Heart failure is considered a worldwide pandemic affecting 26 million people globally. Patients who are unfit or waiting for cardiac transplantation may benefit from alternate mechanical support therapies using ventricular assist devices. It is not uncommon for radiologists, especially those working in institutions with a high volume of cardiac transplantations, to be presented with radiographs containing these devices. The role of the radiologist is not only to accurately identify these devices, but also to evaluate for any complications. The gold standard treatment for HF is cardiac transplantation, but only a select few go on to receive this treatment, either because of donor shortage or being unfit for surgery. Many patients may benefit from alternate mechanical support therapies using ventricular assist devices (VADs). Rapid advances in medical technologies over the last few decades have produced a myriad of new devices and improvements in existing ones. Chest radiographs (CXRs) are typically obtained in these patients, and it is not uncommon for the radiologist to be presented with a CXR containing a cardiac device. The role of the radiologist involves identifying the device on the CXR, as well as careful assessment for accurate placement and excluding complications. The intention of this article is to provide insight into the various VADs found in clinical practice, identifying the most commonly used types, assessing their placement and highlighting complications on CXRs.Heart failure (HF) is considered a worldwide pandemic affecting 26 million people globally. Heart failure is characterised by the decreased ability of the heart to pump and/or fill with blood.Ventricular assist devices are used in patients with ventricular dysfunction – right, left or biventricular – and can be temporary or permanent, based on the clinical indication. Temporary VADs are used as a bridge to myocardial recovery or during cardiac transplantation. Permanent VADs may be used for the same reason but are typically selected in patients who require long-term treatment for myocardial dysfunction and who are not fit for cardiac transplantation.5An intra-aortic balloon pump (IABP) is a polyethylene balloon that spans the entire length of the thoracic aorta, placed percutaneously via femoral artery access. The IABP comes in different lengths with IABP selection determined based on the patient’s height. The IABP inflates during diastole leading to an increase in blood flow to the coronary arteries, great vessels and renal arteries. Immediately prior to systole, it deflates producing a vacuum effect leading to forward blood flow to the aorta and its branches. Although the IABP is predominately radiolucent on a CXR, it has radiopaque tips proximally and distally. On the CXR, the cephalad radiopaque tip should be 2 cm above the carina . An alteExtracorporeal membrane oxygenation (ECMO) is increasingly being employed in adult patients who fail to wean after cardiopulmonary bypass post-cardiac surgery, as well as in patients with severe respiratory failure. The intention of ECMO is to provide oxygenated blood while extracting carbon dioxide. The two main types of ECMO devices are veno-arterial (VA) ECMO and veno-venous (VV) ECMO. Both allow respiratory support, but only VA ECMO allows haemodynamic support, and hence only the latter is used for HF. In VA ECMO, deoxygenated blood is siphoned off from a vein and oxygenated blood is returned to an arterial vessel , while in VV ECMO, the oxygenated blood is returned to a systemic vein or the right atrium. Following appropriate placement, the cannulas are sutured to the skin to prevent displacement and malposition. Radiographs of the chest and abdomen are performed to ensure correct cannula positioning.6  and the right atrium (RA), and the internal jugular vein (IJV) cannula tip at the junction of the superior vena cava (SVC) and the RA. The VV ECMO dual lumen cannula  is inserted through the right IJV into the RA, with the tip in the IVC  and 3. C6 . A chang7The main indication for these devices is a bridge to cardiac transplantation. In Australia, in 2013, nearly 40% of the patients who underwent heart transplant were bridged to transplantation with a long-term VAD. A list of the various indications and contraindications for left ventricular assist devices (LVADs) are summarised in The components of a left ventricular assist device in general include the inflow cannula, the impeller (pump), outflow cannula, the percutaneous driveline connected to a power source and the external system controller. The impeller mechanism enables forward blood flow.First-generation LVADs, also known as volume displacement devices, used a volume displacement device with valves to pump out blood. Because of their poor long-term durability, thrombus formation and increased risk for infections, they have fallen out of favour clinically. Currently, the only adult first-generation VAD still available, albeit rarely used, is the Thoratec VAD. It is a pneumatically driven pump and available as either paracorporeal (Thoratec PVAD) or intracorporeal (Thoratec ventricular assist device [IVAD]) models, both capable of providing univentricular (left or right) and biventricular support. The Thoratec PVAD is implanted on the anterior abdominal wall, while the IVAD is implanted in a pre- or intraperitoneal position.8 The Berlin Heart EXCOR® Ventricular Assist Device , a first-generation VAD, is the most commonly used LVAD worldwide in paediatric patients with end-stage HF as a bridge to heart transplantation.9 It consists of a pneumatically driven paracorporeal translucent pump. The device cannulae are made of silicon rubber and coated externally with Dacron velour at the site where it exits the upper abdominal wall to encourage granulation tissue formation and reduce the risk of infection. The device can provide both univentricular and biventricular support  is the most commonly used second-generation LVAD device. The inflow and outflow cannula placements for this device are like the first-generation LVADs. The HMII can be differentiated from other LVADs as they are placed within the subdiaphragmatic preperitoneal pocket and are therefore visualised below the left hemidiaphragm on a CXR. In addition, the impeller housing unit has a characteristic ‘bell-shaped’ appearance, with its percutaneous single driveline supplying power to the pump exiting from the right upper quadrant of the abdomen.11 During surgical placement, the inflow cannula is oriented posteriorly towards the centre of the left ventricle (LV) cavity and connected to the pump body at roughly a 30° angle, while the outflow cannula is oriented upward to direct blood flow above the diaphragm. Malpositioned HMII pumps contribute to nearly 25% of pump thrombosis. Other factors that may contribute to pump thrombosis or failure are inflow cannula malposition and outflow cannula kink or compression.1213 A sudden onset of pulmonary oedema could suggest LVAD failure. Other complications that may be seen on CXR include pneumothorax, pneumomediastinum, pericardial tamponade and infections. Documented sites of infection include the superficial driveline, pump pocket, the mediastinum and the internal parts of the pump for which CT is more superior than CXR for evaluation. Occasionally, because of device malfunction, the body of the HMII may be replaced without changing the outflow graft, and as a result of variations between the new and old designs, complications such as outflow bend relief detachments and kinking may be seen.14An acceptable CXR, to reduce the errors from patient rotation on inflow angle measurements, would be one where the sternotomy sutures are seen overlying the patient’s spine or with rotations < 2 cm. The various HMII measurements that may be assessed on an AP CXR include: (1) the pump pocket depth (PPD), (2) the outflow cannula angle and (3) the inflow cannula angle. The outflow cannula is fixed to the body of the HMII with a known angle , and any deviation from the known angle is indicative of a CXR set-up error and rotation. It has been shown that the inflow cannula angle measurements should remain constant on serial imaging. An ideal inflow cannula angle should be >55°–65° to reduce the risk of pump thrombosis . Also, tThird-generation LVADs use magnetic levitation technology (MAGLEV) enabling rotation without friction or wear, and the pump mechanism produces centrifugal flow. In addition, because of their smaller size, they are implanted in the pericardial space. On CXRs, the impeller units of the HeartWare LVAD (HVAD) and the HeartMate III (HMIII) can be differentiated from HMII, as the former have a circular appearance with a centrally located inflow cannula. The differentiating feature between the HVAD and HMIII devices are that the radiopaque portion of the HMIII’s outflow cannula is angled, while in the HVAD it has a more linear orientation  and CentriMag (by Thoratec)Surgically implanted temporary VADs:Temporary VADs:First-generation VADs:-Thoratec’s paracorporeal ventricular assist devices ® Berlin Heart EXCORParacorporeal pumps:-HeartMate XVE (Thoratec Inc.)Novacor .Implantable pumps:Second-generation VADs:HeartMate II Incor Berlin Heart Jarvik 2000 FlowMaker Third-generation VADs:HeartWare HVAD System HeartMate III Permanent VADs:Summary of the various permanent VADs:-Pump mechanism: pulsatile flow (volume displacement pumps)-Disadvantages: increased risk of infection, large size, poor durability.-®.No longer used except for Thoratec and Berlin Heart EXCOR-Thoratec PVAD: paracorporealThoratec IVAD: preperitoneal®: preperitonealBerlin Heart EXCORHeartMate XVE: preperitoneal or intraperitonealNovacor: preperitonealImplantation site:First-generation VADs:-Pump mechanism: continuous -Most commonly used VAD. Fewer moving parts when compared to the previous generation (the rotor is the only moving part) and therefore more durable-Implantation site: HMII is implanted below the subdiaphragmatic preperitoneal space. The Jarvik and Incor Berlin Heart are implanted in the pericardial spaceSecond-generation VADs:-Pump mechanism: continuous  flow-Uses magnetic levitation technology (MAGLEV), thereby enabling rotation without friction or wear, more durable, compact size, no pump pocket, simpler surgical implantation-Implantation site: pericardial spaceThird-generation VADs:VAD, ventricular assist devices; IABP, intra-aortic balloon pump; ECMO, extracorporeal membrane oxygenation.All ethical considerations have been taken into account. No patient identity or patient information has been revealed.Ventricular assist devices play a crucial role in the management of patients with HF. With recent advances, newer devices have become smaller and more durable. The role of the radiologist is to identify the salient medical device on the radiograph, to evaluate for appropriate device placement and to exclude device-related complications.


