Pulmonary hypertension contributes to morbidity and mortality in both the term newborn infant, referred to as persistent pulmonary hypertension of the newborn (PPHN), and the premature infant, in the setting of abnormal pulmonary vasculature development and arrested growth. In the term infant, PPHN is characterized by the failure of the physiological postnatal decrease in pulmonary vascular resistance that results in impaired oxygenation, right ventricular failure, and pulmonary-to-systemic shunting. The pulmonary vasculature is either maladapted, maldeveloped, or underdeveloped. In the premature infant, the mechanisms are similar in that the early onset pulmonary hypertension (PH) is due to pulmonary vascular immaturity and its underdevelopment, while late onset PH is due to the maladaptation of the pulmonary circulation that is seen with severe bronchopulmonary dysplasia. This may lead to cor-pulmonale if left undiagnosed and untreated. Neonatologist performed echocardiography (NPE) should be considered in any preterm or term neonate that presents with risk factors suggesting PPHN. In this review, we discuss the risk factors for PPHN in term and preterm infants, the etiologies, and the pathophysiological mechanisms as they relate to growth and development of the pulmonary vasculature. We explore the applications of NPE techniques that aid in the correct diagnostic and pathophysiological assessment of the most common neonatal etiologies of PPHN and provide guidelines for using these techniques to optimize the management of the neonate with PPHN. Persistent pulmonary hypertension of the newborn (PPHN) is a complex disorder that is characterized by the presence of an increased pulmonary vascular resistance (PVR) associated with shunting of deoxygenated blood from the pulmonary to the systemic circulation causing severe hypoxemia.4 It is associated with an increased risk of an adverse outcome  5. The vascular pruning, abnormal vasculature, and vaso-reactivity in infants with bronchopulmonary dysplasia (BPD) set the tone for the development of pulmonary hypertension (PH) in this population as well.8 It is a known complication of BPD, with the incidence increasing with the severity of BPD.9 In infants with ‘severe’ BPD, two recent cohorts put the incidence at >50%.10 Echocardiographic signs of PH in preterm infants in an early phase (72 h to 14 days of age) are associated with decreased in-hospital survival and an increased incidence of moderate-severe BPD.11PPHN occurs in about 1–2 per thousand live born infants, mostly in term and late preterm newborns.13Common risk factors for the development of PPHN in (near-) term infants and PH in preterm neonates are summarized in Table The typical clinical picture is a patient with hypoxic cardio-respiratory failure with a pre-/postductal difference in oxygen saturation of ≥5%, although this difference will be attenuated in the presence of a relevant atrial right-to-left shunt. It should be noted that a pre-/postductal oxygen saturation difference can also be caused by left-sided obstructive heart disease, such as coarctation of aorta, interrupted aortic arch, and hypoplastic left heart disease. Measuring pre- and postductal blood pressure can also be helpful and may give insights regarding the presence of shunts. Postductal blood pressure may be heavily influenced by a right-to-left transductal shunt and falsely miss low preductal blood pressure, which is crucial.Distinguishing between PPHN and cyanotic heart lesions on clinical grounds can be challenging. This, however, is essential since management for these disorders are quite different. Clinical signs and symptoms suggestive of an underlying congenital heart defect are summarized in Table Delay in the diagnosis and appropriate treatment of a cyanotic heart disease is associated with worsening prognosis. It is therefore imperative to have a comprehensive echocardiographic evaluation to rule out any structural abnormality. When in doubt during the time before echocardiography can be performed, it is advised to start prostaglandin E1 in anticipation of a potential heart defect. In a patient with PPHN, prostaglandin E1 might have some pulmonary vasodilatory effects, and in severe PPHN, it will preserve postductal systemic perfusion, albeit at the expense of cyanosis. It should be noted that the institution of a treatment regimen aiming at pulmonary vasodilation may deteriorate the clinical condition of the patients with certain heart defects, such as total anomalous pulmonary venous connection (TAPVC) and hypoplastic left heart syndrome.The following structural heart defects may clinically mimic PPHN: TAPVC, transposition of great arteries (TGA), pulmonary atresia with or without ventricular septal defect (VSD), severe Fallot’s tetralogy, tricuspid atresia, unguarded tricuspid orifice syndrome, severe Ebstein anomaly, and sometimes even left-sided obstructive heart disease .Pulmonary