our study, the trend for lower LVEF and significantly lower cardiac index in the pediatric HSCT recipients compared to the controls seemed to be related to impairments in GLS rather than GCS. GLS and GCS, respectively, can be interpreted as measures of the contractility of the cardiomyocytes in oblique orientation in the subendocardium and those in circumferential arrangement in the mesomyocardium , 30. Acc31P-CMRS) for the assessment of myocardial energetics and perfusion imaging [We hypothesized that aortic stiffening or altered myocardial tissue characteristics would be early markers of cardiovascular disturbances after HSCT, preceding manifest LV dysfunction. Of interest, as chemotherapy is considered to disrupt mitochondrial function and irradiation has been demonstrated to induce microcirculatory damage , several imaging .No differences were observed in aortic stiffness between the HSCT study population and the healthy controls. Based on previous studies, we expected to find a significantly higher aortic stiffness, at least in the patients with HSCT for a malignant disorder, because of the pre-transplant cardiotoxic exposures. Anthracycline and/or chest irradiation in the treatment of the primary cancer may cause endothelial damage due to the generation of reactive oxygen species , 35. AlsPrevious longitudinal studies in patients with breast cancer, lymphoma or leukemia showed that aortic PWV increases by approximately 1.5 to 2-fold upon anthracyclines in the first 4 to 6 months, also for low or moderate dosages, compared to the pre-treatment measurements , 40. AnoThere were no differences in myocardial tissue characteristics and LV concentricity between the HSCT study population and the healthy controls, which otherwise would have been indicative of LV remodeling. To our knowledge, this is the first study in which native T1, as a measure of interstitial fibrosis, and myocardial triglyceride content, as a measure of metabolic remodeling, have been assessed in young adults with prior HSCT. It should be noted that diffuse fibrosis can be estimated based on calculating native T1 or the extracellular volume fraction (ECV); the latter requires CMR contrast administration . Recent From previous studies it is known that the metabolic syndrome, presumably due to changes in myocardial fatty acid uptake and/or oxidation, is associated with myocardial steatosis , 48. Alt1H-CMRS is the gold standard for non-invasive assessment of myocardial steatosis [Strength of this study is the comprehensive CMR evaluation, including measures of both LV systolic and diastolic function, vascular function and myocardial tissue characteristics. CMR rather than ultrasound is the most accurate non-invasive modality to quantify aortic stiffness . Diffuseteatosis . In clinteatosis . CompareOur study did not comprise CMR before and shortly after HSCT, but had a cross-sectional design because of ethical considerations. Therefore, we cannot exclude temporary deteriorations in, for example, aortic stiffness. Our study population was too small to evaluate the patient group with HSCT for non-malignant disease separately. The observed abnormalities in LV diastolic function and the non-significantly lower LV systolic function seemed to be driven by the patients who had received HSCT for a malignant disease. However, based on our study we cannot rule out late LV functional impairment after HSCT for non-malignant disease. Also, we were not able to assess the correlations between the different HSCT conditioning regimens, graft-versus-host-disease or iron overload and cardiovascular measures. However, this study was aimed at identifying CMR parameters which may show deteriorations before overt cardiovascular disease develops, and not to identify HSCT-related factors which may be helpful in late cardiovascular disease risk stratification. Echocardiography was not applied in the present study, which would have allowed for comparison of CMR with echocardiography for the early detection of cardiac effects of HSCT.1H-MRS measurements, it is unlikely that fibrosis related increases in native T1 might have been cancelled out by myocardial iron or fat related native T1 decreases.As a measure of interstitial fibrosis, ECV may be preferable. The native T1 value may be affected by several processes other than edema or increased myocardial collagen in the extracellular compartment . Hence, In young adults who received HSCT during childhood, LV diastolic function was decreased (higher estimated LV filling pressure) and LV systolic function (LVEF and GLS) tended to be reduced as compared to healthy controls, whereas no concomitant differences were found in aortic stiffness (aortic PWV) and myocardial tissue characteristics . Therefore, when using CMR, the assessment of LV diastolic function in particular is important for early detection of patients at risk of HSCT-related cardiovascular disease. Further research, including longitudinal CMR measurements, is needed to show the predictive value of subclinical LV functional abnormalities for the development of symptomatic cardiovascular disease after HSCT. Also, comparative studies of imaging modalities should reveal whether CMR-derived LV function has additive value for screening programs when performed next to the current echocardiography-based follow-up of the cardiovascular late effects of HSCT. For example, CMR may be used for the selection of patients who require frequent follow-up by standard echocardiography.