Myocarditis can lead to myocyte loss and myocardial fibrosis resulting in dilated cardiomyopathy (DCMP). Currently employed methods for assessing the risk for development of DCMP are inaccurate or rely on invasive myocardial biopsies. We hypothesized that molecular imaging of tissue inflammation with contrast enhanced ultrasound during peak inflammation in myocarditis could predict development of fibrosis and impaired left ventricular function.Lc), to CD4+ lymphocytes (MBCD4), and to the endothelial cell adhesion molecule P-selectin (MBPSel) was performed during the expected EAM peak inflammatory activity 21 days after induction. High resolution ultrasound, invasive hemodynamic measurements and fibrosis quantification were done 63 days after EAM assessment. All tested microbubbles correlated to fibrosis , however, correlations were weak overall and the spread of data was considerable. Also, targeted CEU data on day 21 did not correlate to hemodynamic and functional data on day 63.Experimental autoimmune myocarditis (EAM) was induced in Balbc mice by injection of the α-myosin heavy chain peptide. Contrast enhanced ultrasound (CEU) using microbubbles targeted to leukocytes (MBUltrasound molecular imaging using targeted microbubbles during the peak inflammatory activity of myocarditis correlates weakly with later development of fibrosis but not with hemodynamic or left ventricular functional parameters. In myocarditis triggered by infection, systemic diseases, drugs or toxins acute inflammation may develop into a chronic autoinflammatory process . OngoingThe pathogenesis of myocarditis involves acute injury of the myocytes that initiates immune processes with a CD4 T cell response as the main driving force. Multiple factors such as gender, Human Leukocyte Antigen (HLA) haplotype, exposure of encrypted self antigens such as cardiac myosin and molecular mimicry with cross-reactivity of myosin with microbial epitopes contribute to a sustained autoimmune response with T cell and macrophage infiltration of the myocardium ,4,5.For the prediction of ultimate development of DCMP, New York Heart Association functional class upon presentation and immunohistological evidence of inflammation have been shown to be related to poor outcome . HoweverThe Experimental Autoimmune Myocarditis (EAM) murine model has been developed to recapitulate and study the pathophysiologic processes involved in acute and chronic human myocarditis . In suscThe aim of our study was therefore to assess whether, in addition to diagnosis of the acute disease, ultrasound molecular imaging of the peak autoimmune inflammation in the EAM model can be used to predict future left ventricular structural changes or functional deterioration that are observed in DCMP.10.5281/zenodo.3356728.All data have been made publicly available at the Zenodo repository and can be accessed at All experiments were performed in accordance with Swiss Federal Legislation and were approved by the Animal Care Committee of Basel. A total of 54 female BALB/c mice (8 weeks of age) were used for this study. Female animals were used as they are less susceptible to develop myocarditis than males and we have shown a wide range of myocarditis severity on histology using female animals previously . EAM wasLc), distearoyl-phosphatidylserine  was added to the suspension before sonication [PSel) and CD4 (MBCD4), distearoyl-phosphatidylethanolamine-PEG(3400)-biotin  was added to the suspension. Anti-P-Selectin antibody (RB40.34) or anti-CD4 antibody (H129.19) were then conjugated to the microbubble shell using biotin-streptavidin linking as previously described [Iso) with a non-specific control antibody of the same isotype (R3-34) were also prepared. We have previously shown that these protocols result in microbubbles of similar mean sizes of 2.5 to 2.7μm [Perfluorocarbon-filled, microbubbles with a lipid shell were prepared by sonicating an aqueous suspension of distearoyl phosphatidylcholine  and polyoxyethylene-(40)-stearate  that was gas-saturated. For targeting of microbubbles to leukocytes . After high resolution echocardiography and CEU molecular imaging, the cannula was withdrawn, the right internal jugular vein was ligated and the wound was closed surgically. Subsequently, the mice were recovered. 60–65 days after induction of EAM, the mice were again anesthetized. High resolution echocardiography was performed. Subsequently, the right common carotid artery was dissected free from surrounding tissue. A 0.33 mm diameter manometer tipped catheter  was inserted through a small incision in the artery. The catheter was then carefully advanced through the aortic valve into the left ventricle. Pressure parameters were recorded and analyzed with a MPVS System  and included peak first derivative of pressure increase in the left ventricle (dp/dt max), peak first derivative of pressure decrease in the left ventricle (dp/dt min), the left ventricular relaxation time constant Tau, and left ventricular end-diastolic pressure (LVEDP). The mice were then sacrificed and the heart was harvested and preserved in 4% paraformaldehyde for histology.Left ventricular structure and function was assessed using high frequency  ultrasound imaging . M-Mode images of the left ventricle at the mid-ventricular level in short-axis orientation were used to measure left ventricular chamber dimensions  was calculated by multiplying the stroke volume with the heart rate. Fractional shortening (FS) was calculated as ((LVIDd-LVIDs)/LVIDd)*100. E-wave and A-wave velocity were measured using pulsed wave Doppler tracings from a modified apical 4-chamber view to assess flow across the mitral valve. Parasternal long- and short-axis B-mode images were acquired at a frame rate of >200 frames per second. Longitudinal, radial and circumferential global peak strain values were derived from the B-mode images using speckle tracking software  [Is, MBLc, MBPSel, and MBCD4 (5x106 microbubbles per injection) were injected in random order, 9 animals received all 4 microbubble preparations, while 20 animals received 3, 17 animals 2 and 8 animals 1 microbubble preparation, respectively. Of note, due to constraints in terms of intravenous volume application, it was not possible to inject each microbubble species in every animal. Ultrasound imaging was stopped from injection until 8 minutes later when imaging was restarted at a mechanical index of 0.87. Time after injection was derived empirically from prior studies and was optimized to achieve minimal background signal from circulating microbubbles while retaining a maximum of targeted signal. The first image frame was used to determine the total amount of microbubbles within the left ventricular myocardial tissue. The microbubbles in the ultrasound field were then destroyed with several (>10) image frames. Several image frames at a long pulsing interval (every 9 heartbeats) were subsequently acquired to measured signal from circulating microbubbles. After log-linear conversion, frames depicting circulating microbubbles were subtracted from the initial image to compute signal from attached microbubbles. Contrast intensity was measured from a region of interest containing the whole left ventricular myocardium. The region of interest was selected using fundamental frequency anatomic images of the left ventricle imaged at 14MHz. Contrast enhanced ultrasound imaging data were analyzed blinded to all other experimental data by one investigator (D.C.S.). For the assessment of interobserver variability, a total of 40 randomly selected datasets (10 from each microbubble preparation) and for intraobserver variability, 10 randomly selected datasets were reanalyzed by an investigator blinded to previous data (M.P.).CEU molecular imaging  was performed with a high-frequency linear-array probe (15L8). The left ventricle was imaged in a short axis orientation at the papillary muscle level. ECG-gated triggering was used for acquiring end-systolic frames. For the detection of the microbubble contrast agent, a combination of power modulation and pulse inversion imaging with a 7 MHz fundamental frequency with dynamic range set to 50 dB was used. The 15L8 probe and the imaging parameters with a relatively low transmit frequency were employed to maximize sensitivity for the microbubble contrast agent. The gain settings were adjusted below visible speckle and were kept throughout CEU imaging. MBFor the quantification of myocardial fibrosis, heart tissue was fixed in 4% formaldehyde-solution and 5 um thin short axis sections of the left ventricle were prepared using a water-slide microtome . Two 5 μm sections approximately 250 μm apart where the papillary muscles were visible were stained and analyzed per animal. The sections were stained with PicroSirius Red and counter-stained with hematoxylin. Full-spectrum RGB images of the stained myocardium were recorded . The Nikon NIS-Elements software was used for image analysis. User defined low, intermediate and high % fibrotic sections were used to establish two thresholds using the hue, intensity and saturation (HIS) features of the images. The first threshold was aimed to include the entire tissue. The second threshold was devised to comprise the red stained regions. These two thresholds were then applied to the entire data set. On each section a region of interest was defined in the left ventricle and measurements were only performed on that region. Fibrosis % is the thresholded red signal normalized to the thresholded entire LV tissue. The average of the two measurements was used for further analysis. Myocardial fibrosis quantification was performed blinded to all other experimental data by one investigator (A.O).GraphPad Prism (version 6.07) was used for statistical analysis. Data are expressed as median (25th - 75th percentile). Comparisons between data at day 21 and day 63 after induction of EAM were analyzed using a Wilcoxon matched-pair rank test. For correlations between 2 parameters , Spearman correlation was used. A two-sided p value <0.05 was considered as statistically significant. Inter- and intra-observer variability was evaluated using Bland-Altman analysis.Physiologic and echocardiographic measurements of left ventricular dimensions are shown in Left ventricular systolic function and cardiac output was reduced on day 63 after induction of EAM . This waDue to the invasive nature of left ventricular pressure measurements, these parameters were assessed on day 63 only, and thus values are compared to published normal values rather than to values assessed on day 21 . HoweverQuantification of collagen using PicroSirius Red staining showed degrees of fibrosis ranging from 0.3 to 8.4% of the total myocardial area . MyocardLc, signal and LVEF on day 63 . In contrast, there was no correlation between signals from microbubbles versus all other functional parameters on day 63 .The bias (95% limits of agreement) value was calculated for interobserver variability for ultrasound molecular imaging data as -0.02178 (-1.014 to 0.975), while for intraobserver variability the value was -0.06610 (-0.2584 to 0.1262). Correlations of signal from microbubbles targeted to leukocytes, to CD4+ lymphocytes and to P-Selectin as well as for control microbubbles are shown in Correlations between functional parameters on day 21 and the extent of fibrosis on day 63 are shown in Myocarditis and the ensuing autoimmune processes lead to structural damage with myocardial fibrosis, loss of tissue architecture, and impairment in diastolic and systolic function. Thus, myocarditis can ultimately lead to DCMP with heart failure, risk for sudden death and the need for heart transplantation. The clinical presentation of myocarditis varies widely. Estimates of the rate of progression to DCMP derived from prospective studies are lacking. However, prospective studies show that during follow-up patients with a diagnosis of acute myocarditis experience sudden cardiac death or heart transplant in 4–20%, suggesting a rate of progression to DCMP in at least that range . TherefoExperimental autoimmune myocarditis has extensively been used to study the pathophysiology of autoimmune processes that follow acute viral myocarditis. In our study, cardiac myosin induced autoimmune myocarditis lead to a phenotype of DCMP after 63 days. Thus, on high frequency echocardiography, the left ventricle was dilated, LVEF was decreased, and an increased E/A suggested diastolic dysfunction. This was supported by invasive hemodynamics showing an increase in the left ventricular relaxation time constant Tau indicating impaired relaxation and an increased left ventricular filling pressure, as well as increased myocardial fibrosis. As was to be expected from reported rates of successful induction of EAM in female balb/c mice of around 60% [There are a number of reasons that may explain the low predictive value of ultrasound molecular imaging in this particular setting. First, the autoinflammatory process which is of a low-grade intensity in the majority of mice induced  was samp