artery pressure (PAP) is determined by pulmonary blood flow (PBF), PVR, and pulmonary capillary wedge pressure (PcWP), as shown in the following Eq. 1.Under normal circumstances, PAP falls after birth within 2 months to reach a level that is comparable to adult values (systolic PAP <25 mmHg).As can be derived from Eq. 1, PH can be caused by an increase in PcWP ), by an increase in PBF , or by raised PVR . A combination of these factors is also possible.141.1.due to parenchymal lung diseases, such as meconium aspiration syndrome (MAS), respiratory distress syndrome (RDS), hypoventilation, and pneumonia1.2.in response to certain stimuli, such as hypothermia, sepsis, stress, hypercapnia, hypoxemia, acidosis, and hyperviscosity1.3.toxic/pharmacological Maladaption of pulmonary vasculature 2.1.in utero closure of ductus arteriosus 2.2.pulmonary hyperperfusion in congenital heart disease with large left-to-right shunt2.3.infants with fetal growth restrictionMaldevelopment of pulmonary vasculature (remodeling of pulmonary vasculature) in response to:3.1.congenital diaphragmatic hernia3.2.pulmonary hypoplasia .Underdevelopment of pulmonary vasculature , such as in:In PPHN, the rise in pulmonary blood pressure is generally secondary to an increased PVR with the following etiology:15 Recently, it was recognized that PH can be caused by pulmonary venous stenosis, especially in preterm infants with BPD, that is often overlooked.17 In about 10–20%, no specific cause of PPHN is found (‘idiopathic’ PPHN).14Respiratory disorders that are associated with PH include: congenital diaphragmatic hernia, BPD, alveolar capillary dysplasia , lung hypoplasia (‘primary’ or ‘secondary’), surfactant protein abnormalities, pulmonary interstitial glycogenosis, pulmonary alveolar proteinosis, and pulmonary lymphangiectasis.• Right ventricular systolic and diastolic failure secondary to increased afterload• Decrease in RV stroke volume and RV filling• Decrease in pulmonary blood flow with ventilation-perfusion mismatch• RV dilatation causing a D-shaped left ventricle with decreased LV preload• Decreased LV stroke volume• Right-to-left shunting through the ductus arteriosus and/or foramen ovale.The key features in PPHN are an increased PVR resulting in high PAP, ductal and/or atrial right-to-left shunting, and right (and ultimately left) ventricular dysfunction. This leads to:In a severe form of PPHN, this ductal and/or atrial right-to-left shunt may guarantee postductal or preductal systemic perfusion, respectively, however, at the expense of cyanosis.Comprehensive echocardiography is indicated when there is a clinical suspicion of PPHN to exclude congenital heart disease.19 According to the recent AHA/ATS guidelines, iNO can be beneficial for preterm infants with severe hypoxemia that is due primarily to PPHN physiology rather than parenchymal lung disease, particularly if associated with prolonged rupture of membranes and oligohydramnios.20Neonatologist performed echocardiography (NPE) is useful in multiple ways: (a) making the diagnosis and grading the severity, (b) determining the need for specific (pulmonary vasodilator) or supportive (choice of inotrope) therapy, (c) monitoring the response to therapy, and (d) rational weaning of therapy. This is especially relevant when administering inhaled nitric oxide (iNO) for infants <34 weeks’ gestation, where multiple randomized controlled trials  have suggested limited evidence.Once the diagnosis of PPHN is confirmed by echocardiography, the clinical course and the effects of medical interventions can be monitored using NPE with the emphasis on:1. pulmonary artery pressure and PVR,2. myocardial performance, and3. shunting through ductus arteriosus and open foramen ovale.An overview of all echocardiographic parameters that can be assessed with NPE is presented in Table PAP can be assessed by measuring tricuspid valve regurgitation peak velocity, pulmonary regurgitation peak velocity, transductal right-to-left flow peak velocity, interventricular septum (IVS) configuration, and LV systolic eccentricity index (LV-sEI).Systolic pulmonary artery pressure (SPAP) can be estimated by measuring the peak velocity of tricuspid valve regurgitation with the use of the modified Bernoulli’s equation; see Eqs. 2 and 3:25RAP is usually not measured, and a value of 3–5 mmHg is generally assumed. The estimation of SPAP by measuring TR is reliable and often equivalent to pressures measured in the catheter lab while using continuous wave Doppler Fig. . HoweverIn the presence of pulmonary valve regurgitation, mean PAP (MPAP) can be estimated by measuring its peak velocity using Eq. 4:The RVdP is generally assumed to be around 2–5 mmHg.Transductal right-to-left blood flow can be used to estimate SPAP, when it lasts ≥30% of the heart cycle, by measuring its peak velocity using Eq. 5:15 However, measurement of PAP via ductal flow is often not reliable. Assessment of the direction of