Myocardial T1 and T2 mapping are reliable diagnostic markers for the detection and follow up of acute myocarditis. The aim of this study was to compare the diagnostic performance of current mapping measurement approaches to differentiate between myocarditis patients and healthy individuals.Fifty patients with clinically defined acute myocarditis and 30 healthy controls underwent cardiovascular magnetic resonance (CMR). Myocardial T1 relaxation times, T2 relaxation times, left ventricular (LV) function, T2 ratio, early gadolinium enhancement ratio, and presence of late gadolinium enhancement (LGE) were analysed. Native T1 and T2 relaxation times, as well as extracellular volume fraction (ECV) were measured for the entire LV myocardium , within the midventricular short axis slice (mSAX), within the midventricular septal wall (ConSept), and within the remote myocardium (remote). Receiver operating characteristics analysis was performed to compare diagnostic performance.p < 0.05 for all parameters). The global measurement approach showed highest diagnostic performance regarding all mapping parameters . Direct comparison of the different measurement approaches revealed significant differences in diagnostic performance between the global and the remote approach regarding T1 relaxation times and ECV (p = 0.001 and p = 0.002 respectively). Further, the global measurement approach revealed significantly higher T1 relaxation times compared to the ConSept approach  and nearly significant differences compared to the mSAX approach .All measurement approaches revealed significantly higher native T1 and T2 relaxation times as well as ECV values in patients compared to healthy controls .T2 relaxation times showed no significant differences between all measurement approaches  contains supplementary material, which is available to authorized users. Myocarditis is defined as inflammatory disease of the myocardium, diagnosed by established histological, immunological, and immunohistochemical criteria . Acute mCMR based diagnosis of acute myocarditis is based on the “Lake Louise” criteria (LLC), which were recently supplemented by quantitative imaging parameters . T1 and The aim of this study was to compare the diagnostic performance of these currently employed approaches to differentiate myocarditis patients from healthy individuals. Since the mSAX and global approach typically include obviously affected myocardial segments, the true value of quantitative native T1 and T2 relaxation time assessment might be overestimated. Thus, we additionally investigated the diagnostic value of myocardial mapping when only performed in remote myocardium.This prospective study was approved by the local ethics committee and all subjects gave written informed consent before CMR imaging.n = 14), supraventricular tachycardia (n = 9), and RV conduction block (n = 6). None of the patients suffered a major adverse cardiac event within the next 6 months of active surveillance. The control group consisted of 30 healthy subjects and outpatients referred for nonspecific thoracic pain who did not show structural abnormalities on CMR. Outpatients had no medical history and did not take regular medication. Clinical tests including Holter, cardiac enzymes, echocardiography, and cardiac stress test as well as clinical follow-up were unremarkable. Exclusion criteria for all subjects were contraindications to contrast-enhanced CMR imaging .Between 03/2014 and 05/2018 50 patients fulfilling the diagnostic criteria for clinically suspected myocarditis by the European Society of Cardiology [All examinations were performed on a 1.5 T CMR scanner  using a 32-channel torso coil with digital interface for signal reception. Sequences were acquired according to the updated Society for Cardiac Magnetic Resonance recommendations :Functional imaging consisted of ECG-gated balanced steady state free precession cine sequences acquired during breath hold in horizontal long axis (HLA), vertical long axis (VLA), LV outflow tract (LVOT), and short axis (SAX), the latter covering the whole LV from apex to base.myocardial edema was performed using black blood T2- short tau inversion recovery (STIR) imaging in SA, VLA, and transverse orientation.Detection of inflammation-induced Inflammation-induced hyperaemia was assessed using transverse free-breathing T1 weighted images prior and <3 min after intravenous injection of a double dose (0.2 mmol per kilogram body weight) of extracellular contrast agent  as previously described [escribed .Myocardial fibrosis and scarring using the late gadolinium enhancement (LGE) technique was performed 15 min after contrast agent injection using T1 weighted segmented inversion-recovery gradient-echo sequences acquired in HLA, SAX, and VLA. The correct inversion time was determined using the Look-Locker technique.In addition to the standard CMR protocol native and post-contrast T1 and T2 mapping were performed. T2 maps were acquired prior to contrast agent injection in end-diastole in 3 short axis slices  using a multiecho dataset based on two established CMR techniques (gradient spin-echo (GraSE)), as previously described . Before Images were evaluated by two radiologists with 9 and 6 years of CMR experience. Functional analysis (LV end diastolic volume (LVEDV), LV ejection fraction (LVEF), interventricular septal thickness (IVST)) was determined offline using dedicated software . LVEDV and LVEF were quantified manually by tracing the endocardial borders. Papillary muscles were included in the LV volume. Presence of myocardial edema was evaluated both visually and by comparing the signal intensity of the LV myocardium in STIR-weighted SA images against the signal intensity of a reference region within the adjacent skeletal muscle in the same slice (T2 ratio), as previously described . The earT1 and T2 maps were evaluated using dedicated software . Automatic motion correction was performed prior to analysis in all maps. For measurement of T1 and T2 relaxation times different approaches were used: including the complete apical, midventricular, and basal SAX slice , including the complete mSAX, within the midventricular septal wall (ConSept), and within the remote myocardium . For the assessment of global, mSAX, and remote T1 and T2 relaxation times, endo- and epicardial contours of the LV were traced while excluding epicardial fat, pericardium, and blood from analysis. ConSept measurements were performed by placing a region of interest (ROI) conservatively within the midventricular septal wall taking care to avoid contamination with the blood pool, as previously described  . AUCs were compared using the method by DeLong et al. [p value of less than 0.05 was considered significant. A subgroup of 20 LLC-positive patients was investigated to assess inter- and intra-observer agreement regarding the different mapping measurement approaches according to the method of Bland and Altman.Statistical analysis was performed using SPSS software , International Business Machines, Inc., Armonk, New York, USA) and MedCalc 11.0 . Patients’ characteristics are presented as mean ± standard deviation or as absolute frequency. Continuous variables were checked for normal distribution. The independent two-sample Student’s t-test was used for comparison of continuous variables between two different groups. Mean differences between several groups were compared using univariate ANOVA (Turkey-HSD post-hoc test). Dichotomous variables were compared using the χg et al. . A p valp = 0.004). No significant differences could be detected regarding heart rate, LVEDV/body surface area (BSA), and IVST between patients and healthy controls . Troponin I, as well as creatine kinase were pathologically elevated in all patients. Further, blood levels of leucocytes and C-reactive protein were significantly higher in patients (10.4 ± 4.7 103/μmL and 70.7 ± 99 mg/L) compared to healthy controls  . Patients were 44 ± 18 years and 56% were male. Neither LVEF (58.3 ± 9.8%), nor LVEDV/BSA (81.2 ± 27.2 ml/m2) or IVST (10 ± 2 mm) showed significant differences compared to the healthy control group (p > 0.05). Leukocytes were within normal range (9.8 ± 2.6 103/μmL) and the Troponin I level was only mildly elevated (0.4 ng/ml). Creatine kinase accounted for 260.4 ± 235.1 U/L and C-reactive protein for 12.8 ± 28 mg/L. Patients’ characteristics are listed in Table A group of patients showing no visible edema or LGE (CMR negative) was specifically examined  of patients had LGE in a non-ischemic pattern. In these cases, LGE accounted for 12% of the LV mass (range 2–51%). A majority  also showed an increased T2 ratio and/or visible edema. The segmental distribution of LGE and visible edema is shown in Additional file CMR was performed on average 2.9 ± 2.2 days 1–8 days) after onset of symptoms. The majority . The global measurement approach showed highest diagnostic performance regarding all mapping parameters . Direct comparison of the different measurement approaches revealed significant differences in diagnostic performance between the global and the remote approach regarding T1 relaxation times and ECV (p = 0.001 and p = 0.002 respectively). Further, the global measurement approach revealed significantly higher T1 relaxation times compared to the ConSept approach  and nearly significant differences compared to the mSAX approach .All measurement approaches  revealed significantly higher T1 and T2 relaxation times as well as ECV values in the respective myocardial regions in patients compared to healthy controls . Measurement results and diagnostic performance of the different measurement approaches are listed in Tables T2 relaxation times showed no significant differences between all measurement approaches  All measurement approaches  allowed for reliable distinction between healthy and diseased myocardium, irrespective of the mapping technique used; 2) even measurements in the remote myocardium reliably differentiated healthy from myocarditis patients; 3) the global measurement approach showed overall the highest diagnostic performance.Native T1 relaxation times reflect information from intra- and extracellular space, thus allowing for both, detection of myocardial edema and fibrosis. Native T1 has further shown to be an excellent discriminator between healthy and myocarditis patients, even exceeding the diagnostic performance of the standard LLC . Unlike ECV represents a reliable marker for myocardial remodelling and fibrosis respectively and has proven to reliably differentiate between myocarditis patients and healthy subjects in numerous previous studies , 23–26. In the underlying study, all measurement approaches showed only moderate diagnostic performance using ECV, again with best results obtained by using the global measurement approach. One of the reasons for these findings might be the short time interval between onset of symptoms and CMR in the current study. With an average time to CMR of 3 days, intracellular edema is most likely the predominant underlying pathophysiology  and the T2 relaxation times closely correlate with free tissue water content, thus making them an ideal marker for disease detection –12, 23. Our results regarding diagnostic accuracy of mSAX T1 (83%), T2 mapping (81%), and ECV (69%) are in line with previously published data by Lurz et al., who investigated the diagnostic performance of myocardial mapping using the mSAX approach versus endomyocardial biopsy in patients with suspected myocarditis  . It shouThe diagnostic value of T1 and T2 relaxation times as well as ECV in patients with clinically suspected acute myocarditis has been investigated extensively in the past , 25, 26.In our study, 9 patients with a clinical diagnosis of myocarditis were included, who neither showed LGE, nor visible edema and, thus were missed by the classic LLC. Although these patients did not show significant differences in LV function  or semiquantitative imaging parameters (i.e. T2 ratio and aMe) compared to controls, native T1, T2, and ECV values were significantly higher using the global measurement approach. These results corroborate the findings by Ferreira et al. who were the first to show that native T1 is able to detect a significantly larger extent of myocardial injury compared to STIR imaging and LGE in this patient cohort . In thisOwing to an evenly distribution of T2 relaxation times within patients’ LV myocardium, all three measurement approaches revealed comparable diagnostic performances in detecting acute myocarditis using T2 mapping. This did not hold true for T1 mapping, where differences in diagnostic performances were present between the different measurement approaches, with best results for the global and the mSAX approach Table . This raAcquisition time and post-processing effort should not play a major role in decision making as the acquisition of one image slice accounts for one breath hold and also drawing of one vs. three endo- and epicardial contours accounts for less than two minutes when performed by an experienced examiner. It is rather the severity of disease as well as the time interval between onset of symptoms and CMR which decide about the added value of myocardial mapping in patients with myocarditis. As was shown in the subgroup of patients who did not fulfil the original LLK, both myocardial T1 and T2 mapping increased the diagnostic performance of CMR. In these patients, it is crucial to use the method with highest sensitivity and best reproducibility, which was the global approach. This is most likely also the case in subacute and convalescent stages of disease, however further studies are necessary to confirm this assumption. On the other hand, the mSAX and especially the ConSept approach could be used as an easier method to monitor convalescence of disease in case of follow-up examinations.As has been the case in almost all previously published CMR studies, diagnosis of myocarditis was based on validated clinical guidelines  rather tThe results obtained in this study are only valid for patients with acute symptoms of myocarditis. In case of convalescent stages of disease, results may differ, as indicated above.It has been shown that myocarditis coincides with atrial involvement . In addiNative T1 and T2 mapping as well as ECV allow for accurate detection of disease in patients with acute myocarditis irrespective of the measurement approach used. Even measurements performed exclusively within remote myocardium allow for reliable detection of acute myocarditis, proving diffuse involvement of disease despite a mostly regional or patchy distribution pattern of visible pathologies. The global measurement approach provides the overall best diagnostic performance in acute myocarditis for both T1 and T2 mapping.Additional file 1:Segmental distribution of LGE and visible edema. Segmental distribution of LGE (A) and visible edema (B) according to the 17 segment AHA-model. Values are presented in absolute numbers and percentage (listed in parentheses) of affected patients. (PNG 2869 kb)Additional file 2:Segmental distribution of native T1 and T2 relaxation times as well as ECV. Segmental distribution of mean native T1 (A), ECV (B), and T2 relaxation times (C) of patients (red) and controls (black). (TIF 1562 kb)Additional file 3:Bland-Altman plots showing intra (A)- and inter(B)-observer agreements of the different measurement approaches. (PPTX 444 kb)


That form and function are related is a maxim of anatomy and physiology. Yet, form-function relations can be difficult to prove. Human subjects with excessive trabeculated myocardium in the left ventricle, for example, are diagnosed with non-compaction cardiomyopathy, but the extent of trabeculations may be without relation to ejection fraction. Rather than rejecting a relation between form and function, we may ask whether the salient function is assessed. Is there a relation to electrical propagation, mean arterial blood pressure, or propensity to form blood clots? In addition, how should the extent of trabeculated muscle be assessed? While reviewing literature on trabeculated muscle, we applied Tinbergen’s four types of causation—how does it work, why does it work, how is it made, and why did it evolve—to better parse what is meant by form and function. The paper is structured around cases that highlight advantages and pitfalls of applying Tinbergen’s questions. It further uses the evolution of lunglessness in amphibians to argue that lung reduction impacts on chamber septation and it considers the evolution of an arterial outflow in fishes to argue that reductions in energy consumption may drive structural changes with little consequences to function. Concerning trabeculations, we argue they relate to pumping function in the embryo in the few weeks before the onset of coronary circulation. In human fetal and postnatal stages, a spectrum of trabeculated-to-compact myocardium makes no difference to cardiac function and in this period, form and function may appear unrelated. Four weeks into human embryonic development, a single vessel connects the developing pulmonary vasculature to the left atrium . Eleven The example of the number of pulmonary veins illustrates some of the pitfalls of establishing relation between form and function. First, at what level of biological organization should form-function relations be assessed: on the level of the cell, tissue, chamber, organ, or organism? Second, which function should be assessed? Any structure of the body impacts on (parts of) the body and it is in principle possible to establish a consequence of the presence of the structure. However, consequences are different with regard to adaptation in evolutionary biology. An adaptation is a trait that has been favored by natural selection and, thus, relates directly or indirectly to the reproductive success of the organism . Third, Mechanism , how does it work?Example: The heart pumps blood.Function , why does it work?Example: because it perfuses the tissues with blood.Ontogeny , how is it made?Example: cardiogenic mesoderm surrounds a blood-filled cavity.Phylogeny (efficient cause), why did it evolve?Example: the propulsion of blood through the tissues compensates for the increased diffusion distance between tissue and environment associated with greater body sizes.When attempting to establish causality, Niko Tinbergen suggested the application of four types of questions, which are derivatives of the four categories of causes of Aristotle (given in parenthesis):Tyrannosaurus rex use its tiny front limbs for?” will likely receive an unsatisfactory and unfalsifiable answer. In contrast, we can reasonably answer “how did the Tyrannosaurus rex get its tiny front limbs” because the fossil record shows a conspicuous reduction of the front limbs concomitant with increments in the size of the hind limbs and head ,1312,13]Third, electrical activation spreads from the ventricular septum rather than from the base to the apex as in non-crocodylian reptiles E 14,22,,22,23.Consequences of the ventricular septum can be established as above, but it is surprisingly difficult to ascertain its functional advantage besides the basic properties of myocardium . The specialized manner of ventricular electrical activation does not shorten ventricular activation time as it does in mammals and birds . Oxygen-The case of the crocodylian ventricular septum shows any one form may have multiple functional consequences. Ventricular septation in pythons also leads to pronounced pressure differences and a reduction of shunts ,30. In bper se promotes proper heart morphogenesis . It. It89]. elnb . Despiteelnb ,94.A key difference may be that sarcomeric contraction is the basis of conus function while recoil of elastic elements is the basis of bulbus function ,94. GiveLoss of lungs evolved among amphibians in some aquatic caecilians and salamanders, presumably to reduce buoyancy in fast-flowing water where oxygen is abundant ,103. BesWe have attempted to apply the four causes of Aristotle that Tinbergen adapted to biology. Our motivation came from the confusion and conflicting views concerning the role of trabeculated muscle in vertebrate hearts. ‘Function’ is a concept that often implies purpose and teleology may exacerbate the confusion. The application of the four causes has revealed that function can be interpreted in several ways. In part, this is because function may be assessed under conditions that are not conducive to test a particular form-function relation. While our cases are based mostly on evolutionary biology, we would argue that there is relevance for medicine. Left ventricular non-compaction cardiomyopathy is characterized as a distinct form of cardiomyopathy by the American Heart Association and is diagnosed when trabeculated myocardium is excessive ,66.  because of developmental changes to the mesoderm that gives rise to both lungs and cells of the cardiac septa. That is, if cardiac changes are seen in isolation, we may miss the primary adaptation. It also follows that it may be futile to assess the functional advantage of the reduction of the cardiac septa because the advantage may not be there anymore. Similar concerns for establishing form-function relations can be expressed when trying to understand the significance of the myocardial to arterial identity change of the outflow tract of fishes. Possibly, the primary adaptation relates to energy consumption with form-function relations being secondary.In conclusion, we propose a negative derivative of the Krogh principle  namely,