transductal blood flow is more useful and will indicate the relation between pulmonary and systemic pressures.A ductal right-to-left or bidirectional shunt is observed in 73–91% of the patients with PPHN.5 It is best analyzed at the end of systole in the parasternal short axis view above the level of the papillary muscles.26An alternative, although more subjective, estimation of PAP is based upon the alignment of the IVS Table . Normall27 LV diastolic EI is more a marker of volume overloaded right ventricle; for clinical conditions such as PPHN, pressure overload predominates, and hence the usefulness of the sEI.A more objective estimation is made by calculating the LV-sEI, which is the ratio of LV dimension parallel and perpendicular to the septum, respectively. Figure [RVOT]-ratio (ratio between tricuspid regurgitation velocity (TRV) and the velocity–time integral (VTI) of blood flow through the right ventricular outflow tract (RVOT)), and pulmonary artery compliance.PVR can be assessed by measuring right ventricular systolic time intervals (pulmonary artery acceleration time (PAAT), right ventricular ejection time (RVET), right ventricular pre-ejection time (RVPET)), TRV:VTIRight ventricular systolic time intervals are another validated method for the estimation of PVR. The following right ventricular time intervals can be derived from the Doppler PBF velocity curve: RVET, RVPET, and PAAT, also referred to as time to peak velocity (TPV) see Fig. .Fig. 4Ri30 However, PAAT has recently been validated as a feasible and reproducible, non-invasive echocardiographic imaging marker, for detection of pulmonary vascular disease and PH in neonates and children.31 This study, with simultaneous Doppler echocardiography and invasive catheterization, established PAAT-based regression equations in children to accurately predict invasive catheterization-derived SPAP and PVR. A cutoff value of <90 ms reliably detects pulmonary vascular disease, and a value <40 ms detects pulmonary vascular disease in its most severe form of PH. The normal value of the PAAT:RVET ratio is approximately 0.31 or greater. A PAAT:RVET ratio less than 0.23 and/or an increased RVPET:RVET ratio is indicative for increased PAP.31 Visual inspection of the shape of the Doppler flow envelope pattern across the RV outflow tract is a sensitive predictor of PH and right heart dysfunction in children and infants. The mid-systolic notch, also referred to as the “flying W”, is associated with elevated PVR and PAP  non-invasively by measuring pulmonary diameter in systole (Ds) and diastole (Dd) and analyzing the TR jet to calculate SPAP.36 There is a paucity of data on this measurement in the term and preterm neonatal population.Lower CdynPA is found in children with PH.40An increased PVR can cause an increased pulmonary artery diameter. Impaired right ventricular systolic and diastolic performance will lead to dilation of the right ventricle, right atrium, and inferior vena cava. Normative data for right ventricular size have been published.25Biventricular dysfunction can be found in up to 70% of patients with PPHN and is thought to be related to increased right ventricular afterload, decreased left ventricular preload in addition to possible myocardial ischemia.41Classical PPHN  is a pre-capillary disorder. The right heart is dilated but the LV is not . One might find lower PcWP, as the malady is caused by elevated PVR. Hence, pulmonary vasodilators work well. BPD associated PH is another beast, and some infants have post-capillary pathophysiology as an important contributor. This group is clinically characterized by an elevated PcWP and no response to or deterioration after start of pulmonary vasodilators such as iNO and sildenafil. Unfortunately, invasive cardiac catheterization is not easily available, and many of these infants may not tolerate that. Echocardiographic clues to this malady are dilated LV and increased LA end-diastolic pressure. This cohort needs systemic and not pulmonary vasodilators as the pathophysiology centers on elevated ‘systemic’ more than ‘pulmonary afterload’.25A nearly consistent finding in (near-)term patients with PPHN is a low left ventricular output (LVO) and reduced LV stroke volume (LV-SV) in combination with normal or mildly decreased LV-EF, that is explained by reduced preload secondary to right-to-left shunting (decreased pulmonary venous return) and ventricular–ventricular interaction (flattening of IVS).23Echocardiographic markers of left ventricular failure (reduced LV size and stroke volume) are associated with the need for more intense treatment, such as high frequency ventilation and ECMO in newborn infants diagnosed with PPHN.Right ventricular function can be assessed by measuring the fractional area change (FAC), myocardial performance index (RV-MPI), right ventricular systolic to diastolic duration ratio (RV S/D ratio), and tricuspid annular plane systolic excursion (TAPSE).Left