FXN gene (GAA1).Although a concentric pattern of left ventricular (LV) geometry appears to be common in Friedreich ataxia (FRDA), there is no accepted method for diagnosing LV abnormalities in FRDA, sex and body size have often not been taken into consideration, and it has not been clear whether children and adults should be classified using the same criteria. The aim of this study was to better define the LV geometric changes in FRDA with respect to sex, body size and subject age, and to investigate the relationship of LV changes with genetic severity, as assessed by GAA repeat length within the shorter allele of the Echocardiography was performed in 216 subjects , measurements were made at end-diastole of LV internal diameter (LVEDID), septal wall thickness (SWT), LV length (LVEDL) and LV volume (LVEDV), and calculations were made of relative wall thickness (RWT), LV mass and LV ejection fraction (LVEF).The most common LV abnormalities in both adults and children with FRDA were increases in RWT and age-normalized RWT. In adults with a normal LVEF, all LV variables other than RWT were larger in males independent of body surface area (BSA), and all LV variables other than SWT and RWT were positively correlated with BSA. After adjustment for sex and BSA, GAA1 was a positive correlate of SWT and RWT (but not of LV mass), and was an inverse correlate of LVEDID, LVEDL and LVEDV. In children with a normal LVEF, SWT, LV mass and LVEDL were larger in males than females after adjusting for BSA, and in combination with sex, BSA was a positive correlate of all the LV variables except SWT and RWT. In children there were no correlations of GAA1 with any of the LV variables.In FRDA, increases in RWT and age-normalized RWT are the most frequent LV structural abnormalities, sex and body size are important determinants of most other LV structural variables in both children and adults, and increased genetic severity is associated with a smaller left ventricle and increased LV wall thickness in adults, but not associated with LV size or wall thickness in children. FXN which encodes for the mitochondrial protein frataxin [FXN, and in the remainder there is a deletion or point mutation within one of the alleles and a GAA expansion in the other allele. Cardiac disease is a frequent accompaniment of FRDA and not only can lead to arrhythmias and cardiac failure, but has been reported to be the most common cause of death [Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by a defect in the gene frataxin . In approf death , 3. LV sof death –11. It iof death . NeverthFXN gene (GAA1) is inversely related to cellular levels of frataxin [The number of GAA repeats in the shorter allele of the frataxin , 14, andfrataxin , increasfrataxin , 16, 17,frataxin , LV massfrataxin , 19 and frataxin  and a smfrataxin , 9. In afrataxin –24, the frataxin , 24, thefrataxin , 23 and frataxin , and wheThere are factors independent of the disease process in subjects with FRDA which are likely to influence LV cavity size, wall thickness and LV mass, and may need to be taken into account when investigating the LV structural and functional changes in FRDA. First, all LV structural variables are normally dependent on body size and while there may not be an ideal method for indexation to body size , not indAccordingly, the main aims of this cross-sectional study in FRDA subjects were (1) to investigate the relationship of LV variables with various measures of body size and to compare these methods in children and adults, (2) to determine the effects of sex after adjustment for body size on LV variables in children and adults, and (3) to determine the relationships of GAA1 and GAA2 with LV structural variables in children and adults after appropriate adjustment for other associated variables.The study design was approved by the Monash Health Human Research and Ethics committee (RES-18-0000-732Q) and all clinical investigation was conducted according to the principles expressed in the Declaration of Helsinki. The need to obtain consent from adult subjects, or consent from the parent or guardian of subjects who were minors, was waived for this retrospective study of clinically indicated testing. We identified 216 subjects with genetically confirmed FRDA who had attended the multidisciplinary FRDA clinic at Monash Medical Centre, Monash Health and had undergone echocardiography.Transthoracic echocardiography was performed using a Sonos 5500 ultrasound machine  in 131 subjects, a Vivid 7  in 79 subjects, an E9  in 2 subjects and an IE33  in 4 subjects. The vast majority of studies (>90%) were performed by one of two experienced sonographers (LD & RH) using a standardized protocol. M-mode images of the left ventricle were obtained in the parasternal long axis and short-axis views just distal to the mitral valve leaflet tips after alignment of the cursor perpendicular to the LV wall. Two dimensional images were used to facilitate identification of the endocardium. Measurements were performed off-line using Xcelera V1.2 L4 SP2 (Philips), including standard M-mode measurements of LV SWT, posterior wall thickness, LVEDID and LV end-systolic diameter . In subj2 and height2.7 [2) and females (>95 g/m2) [2.7 were used for male adults (>50 g/height2.7), female adults (>47 g/height2.7), male children (>44 g/height2.7), and female children (>40 g/height2.7) [LV end-diastolic external diameter was calculated by adding LVEDID to SWT and posterior wall thickness, as described by Stoylen et al . Fractioeight2.7 . Sex-spe95 g/m2) , and ageight2.7) . In chilight2.7) .Four- and 2-chamber loops of LV contraction were recorded and used for measurement of LV end-diastolic volume (LVEDV) and LV end-systolic volume, and the calculation of LVEF using the biplane method of discs. LV end-diastolic length (LVEDL) was generated during the automatic measurements provided during volume and LVEF calculations in the 2- and 4-chamber views, and the longest length from the 2-chamber and 4-chamber views has been used in the analysis .LV inflow velocities were recorded using pulsed-wave Doppler in the apical 4-chamber view with the sample volume located at the level of the mitral leaflet tips. The peak velocity (E) and deceleration time of early diastolic filling and the peak velocity (A) of the atrial phase of LV diastolic filling were measured.FXN was established by PCR analysis, as previously described [The presence and size of the GAA expansion on both alleles of escribed .Statistical analysis was performed using Systat V13 . Results are expressed as mean ± SD, or median (range) if not normally distributed. The relationships of standard LV measurements with anthropometric data, sex, age and the disease specific variables of GAA1, GAA2, AOS and symptom duration was analyzed using linear regression analysis in subjects who had a normal LVEF, were homozygous for GAA repeat expansions and had GAA measurements made at our institution. Univariate and multivariate analyses of LV measurements were performed separately in adults and children. The generalized linear model was used for multivariate analyses which combined continuous with categoric variables such as sex, or child versus adult. BSA was entered first in all models and a contribution from sex was considered as the second step. GAA1 or GAA2 were added as a third step, starting with whichever variable had the higher r value on univariate analysis. Age was added as a fourth step in the model and AOS was added next if it was a significant correlate of the dependent variable on univariate analysis.FXN point mutations, 202 were homozygous for GAA repeats and had results available from our laboratory, and 5 were known to be homozygous for GAA repeats on the basis of testing at other institutions. There were 9 subjects with a diagnosis of diabetes. The clinical and available genetic data regarding GAA1 and GAA2 of the total group divided into children (≤18 years) and adults (>18 years) are shown in Of the 216 subjects with FRDA who had an echocardiogram performed during the study period, 9 had There were 2 adults in atrial fibrillation, 2 adults with a pacemaker and the rest of the cohort were in sinus rhythm. There were 15 individuals with a LVEF ≤50%, of whom three were children. Characteristics of the 12 adults with a LVEF ≤50% included an age of 31±10 years, one subject with a point mutation, GAA1 of 578±223, GAA2 of 968±148 in the other 12 subjects, AOS of 10 (5–29) years and symptom duration of 13 (4–30) years.All subsequent analyses have been performed on the group of subjects who were homozygous for GAA repeat expansions, had GAA measurements performed in our laboratory, and had sinus rhythm and a LVEF >50%. The LV and transmitral Doppler variables of subjects who fulfil these conditions are shown in 2) was increased in only 47% and the sex specific LV mass index (g/height2.7) was increased in only 48%. There were 83% children who had at least one abnormality based on the above LV structural criteria. The mean Z-scores for LVEDID and LV end-systolic diameter were negative  and the mean Z-scores for SWT, posterior wall thickness and LV mass were positive .In homozygote children who were in sinus rhythm with a LVEF >50% (n = 60), the RWT was increased (>0.42) in 80%, the age-normalized RWT was increased (>0.39) in 83%, whereas the sex specific LV mass index (g/m2 or g/h2.7) or LVEDV . RWT and age-normalized RWT were both inversely correlated with age and AOS, and age-normalized RWT, but not RWT, was positively correlated with symptom duration. None of the LV variables were correlated with either GAA1 or GAA2. In contrast to the normal pattern of a positive correlation between LVEDID and SWT seen in healthy children [On univariate analysis, there were positive correlations of LVEDID, LV end-diastolic external diameter, LV mass, LVEDL and LVEDV with all the anthropometric variables, but no correlations of SWT with any of the anthropometric variables. RWT and age-normalized RWT were inversely correlated with all the anthropometric variables . Male sechildren , LVEDID Multivariate analyses were performed in homozygote children in sinus rhythm with a normal LVEF. For those dependent variables which were positively correlated with body size, modelling began with the addition of sex to BSA and then with the sequential addition of GAA1, GAA2 and age. Only variables that remained statistically significant during this process are shown in the models in 2) was increased in only 24%, and the sex specific LV mass index (g/height2.7) was increased in only 18%. At least one abnormality based on the above criteria was present in 65%. On univariate analysis (In homozygous adult subjects in sinus rhythm with a LVEF>50% (n = 124), the RWT was increased (>0.42) in 57%, the age-normalized RWT was increased (>0.42) in 61%, whereas the sex specific LV mass index  and GAA1 , and was smaller in males than females (p = 0.002), whereas A was positively correlated with age  and inversely correlated with GAA1 , but not affected by sex.Selected multivariate analyses were performed in the combined group of children and adults with a normal LVEF and homozygous for GAA repeat expansions (n = 184) to allow comparison with previous studies, and also to investigate whether there could be statistical differences between children and adults in the relationship of LV variables with GAA1 and GAA2. GAA1 was correlated with GAA2 in this combined group  and both GAA1 and GAA2 were inverse correlates of AOS , but when GAA1 and GAA2 were both entered in a model of AOS only GAA1 remained a significant correlate (p<0.001). In models which included sex, BSA and age, the addition of either GAA1 or GAA2 contributed to the prediction of LVEDID and LVEDL, but only GAA1 contributed to the prediction of LVEDV . HoweverThere are a number of new findings from the present study regarding LV structural features in FRDA. (1) The most common abnormal LV findings in FRDA in both children and adults in our cohort were increases in RWT and age-normalized RWT. (2) In separate analyses of children and adults with FRDA, body size was an independent determinant of all the measures of LV size and LV mass other than wall thickness, RWT and age-normalized RWT in both age groups. (3) Male sex was a determinant of a larger magnitude of all the measures of LV structure other than RWT and age-normalized RWT in adults with FRDA, and this effect was independent of body size. Male sex was also an independent determinant of larger SWT, LV end-diastolic external diameter, LV mass and LVEDL in children with FRDA, but was not an independent determinant of LVEDID, RWT or age-normalized RWT. (4) In adults with FRDA, GAA1 was an independent determinant of both smaller LV size and increased wall thickness, and possibly because of this combination, was not a determinant of LV mass. In contrast, there were no associations of GAA1 with LV size or wall thickness seen in children. (5) GAA2 was positively correlated with GAA1 in both children and adults, but was not an independent predictor of any of the LV variables in either children or adults. (6) Increasing age in adults with FRDA and a preserved LVEF was independently associated with decreases in LV size and LV mass, however, after adjustment for body size and sex there was no effect of age on measures of LV size or LV mass in children.That LV size and mass are determined in part by body size is well recognized from studies in healthy adults , 38, andPrevious studies in healthy adults have generally shown that male sex is associated with larger magnitudes of all LV variables (other than RWT), and that at least part of this sex effect is independent of body size , 38. Con2.7, and despite the use of sex-specific cutoffs.There are limitations of using a RWT of >0.42 to define LV remodeling in a mixed group of children and adults, not only because the normal range of RWT differs between adults and children, but also because RWT increases with age in both children and adults , 31. In The relationships of GAA1 with LV variables have been evaluated in a number of previous studies but there has been considerable divergence in the reported findings , 24, 42.LV end-diastolic external diameter was calculated in FRDA for the first time in this study and in contrast to healthy aging where older age is accompanied by increases in both RWT and LVEDED , higher GAA2 was positively correlated with GAA1 in both adults and children in the present study, and was also an inverse correlate of AOS in adults, but it was not a correlate of AOS in children, was not a correlate of AOS in adults independent of GAA1, and was not a correlate of any of the LV structural variables when children and adults were analyzed separately. There have been previous reports that GAA2 is associated with AOS , 21–24 aUnderstanding the nature of LV remodeling in FRDA is made more difficult given there can be a progressive process of wall thinning, positive remodeling and reduced LVEF in some subjects with FRDA. Indeed, there is evidence from a previous study that age is inversely associated with LV mass index in FRDA , suggestComparison of LV echocardiographic findings in adult subjects with FRDA with age and sex-matched control subjects has been reported previously in subgroups of the current cohort who were part of studies which investigated LV and right ventricular long-axis function , 11. FinThere are a number of limitations of this cross-sectional study. Early mortality will alter the makeup of the population of subjects with FRDA available to be included in a cohort study and this could distort our understanding of the LV structural changes in FRDA if a particular pattern of LV myocardial involvement was more likely to lead to premature death. Similarly the analysis of a group with normal LVEF has necessarily excluded a proportion of subjects who had previously progressed over time to have a reduced LVEF, and this could also confound analyses which include age or symptom duration. Unfortunately this limitation can only be fully addressed by long-term serial studies, preferably in which echocardiographic data was available prior to symptom onset. We have used an arbitrary definition for children as being up to the age of 18 years, but the definition of child versus adult has varied in population studies of LV structure. A diagnosis of reduced LVEF was based on a cutoff of <50% in the present study, but this number is also arbitrary, may not be ideal choice in FRDA, and based on data in population studies, possibly should vary depending on subject age and sex . HoweverIn conclusion, RWT and age-normalized RWT are the most sensitive echocardiographic measures for identifying LV involvement in FRDA and they have the advantage of being independent of sex and body size in both children and adults. Sex and body size are important determinants of most other measures of LV structure in FRDA, as they are in a healthy population, and it is therefore an important limitation of some previous FRDA studies that sex and/or body size were not taken into consideration in either defining abnormality or in assessing the relationship between GAA1 and LV structure. GAA1 is an independent determinant of both increased LV wall thickness and reduced LV size in adults, but not in children, and the existence of a difference between children and adults could be a contributing factor to previous discrepant findings with respect to the relationship of GAA1 with LV structure in FRDA. GAA2 is not an independent correlate of LV structural variables in either children or adults and previous positive findings with respect to GAA2 may just reflect the presence of a currently unexplained association between GAA2 and GAA1. Age is an independent predictor of smaller LV size and mass in adults, possibly reflecting in part the nature of cardiac disease progression in FRDA, however, additional longitudinal data will be required to further clarify this relationship, and also the determinants and time course of a reduced LVEF.S1 File(XLS)Click here for additional data file.


Permanent pacemaker implantation is a class I indication for all symptomaticpatients with complete heart block either congenital or acquired. However,certain portions of patients with congenital complete heart block areasymptomatic. Those patients are often very young, and implanting a permanentpacemaker is not always an easy decision. A therapeutic dilemma arises when aselect patient population does not meet certain criteria to gain the maximumbenefits out of prophylactic pacemaker therapy. Most asymptomatic patients withcongenital complete heart block will eventually become symptomatic and requirepacemakers at some point in their life but the definitive answer for the idealtime to initiate pacemaker therapy in such population has not been established.We present a case of asymptomatic congenital complete heart block withjunctional escape rhythm, which is capable of incrementing the heart rate withphysical activity to result in a challenge in diagnosis as well as the treatmentstrategy. Third-degree heart block is widely known as complete heart block (CHB). The diagnosiscriteria include the presence of complete atrioventricular (AV) dissociation withthe atrial rate being higher than the ventricular rate. Majority of patients withCHB are symptomatic due to profound bradycardia. Implanting a permanent pacemaker(PM) is a class I indication for all symptomatic patients with CHB, eithercongenital or acquired. However, certain portions of patients with congenitalcomplete heart block (CCHB) are asymptomatic. A therapeutic dilemma arises when aselect patient population does not meet criteria to gain the maximum benefits out ofprophylactic PM therapy. We present a case with asymptomatic congenital CHB withjunctional escape rhythm, which is capable of incrementing the heart rate withphysical activity to result in a challenge in diagnosis as well as in the treatmentstrategy.A 23-year-old African American female with no known past medical history presented tothe emergency department with 3 days history of nonproductive cough and runny nose.Review of systems was otherwise negative denying chest pain, dizziness, palpitation,or syncope. The patient was not taking any medications. She had no recent travel orpositive family history. On physical examination, the patient appeared comfortable.She was afebrile with blood pressure of 107/74 mm Hg, heart rate of 45/minute, andoxygen saturation of 99% on ambient air. The patient had mild pharyngeal edema butno jugular venous distension. Auscultation of the heart revealed slow heart rate,but it was regular with normal first and second heart sounds having no murmurs.Auscultation of bilateral lungs revealed clear breath sounds. There were neitherskin rash nor pedal edema.Admission electrocardiogram ECG;  showed CThe patient was admitted to the cardiac care unit in the diagnosis of CHB withprofound bradycardia at rest. Throughout her hospital stay, the patient remainedasymptomatic. She occasionally switched to apparent 2:1 heart block on thetelemonitor as shown in Her hospital course was uneventful, and the patient was discharged with an outpatientcardiology appointment. She was also scheduled to receive a loop recorderimplantation.2CHB occurs when auricular and ventricular contractions are not communicated to eachother beating at their own paces to result in a negative effect in cardiac function.CHB may occur in AV node, intra-Hisian, or infra-Hisian sites. Intranodal orintra-Hisian blocks almost always feature escape rhythms with narrow QRS complexesin the mean while infra-Hisian block often presents with wide QRS complexescapes.3 As His-bundle escape rhythms are chronotropically competent to maintainadequate ventricular rate, those patients often remain asymptomatic. One shouldalways consider the diagnosis of CCHB at the top of differentials tree when it comesto a young patient without past medical history presenting with CHB. Reversible andacquired etiologies of CHB need to be ruled out before committing to the diagnosisof congenital one. Comprehensive laboratory testing in our patient excluded Lymecarditis, electrolytes imbalance, or autoimmune diseases. Although cardiacsarcoidosis often presents with CHB, one of its characteristic ECG features includeswide QRS complexes owing to granulomatous infiltration of the conduction system.4 Therefore, CHB is most probably congenital in our case.Our patient had CHB with narrow complex junctional escapes as shown in 58 CCHB may be isolated orassociated with other structural heart diseases. One of the common complications ofisolated CCHB is progressive enlargement of left ventricle leading to dilatedcardiomyopathy even in asymptomatic patients. In a review of a multicenterretrospective study of 149 CCHB patients with CCHB, PM therapy may result in adecreased stress on the left ventricular over the time and may also benefithemodynamically from prophylactic pacing. In the same study, most patients whoreceived PM were found to have a decrease in their heart size during theirfollow-ups with echography.9 Data from few other studies also supported the aforementioned theory whenconsidering prophylactic PM implantation.11 Strongly, PM therapy needs tobe considered in asymptomatic patients with CCHB when there is average heart rateless than 50 beats per minute beyond the first year of life or less than 55 beatsper minute in infants, presence of wide QRS complex escapes, ventriculardysfunction, prolonged QTc, or complex ventricular ectopy.1214 Similar recommendations arealso mentioned in current guidelines from the American Heart Association for PMtherapy.16 Most of the asymptomatic patients with CCHB will eventuallybecome symptomatic and require a PM at some point in their life.18 The onlyquestion is when would be the ideal time to implant a PM for those individuals whodo not meet the above-mentioned criteria, since PM therapy itself also carries asignificant rate of complications such as thrombosis, lead fractures, and so on,which may occur in up to 25% of cases.11 To the present day, the question remains unanswered.Most cases of CCHB are immune-mediated and presumed to be related to maternalanti-Ro/SSA and/or anti-La/SSB antibodies that enter the fetal circulation duringgestation to result in fibrous degeneration of AV node and conductionsystem.1922 In addition, all the rhythmsin 23There are some other diagnostic pearls worth to learn from ECGs in our case. Treatment of asymptomatic CCHB with narrow complex escape rhythm is challenging.Those patients are often very young, and implanting a permanent PM is not always aneasy decision. The likelihood of renewing multiple generators, potential ofdeveloping infections, and vascular complications sometimes outweigh the benefits ofearly intervention, and the ideal time for implanting a PM in those patients stillremains a subject for further investigation. Nevertheless, the select group willbenefit from close follow-ups, annual echocardiography, and rhythm monitoring by aloop recorder when they opt for a conservative approach without PM therapy.