ventricular function can be analyzed by monitoring myocardial performance (LV-MPI), LV-SV and LVO, and ejection fraction (EF biplane Simpson).By using tissue Doppler imaging (TDI) and speckle-tracking echocardiography (STE), the performance of both ventricles can be assessed.42 Diminished TAPSE (<4 mm) is predictive for the need of ECMO and death in infants with PPHN.43TAPSE is a measure of RV longitudinal function and obtained from the 4-chamber view using the M-Mode with the cursor aligned along the direction of the lateral annulus see Fig. . TAPSE pFAC is a planimetric measure of the ratio of systolic to diastolic area in apical 4- or 3-chamber view by manual tracing of the endocardial border of the right ventricle. Unlike TAPSE, right ventricular FAC is affected by radial, basal, and apical functions as well as longitudinal fiber shortening, but it is considered to be more prone to operator-dependent variation. FAC is calculated by the following formula:44 Median values of 19% were associated with the need for ECMO or death.43It is important that the entire ventricle is visualized when tracing the endocardium in systole and diastole including the outflow tract and the lateral wall Fig. . Trabecu46 MPI of both the RV and LV are significantly elevated in infants with PPHN.25The MPI, also referred to as Tei index, represents the relation between the sum of isovolumic contraction and relaxation time and ejection time and can be derived from pulsed Doppler or tissue Doppler Fig. . Right vGlobal RV myocardial performance index (MPI) can subsequently be calculated using Eq. 8 .47Reference values for these parameters in the neonatal period have been published recently.The right ventricular systolic to diastolic duration ratio (RV S/D ratio) is an index of systolic and diastolic  function of the right ventricle and is assumed to reflect ventricular loading and contractility. An increase in S/D ratio is seen as a sign of global right ventricular dysfunction secondary to increased afterload.48 The RV S/D ratio is related to SPAP and RV performance.48 An increased RV S/D ratio (>1.3) is associated with the need for ECMO or death.25The S/D ratio is calculated from the Doppler signal of tricuspid valve regurgitation. The duration from onset to termination of tricuspid valve regurgitation is the systolic duration (SD) and the diastolic duration is the time between two jets of tricuspid regurgitation (DD), see Fig. Diastolic function is traditionally studied by measuring the tricuspid valve inflow velocities (Early (E), Late (A), and ratio (E/A)) during diastole by PW Doppler from the apical 4-chamber view.TDI derived deformation imaging calculates strain rate by assessing the difference in velocity (the velocity gradient) between two points along the longitudinal plane of the 4-chamber view. Strain is then derived by integrating time into the strain rate values. Only deformation along  the beam of the ultrasound is measured by the TD method and is therefore highly dependent on the angle of insonation.TDI of the right ventricular lateral wall with the sampling gate positioned at the junction of tricuspid annulus allows assessment of systolic and diastolic velocities.Peak systolic (s′), early and late diastolic (e′ and a′) myocardial velocities can be easily obtained by TDI, including time periods of closing to opening of the tricuspid valve (TcOT′), isovolumic relaxation time (IVRT), and the duration of systole (S) and diastole (D) with the resultant S/D ratio.49 In addition, reduced early diastolic velocity on days 1 and 2 of life predicted early respiratory outcome in infants with congenital diaphragmatic hernia.50Reduced systolic and diastolic TDI velocities have been found in neonates with PH.51 This further highlights the ability of deformation parameters to identify myocardial dysfunction and monitor treatment response.In term infants with severe PPHN not responsive to iNO, RV strain (−17%) and strain rates (−1.5 1/s) significantly improves following the administration of milrinone over a 24-h period .53 As the longitudinal shortening is the main deformation of the right ventricle, longitudinal strain seems to be the most robust parameter in describing systolic right ventricular function.52 In addition, diastolic measurements of early and late myocardial movements can be obtained. As an angle-independent method, it does not require geometric assumptions and has been used in the neonatal and preterm population. In term infants with PPHN, a reduced global systolic peak strain of the RV was associated with progression to death or ECMO.43 In comparison to healthy controls, term infants with PPHN in the first week of age have worse RV function as shown by a decrease in the magnitude of RV global longitudinal strain.54 Similarly, preterm infants with late onset PH  also displayed lower values of RV global and free wall longitudinal strain when compared to preterm infants without PH.55 