Despite advancements in pharmacological and device-based treatment, heart failure (HF) continues to impose an enormous burden for health care system worldwide. Decompensation of HF is one of the main causes of hospitalization, therefore the identification of patients with the highest risk of such complication is still of great clinical importance. The prognostic significance and utility of global longitudinal strain (GLS) has been previously studied in patients with the broad spectrum of cardiovascular diseases in various endpoints, however its role in assessing the risk of hospitalization due to HF exacerbation of optimally treated outpatients has not been fully explored. Therefore, the aim of the study was to verify whether the GLS of the left ventricle (LV) derived by 2D speckle tracking echocardiography has, independently of other well-known clinical parameters, an additional impact on the risk of HF decompensation in stable patients with LV systolic dysfunction of ischemic origin.In 193 clinically stable HF outpatients with LV ejection fraction (LVEF) ≤ 50%, GLS, additionally to other clinical parameters, was analyzed. During 34 (14–71) months of follow-up, 58 patients were hospitalized due to HF decompensation (EVENT).EVENT was significantly associated with age, QRS width, NYHA functional class, left atrium diameter, LV systolic and diastolic volume, LVEF, hemoglobin, brain natriuretic peptide, diuretic treatment, absence of beta-blockers, impaired renal function and history of diabetes in univariate Cox analyzes. GLS with pre-specified cut-off value of -9.4% was also significantly associated with the EVENT . After adjusting for above-mentioned parameters GLS was still a significant predictor of hospitalization due to HF decompensation.GLS measurement can provide incremental information on the risk of HF decompensation in stable outpatients with LV systolic dysfunction of ischemic origin. Constantly rising heart failure (HF) prevalence is a major clinical and public health concern. Despite compelling advancements in pharmacological and device-based treatment of HF, the mortality is still high , 2. Corothe aim of our study was to verify whether GLS of the LV derived by 2D STE provides, independently of other well-known clinical parameters, an additional impact on the risk of hospitalization due to HF decompensation in clinically stable outpatients with LV systolic dysfunction of ischemic origin.Over the years, many prognostic risk factors for HF exacerbation have been identified, including clinical, laboratory and echocardiographic parameters. Among the clinical parameters, the well-known are: new coronary events, poorly controlled hypertension, both ventricular and supraventricular arrhythmias with rapid ventricular rate, infections—especially respiratory system, high NYHA functional class, short distance in a 6-minute walk test, the presence of comorbidities, in particular: coronary artery disease, diabetes, renal failure, anemia and depression. In the group of laboratory parameters, increased levels of natriuretic peptides, troponins, catecholamine’s, urea, creatinine and low sodium levels have high prognostic value. In addition, one should not forget about other sociodemographic factors such as: age, marital status, compliance with dietary and therapeutic recommendations –9. Many Between October 2009 and October 2018 we prospectively enrolled consecutive stable patients with ischemic HF and LVEF ≤ 50%. The protocol of the study was approved by the Local Ethics Committee of the Medical University of Gdansk. Several clinical parameters were taken into account: a comprehensive baseline clinical history and physical examination, 12-lead ECG, routine laboratory blood tests and 2D-transthoracic echocardiography parameters, medical treatment and concomitant diseases. All patients had sinus rhythm and were clinically stable for at least 3 months before the enrollment. Patients received optimal medical therapy and coronary revascularization according to current guidelines . The excGE Ultrasound, Horten, Norway) equipped with phased-array transducer (M5S). Data were acquired from parasternal long-and short-axis views and the three standard apical views. For each view, cine loops were obtained by recording 3 consecutive heart cycles. Grayscale recordings were optimized for LV evaluation at a frame rate of 50–80 frames per second. All echocardiograms were stored digitally and analyzed with offline software on EchoPAC workstation . Standard echocardiographic parameters such as: LV end-diastolic (EDV) and end-systolic (ESV) volume, left atrium diameter (LADs) were analyzed according to the principles described in the recommendations [Transthoracic echocardiography was performed in patients in the left lateral decubitus position using a GE VIVID E9 ultrasound system . Briefly, three myocardial markers were placed in an end-diastolic frame in the apical 4-, 2- and 3-chamber views, respectively. The software automatically tracked the contour of the myocardium throughout the heart cycle to cover the entire thickness of the LV wall. Adequate tracking could be verified in real time and corrected by adjusting the region of interest or by manually correcting the contour to ensure optimal tracking. The value of peak GLS derived by 2D STE was analyzed from three apical views and calculated in the 17 segments  in relation to the strain magnitude at aortic valve closure  [LV longitudinal function was assessed by the semiautomatic algorithm (er view) . The autAll patients were followed-up at the University outpatient clinic every 6 months, or earlier if it was clinically required. The primary endpoint was hospitalization due to HF exacerbation (worsening signs of LV or right ventricular failure resulting in administration of intravenous diuretics) including those with fatal outcome (EVENT). The first episode of the EVENT was the end of follow-up period for a given patient. None of the patients were lost during the follow up.th - 75th percentiles), or numbers (n) and percentages (%). Comparisons between EVENT(+) and EVENT(-) group were made with the Fisher's exact test, U Mann-Whitney’s test or paired Student's t-test. An association between the analyzed parameters and the endpoint was assessed using the Cox hazard models. The accuracy of pre-specified cut-off values for analyzed parameters and their association as potential predictors of the study endpoint was determined by area (AUC) under the receiver-operating characteristic (ROC) curve. The time course of the endpoint, stratified according to the established cut-off value for GLS, was estimated using the Kaplan-Meier method, and the association between compared groups was estimated by the log-rank test. All the results were considered statistically significant at p ≤ 0.05. The statistical analysis was conducted with STATISTICA 9.0  and R 2.15.2.Continuous data are presented as the median  years, most of them were men (92%) and 91% underwent myocardial infarction, average LVEF was 33% and GLS -12.3%. Concomitant diseases such as diabetes, hypertension, chronic kidney disease (in stage III or higher) and hypercholesterolemia were present in 53 (27%), 131 (68%), 43 (23%) and 132 (68%), respectively. Regarding pharmacotherapy, a significant proportion of patients received an optimal medical therapy. Baseline clinical, demographic and echocardiographic characteristics of the entire study group are presented in During 34 (14–71) month follow-up, 58 patients (30%) reached the study endpoint. Patients from the EVENT(+) group were older, had a wider QRS complex, more advanced NYHA functional class, lower hemoglobin, higher brain natriuretic peptide (BNP) level, they were more likely to have diabetes, chronic kidney disease, they less likely used beta-blockers but more often diuretics and digoxin. With regard to the echocardiographic examination, EVENT(+) patients had larger LADs, greater EDV and ESV as well as lower LVEF and worse GLS: respectively -8.4% (-8.9 –-7.6) versus -12.6% (-14.9 –-10.3) in EVENT(-) group (p < 0.009). 2 as significant predictors of the EVENT. Pre-specified cut-off values with the highest risk of the EVENT were: age ≥ 72 years, QRS ≥ 118 ms, hemoglobin < 14.8 g/dl, BNP ≥ 214 pg/ml, LAD ≥ 45 mm, EDV ≥ 166 ml, ESV ≥ 89 ml, LVEF < 32%, GLS ≥ -9.4%  with high positive predictive value (PPV) of 98%, whereas the rest of the analyzed parameters were characterized by lower discriminatory powers as presented in GLS maintained its statistical significance as a predictor of the EVENT even after adjusting to other above-mentioned parameters. In this study, we proved that GLS with a cut-off value of ≥ -9.4% is a statistically significant indicator of hospitalization due to HF decompensation, independent of other known risk factors in a well-defined group of stable individuals with ischemic cardiomyopathy with LVEF up to 50% who were optimally treated. In our opinion, assessment of GLS in clinical practice seems to be useful in identifying which patients should receive expanded ambulatory care to reduce the risk of HF exacerbations.The role of GLS as a marker of cardiovascular events has been studied extensively in different groups of patients with regard to various endpoints , 27–30. GLS cut-off value of ≥ -9.4% determined in the present study in HF patients with LVEF up to 50% is within the range of values presented by other authors, varying from about -7% to -14% , 31–34. Particularly noteworthy is that GLS cut-off value established in the present study was characterized by the highest discriminatory power in revealing the risk of HF decompensation. AUC for GLS ≥ -9.4% was 0.81, while for broadly acknowledge LVEF it was lower (0.76). Furthermore, in the case of GLS values ≥ -9.4%, the relative risk of hospitalization due to HF decompensation was 15 times higher, while for others at most 2–3 fold. It is also worth to emphasize the very high PPV of GLS (98%), which was the highest PPV of all analyzed parameters. Sensitivity and specificity of this parameter were also high . Thereby, GLS proved to be the strongest indicator of HF decompensation in the group of stable patients with ischemic cardiomyopathy with LVEF ≤ 50%. In addition, it is a quick and easy to obtain parameter, even at the patient's bedside, more objective and not based on geometrical assumptions, as in case of LVEF. GLS seems to be considered as a standard parameter evaluated in patients with HF for identification the most at-risk persons requiring special care.It was a small, single-center investigation and due to the relatively small number of patients, it was impossible to create a more stable subpopulation of patients who reached the endpoint, and thus the results need to be confirmed in a larger group of patients. Next, functional performance of the studied population was not evaluated  Click here for additional data file.