Sehgal et al. recently reported the case of a 3-month-old infant where RV function was monitored using STE in response to iNO administration.56 A sequential change in global and segmental strain was observed and regional asynchrony in segmental deformation was noted additionally in response to iNO administration. Basal and middle lateral segments showed paradoxical strain . Assessment of regional RV function helped understand adaptive mechanisms and assess therapeutic interventions.STE has been successfully used in the estimation of right ventricular function in term and preterm infants, although the technique was originally developed and validated for the left ventricle of adults.Secondary to increased pulmonary arterial pressure, deoxygenated blood can shunt through the fetal channels  to the systemic circulation leading to hypoxemia Fig. .Fig. 9Tr25 A bidirectional shunt with a systolic right-to-left duration ≥30% of the total heart cycle is considered non-physiologic and likely to represent PPHN. An atrial bidirectional or right-to-left shunt is detected in 73–100% of PPHN patients.25 Also, left-to-right shunting over the interatrial septum is possible, since in PPHN diastolic pulmonary artery pressure is generally sub-systemic with suprasystemic SPAP. A pure right-to-left shunt at the atrial level suggests TAPVC until proven otherwise.In 73–91% of patients with PPHN, a transductal right-to-left or bidirectional shunt can be observed.22 However, this does not imply that shunting is the primary problem; it is merely a marker of disease severity. In the presence of RV dysfunction, shunting through the fetal channels is a mechanism to augment systemic blood flow and offset high RV afterload. The PFO functions as the modulator of  cerebral blood flow, whereas the PDA modulates blood flow to the body and to some extent to the brain.An exclusive right-to-left transductal shunt in patients with PPHN is associated with an increased risk of mortality.Structural assessment of the heart to rule out any congenital heart defect, especially duct-dependent heart conditions or significant congenital heart defects; should be done on the first echocardiogram or at the earliest opportunity in a sick neonate.Assessment of (systolic) PAP—this can be measured accurately if there is tricuspid regurgitation (TR). Absence of TR or minimal TR does not rule out PPHN. Assessment of PAP cannot be reliably done via ductal or atrial shunt. However, direction of the shunt will give a good indication about the pressure in relation to the systemic blood pressure.Assessment of the shunt direction across ductus arteriosus—right to left, left to right, or bidirectionalAssessment of shunt across foramen ovale—right to left, left to right, or bidirectional. If atrial shunt is purely right to left it should be considered secondary to TAPVC until proven otherwise.Assessment of IVS morphology—flattening or bowing of IVS towards LV suggest supra-systemic PAP or significant volume overloading of the right ventricle (failing right ventricle)Right ventricular size—dilated or hypertrophied or both. RV, RA, and pulmonary artery are commonly enlarged.Objective assessment of RV function  is recommended. Subjective assessment of RV performance is unreliable and inaccurate.Trend of VTI across pulmonary valve or right ventricular output can be used in monitoring the progress without estimating the cardiac output. The cardiac output is often contaminated by the shunts in this population.Objective assessment of LV function , LV-SV and LVO, ejection fraction (EF biplane Simpson), TDI of IVS and LV free wall, or STE) is recommended.Focused serial echocardiography should be performed to observe the progression, especially in sick infants who are not responding to the intervention.One of the most important uses of echocardiography in the NICU is in the management of PPHN. Echocardiography should be performed to rule out a congenital heart defect, diagnose PPHN, assess myocardial function, and guide therapy . Serial echocardiography is useful in monitoring the response to the treatment in PPHN. We propose a guidance on the assessment of PPHN using NPE, as depicted below. This list is not exhaustive, although not all patients would need all the measurements in the management of PPHN.PH is a serious disorder that may occur in both term and preterm infants. Neonatologist performed echocardiography is very useful for the timely diagnosis of PH and targeting treatment to prevent morbidity and mortality. For these purposes, many echocardiographic variables can be evaluated, but unfortunately not one of them is the ultimate predictive parameter to assess and manage PH. It is advised to always perform a comprehensive echocardiographic examination. One should bear in mind that NPE will not improve outcome on its own, but it is used to guide treatment and monitor hemodynamic responses that might prove beneficial for the patient’s prognosis.


Speckle tracking analysis (STE) of the left ventricle offers a new method to assess left ventricular (LV) diastolic function. LV diastolic strain measurements offer a non-invasive, global and direct measure of LV diastolic function. However, there is little data on normal values and the influence of anthropomorphic factors which is crucial in clinical practice for new techniques. The aims of this study were to formulate reference values for LV diastolic strain rate, elucidate effects of age and sex on LV diastolic strain analysis and compare STE measurements with conventional LV diastolic measurements. One-hundred-forty-seven healthy subjects aged 20–72 years (≥ 28 subjects per age decade) were prospectively included  and examined with electrocardiography and 2D-echocardiography, including speckle tracking. Left ventricular peak early diastolic strain rate (Sre) was measured in the apical windows, using STE. Men had significantly lower LV Sre values than women . Left ventricular Sre was inversely associated with age, with values decreasing with ageing. An inverse relation was also found with blood pressure and body surface area. Linear regression analysis showed that LV Sre was independently associated with both age and sex. A multivariable linear regression analysis for LV Sre with conventional LV diastolic variables accounted for 70.9% of the variation of LV Sre, showing good model performance. Reference values for LV Sre are reported and found to be both age- and sex-dependent. Therefore we recommend age- and sex-specific references values to be used in daily clinical practice.The online version of this article (10.1007/s10554-018-1480-4) contains supplementary material, which is available to authorized users. Left ventricular (LV) diastolic disease is increasingly being recognized as an important cause of LV heart failure. Approximately 40% of the patients present themselves with symptoms of heart failure while having a preserved ejection fraction . IncreasReference values are of vital importance for clinical practice and possibly even more so for new techniques. A recent study published normal values for LV diastolic peak strain rate, but the influences of age and sex were not elucidated . Therefo2) and women who were pregnant or had breast implants were excluded. Details have been published earlier . Categorical data are presented as frequencies and percentages. For comparison the paired Of the 155 eligible volunteers, 147 were included in the study. Reasons for exclusion were breast implants n = 2), valvular pathology (n = 2), surgically closed duct (n = 1), hypertension (n = 1), morbid obesity (n = 1) and right bundle branch block on ECG (n = 1). Baseline characteristics of the study population per age group are shown in Table , valvula−1, A2C Sre: 1.09 SD 0.25 s−1 and A3C Sre 1.09 SD 0.25 s−1. The mean LV global Sre was 1.11 SD 0.24 s−1. The LV Sre values per age group are presented in Table Strain rate analysis was highly feasible, it was possible to measure global strain rate in 98.0% of the patients in the A4C-view, 97.3% of the A2C-views and 95.9% of the A3C-views. Of the entire cohort the mean global LV Sre values of each view were: A4C Sre 1.14 SD 0.29 sLeft ventricular Sre values were sex-dependent, with lower values for males in every segment Table . This fiUnivariable linear regression analysis was performed between baseline characteristics and LV Sre Table . Both a Table 2 was 0.709, meaning 70.9% of the variation of LV Sre can be predicted with this model. E-wave velocity and e′ were independently correlated with LV SRe, as were the systolic indices LV EF and LV GLS.A second multivariable linear regression analysis was performed Table  which inThis study demonstrates a clear relation between LV early diastolic peak strain rate and age. There is a clear decrease of LV Sre with ageing, which is especially notable after the fifth decade. The second important finding is that there are significant sex-dependent differences, with males having consistently lower LV Sre values than females.−1, based on their mean value of 1.56–2SD. The mean in our cohort was notably lower, namely 1.10 ± 0.24, which would result in a lower limit of normal of 0.62 s−1. A possible explanation for this difference may be the higher mean age of our study population .It has been widely recognized that with age, LV diastolic function decreases even in the absence of cardiovascular disease . It cons−1. Marwick et al. reported that sex is independently correlated with LV diastolic Sre [Though the current guidelines do not mention differences in LV diastolic function between men and women, we found consistently lower LV diastolic Sre values in men. The difference in mean LV Sre between men and women was 0.16 solic Sre , and Morolic Sre . These sA few studies have looked at LV Sre in populations with a wide variety of diseases and conditions, but only a few studies have actually looked at LV Sre in a cohort of healthy subjects. Besides age and sex, body size, blood pressure and QRS-duration were correlated with LV diastolic Sre. We also expected heart rate to correlate with LV diastolic function, but this was not the case in our study, most likely due to the lack of variation in heart rate (62 SD 10 bpm in our study population).The current algorithm to assess LV diastolic function is very good but relies on variables which have some limitations; the early diastolic peak velocity of the mitral annulus assessed with TDI which is angle-dependent, maximum LA volume can be enlarged is in the absence of LV diastolic dysfunction as it is an indirect measure of LV diastolic function, and E- and A-wave velocities are dependent on LV and left atrial filling pressures . This maThe results also showed that LV systolic function was independently associated with LV Sre. A better systolic function logically leads to better diastolic function  Supplementary material 2 (DOCX 17 KB)