LVLAVR at ventricular end‐diastole step wisely decreased to advanced aging, and had a highest F ratio compared with other left chamber volumetric parameters in both genders. LV mass and LA ejection fraction were significantly associated with LVLAVR at ventricular end‐diastole. In contrast, LV mass and LV ejection fraction were significantly coupled with LVLAVR at ventricular end‐systole. This study provides the reference values for LVLAVR from a relatively large number of healthy subjects. LVLAVR may be a sensitive parameter to reflect age‐ and gender‐related change in LV and LA volumes. Further studies should be required to determine its clinical usefulness over traditional echocardiography parameters in various cardiovascular diseases.We hypothesized that left ventricular and left atrial volume ratio (LVLAVR) assessed by three‐dimensional echocardiography (3DE) reflects age‐ and gender‐related change in left chamber size. We aimed to (1) determine the reference values of LVLAVR, (2) investigate their age and gender dependency, and (3) clarify which anthropometric and echocardiography parameters are closely associated with these indices. Both left ventricular (LV) and left atrial (LA) volume curves were obtained using 3DE speckle tracking analytical software, and the LVLAVR curve throughout one cardiac cycle was created, from which LVLAVR at ventricular end‐diastole and at ventricular end‐systole were determined in 313 healthy subjects . The mean values of LVLAVR at ventricular end‐diastole and ventricular end‐systole in male subjects were 5.74 ± 1.54 and 1.37 ± 0.35, respectively. Corresponding values in female subjects were significantly lower  using three‐dimensional echocardiography. We determined age‐ and sex‐specific reference values of LVLAVR at end‐diastole and end‐systole from a relatively large number of healthy subjects. Detailed assessment of LVLAVR clarifies the temporal status of LV−LA coupling at different time points of the cardiac cycle, and thus, would provide further insights for LV−LA coupling. We also hypothesized that this ratio would reflect the temporal status of LV–LA coupling at different phases of the cardiac cycle, and the contribution of other anthropometric and echocardiography parameters for LVLAVR is different at different time points of the cardiac cycle.Accordingly, the aims of this study were to (1) determine the reference values of LVLAVR in healthy subjects, (2) investigate their age and sex dependency, and (3) clarify which anthropometric and echocardiography parameters are closely associated with these indices.22.1Using 3DE database, we retrospectively searched adult healthy Japanese volunteers without hypertension, diabetes, hypercholesterolemia, and cardiovascular disease who underwent 3DE examination. Among 313 subjects who fulfilled eligibility criteria, majority were hospital employees and their relatives, residents, and fellows. Some 3DE datasets used for this study have been used for the previous publications . The depth and sector angle were adjusted to include the entire left ventricle and left atrium with the highest frame rate. 3DE full‐volume datasets were acquired with multibeat acquisition.2.3The image quality of 3DE datasets were evaluated subjectively, considering the completeness of LV and LA border visualization, and categorized as good, fair, poor, and extremely poor. The 3DE analysis for LV and LA volume measurements was performed with the use of a novel 3DE software  by an experienced investigator. Initially, the LV endocardial border was semiautomatically determined after two‐point clicks of the LV apex and center of the mitral valve annulus on the apical four‐chamber, two‐chamber, and long‐axis views extracted from 3DE datasets. The manual adjustment of the endocardial border was performed, when required. Subsequently, the software performed a 3DE speckle tracking analysis throughout one cardiac cycle Figure a. To meaFor the LA view adjustment, the center of the mitral valve and the LA roof was determined on apical four‐chamber and long‐axis views Figure d. After 2.4Both LV and LA volume curve data were exported as a text file. Each curve was interpolated by 100 points during ventricular systole and 100 points during ventricular diastole from one cardiac cycle using interpolation software . Temporal LVLAVR was calculated on 200 sampling points, and finally, LVLAVR curve was generated in each subject. The mean value of LVLAVR from different age groups were separately plotted on 200 points by male and female subjects.2.5The transmitral peak velocities during early (E) and late (A) ventricular diastole were measured on pulsed‐wave Doppler echocardiography. Mitral annular velocities during early ventricular diastole (e’) at both septal and lateral corners of the mitral annulus were measured, and average E/e’ was obtained in each subject.2.6Intraobserver variability was assessed by having the observer to repeat the measurement of LVEDV, LV end‐systolic volume (LVESV), maximal LA volume (LAVmax), minimal LA volume (LAVmin), LVLAVR at ventricular end‐diastole and ventricular end‐systole 2 weeks apart in 25 randomly selected subjects. Interobserver reliability was determined by employing a second observer to perform these measurements in the same 25 subjects. The intra and interobserver variability was calculated as the absolute differences between the corresponding two measurements in percentages of their mean and intraclass correlation (ICC).2.7SD) or median and interquartile interval (25th–75th percentile) based on the data distribution. Categorical data were expressed as numbers or percentages. The subjects were grouped into age decades (from the 3rd decade to ≥7th decade) based on sex. Group comparison between age decades was conducted using the one‐way analysis of variance (ANOVA). Two‐way ANOVA was performed to determine the effect of age and sex group for each echocardiography parameter. Univariable regression analysis was performed to determine the contribution of anthropometric and echocardiographic parameters for LVLAVR at ventricular end‐diastole and LVLAVR at ventricular end‐systole. Variables showing p < .1 were used for multivariable regression analysis with stepwise selection based on Akaike's information criterion. A two‐sided p < .05 was considered statistically significant. All statistical analyses were performed using commercial software .Continuous data were presented as mean ± standard deviation , fair in 131 (41%), poor in 112 (37%), and extremely poor in 26 subjects (8%), respectively. Both LV and LA volume curves could be generated in 280 subjects . The median frame rate of 3DE datasets was 20/s . The mean values of LVLAVR at ventricular end‐diastole and at ventricular end‐systole were 5.48 ± 1.53 and 1.25 ± 0.34, respectively, indicating that the LV volume was more than 5.5 times larger than the LA volume at ventricular end‐diastole, and the LV volume was 1.3 times larger than the LA volume at ventricular end‐systole.3.1The reference values for LV and LA volumes, ejection fraction, LV mass, and LVLAVR at ventricular end‐diastole and ventricular end‐systole are summarized according to age group, and displayed separately by male and female subjects Tables  and 2. A3.2Two‐way ANOVA showed that age group was significantly different for LVLAVR at ventricular end‐diastole, but sex group was not different. With regard to the LVLAVR at ventricular end‐systole, both age and sex groups were significantly different.3.3Table 2; 0.615, p < .001). Multivariable analysis, including age, sex, BSA, HR, SBP, DBP, LV mass, LVEF, and E/e’, showed that age, sex, BSA, HR, LV mass, and LVEF significantly contributed to the LVLAVR at ventricular end‐systole .Multivariable analysis including age, sex, BSA, HR, systolic blood pressure (SBP), diastolic blood pressure (DBP), LV mass, and LAEF, showed that age, sex, BSA, HR, LV mass, and LAEF significantly contributed to the LVLAVR at ventricular end‐diastole  We established the reference values of LVLAVR at ventricular end‐diastole and at ventricular end‐systole; (b) significant age dependency of LVLAVR was observed in both sexes, showing that highest and lowest values were observed in the 3rd and ≥7th decades, respectively; (c) there was also gender dependency, reflecting lower values of LVLAVR at both ventricular end‐diastole and ventricular end‐systole in female subjects than in male subjects; (d) the contribution of echocardiography parameters was different for LVLAVR at ventricular end‐diastole and LVLAVR at ventricular end‐systole, characterizing that LV mass and LA functional parameters were correlated with LVLAVR at ventricular end‐diastole, and LV mass and LV functional parameters were associated with LVLAVR at ventricular end‐systole.n = 19; mean age, 51 years) than younger group , which was in agreement with the results in this study. We expand their findings further using a different imaging modality, 3DE, that is more widely available and semiautomated software that is more user friendly and less time consuming and determined age‐ and sex‐related reference values of LVLAVR in a large number of healthy subjects.3DE provides accurate and reliable cardiac chamber volumes and their function in clinical practice . The other authors report no conflicts.