Pulmonary hypertension (PH) is a complication of bronchopulmonary dysplasia (BPD). The underlying pathophysiology of BPD-associated PH is complex and poorly understood. Echocardiogram may underestimate the severity of pulmonary hypertensive vascular disease in severe BPD. Digital subtraction pulmonary angiography (DSPA) is a potentially useful imaging modality for evaluating changes in the pulmonary vasculature of BPD-associated PH. In this study, we objectively quantified the pulmonary hypertensive vascular changes demonstrated by DSPA using a novel pulmonary vascular underperfusion score (PVUS) and correlated the scoring system with echocardiography parameters and cardiac hemodynamics by right heart catheterization. Premature births cause developmental arrest of lungs and impair pulmonary vascular angiogenesis, which decrease the cross-sectional area of pulmonary blood flow and in turn results in bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH). The American Heart Association published guidelines for the management of PH in infants and children . HoweverThis was a retrospective, single-center study and included 10 consecutive patients with severe BPD, who were referred to our PH service between January 2016 and December 2018 for further evaluation and management. For the purpose of the study, BPD was defined as high oxygen (≥30% fraction of inspired oxygen (FiO2)) and respiratory support requirements at 36 weeks of corrected gestational age per published guidelines . InstituThe potential advantages of the DSPA technique as previously described include a lower dose of radiographic contrast compared to conventional pulmonary angiography . A BermaThe DSPA images for each patient were analyzed for pulmonary vascular underperfusion score (PVUS) by manually counting the areas of perfusion defects: score (0) = pulmonary capillaries seen up to the periphery in uniform manner ; (1) = pulmonary capillary perfusion defect <3 mm from the outer margin of lung parenchyma or patchy defects along the lung periphery, (2) = 3 to <5 mm short from the lung outer margin, (3) = 5–7 mm short from the lung outer margin (winter-tree appearance); and score of 1 for each perfusion defect along the distribution of major inter-lobar branch pulmonary arteries. All scores from both lungs in each subject were then added and a total score was assigned as PVUS for individual patient. Each patient’s PVUS score estimated by 2 observers separately and when there was discrepancy, the observation by senior author (KCC) was the final value used for this study. At the time of RHC, all patients had acute vasoreactivity testing (AVT) with inhaled nitric oxide (iNO) 20 ppm and 100% oxygen. A patient was diagnosed as responder to AVT if the subject experienced a 20% decrease in mean PA pressure and unchanged or improved cardiac index .Echocardiographic images were available in each patient within first 7 days of life and were reviewed. The diagnosis of PH was made by echocardiography based on the following criteria: (1) a tricuspid regurgitation (TR) velocity ≥ 3 m/s in the absence of pulmonary stenosis and/or (2) a flat or left deviated interventricular septal configuration with right ventricular (RV) hypertrophy as previously described . The echThe demographics and clinical data of 10 preterm infants  with severe BPD were summarized in 2) pulmonary vascular resistance (PVR) but only six patients were reactive to AVT with inhaled nitric oxide (iNO) and 100% oxygen using Barst criteria [p = 0.0048). N = 6) and non-responders (N = 4) (p = 0.005). The intraclass correlation coefficient (ICC) for interobserver variability in estimating PVUS was 0.87, mean difference was 0.67 with 95% confidence interval (CI), −1.3 to +1.3 (The hemodynamic parameters were summarized in criteria . There w to +1.3 .p = 0.38) for pediatric heart transplant patients with similar BSA undergoing right heart catheterization and conventional PA angiography as a part of their routine cardiac catheterization (control group). Total fluoroscopy time in patients was 12.5 ± 4.4 min compared to 11.5 ± 2.5 min in the control group (p = 0.52). However, the radiation dose and fluoroscopy time were for the total RHC procedure and not for pulmonary angiography alone in both groups.Total radiation exposure in 10 BPD cases was 93.6 ± 30 mGy compared to 82.6 ± 31 mGy  with subsequent clinical improvement, but our findings may not be generalized to all BPD patients. We speculate that some BPD infants who do not respond to sildenafil may have developed advanced changes in pulmonary vasculature. Large multicenter studies are required to confirm our findings that PVUS can be used to risk stratify patients with BPD-associated PH.


Myocardial pathology results in significant morbidity and mortality, whether due to primary cardiomyopathic processes or secondary to other conditions such as ischemic heart disease. Cardiac imaging techniques characterise the underlying tissue directly, by assessing a signal from the tissue itself, or indirectly, by inferring tissue characteristics from global or regional function. Cardiac magnetic resonance imaging is currently the most investigated imaging modality for tissue characterisation, but, due to its accessibility, advanced echocardiography represents an attractive alternative. Speckle tracking echocardiography (STE) is a reproducible technique used to assess myocardial deformation at both segmental and global levels. Since distinct myocardial pathologies affect deformation differently, information about the underlying tissue can be inferred by STE. In this review, the current available studies correlating STE deformation parameters with underlying tissue characteristics in humans are examined, with separate emphasis on global and segmental analysis. The current knowledge is placed in the context of integrated backscatter and the future of echocardiographic based tissue characterisation is discussed. The use of these imaging techniques to more precisely phenotype myocardial pathology more precisely will allow the design of translational cardiac research studies and, potentially, tailored management strategies. The primary aim of non-invasive cardiac imaging is to provide information on the diagnosis and severity of underlying cardiac conditions. Many myocardial pathologies are distributed non-homogeneously and thus diagnosis may be unreliable using global assessments . More advanced characterisation of the underlying tissue, such as with cardiac magnetic resonance (CMR) imaging may allow more accurate diagnosis Fig. . With noOne such method is speckle tracking-echocardiography (STE). The tracking of grayscale speckles is independent from insonation angle and partially independent from translational movement of the heart, allowing myocardial deformation analysis without being restrained by the limitations of earlier technologies that were dependent on tissue velocity . The mosDeformation of a particular myocardial segment is dependent on cardiomyocyte function, myofibre architecture, tissue elasticity and fibrosis, as well as being affected by intracavity pressure and the function of neighboring segments . In thisWhile other modalities such as CMR assess tissue characteristics through changes in the acquired myocardial tissue images , STE defSTE deformation can be assessed on both global and segmental levels . Global Conversely, pathologies globally affecting the myocardium have been shown to be significantly correlated with deformation parameters. Myocardial fibrosis in patients with advanced heart failure have been linked to the degree of change in LV global longitudinal strain (GLS) . SimilarThere has been only limited investigation into the relationship between deformation and other myocardial pathologies at the tissue level. In cardiac amyloidosis, GLS magnitude is inversely correlated with severity of amyloid deposition on endomyocardial biopsy . AlthougThe following sections discussing segmental STE deformation in hypertrophic cardiomyopathy, aortic stenosis, and dilated cardiomyopathy are summarised in Table HCM is characterised by histopathological changes including hypertrophy of cardiomyocytes, interstitial fibrosis, myocyte disarray, and small vessel disease ) , with exThe same group correlated STE deformation parameters with in vitro mechanics of isolated trabecular muscle in 122 HCM patients .STE strain was compared with histological analysis of basal septal myocardial biopsy obtained in 23 patients with AS undergoing aortic valve replacement surgery . Histolo2+ ATPase (SERCA2a) and phospholamban was correlated with segmental deformation measures, but again, likely due to the limited range of values, no association was seen with fibrosis-related mRNA and measured protein expression . The titin isoforms N2B and N2BA tend to relate, respectively, to increased and decreased myocardial stiffness, and the study confirmed this by finding a negative correlation between deformation measures and N2B, and a positive correlation with N2BA. In a separate group of 8 patients, repeated measures were made in patients having LV assist device implantation, and this showed a strong association between change in SERCA2a and titin N2BA, and longitudinal and circumferential strain and SR .Samples from hearts explanted from patients with dilated cardiomyopathy (DCM) undergoing heart transplantation provide an invaluable opportunity to analyze STE associations, albeit in a select population. In a very elegant study by Cordero-Reyes et al., histological features, messenger RNA and protein expression, were compared with segmental STE deformation  free wall) in 20 individuals with DCM . A statiWhile segmental STE deformation imaging has an important role in the diagnosis of cardiac amyloidosis , 34, onlTo summarize, the above-mentioned studies comparing STE deformation imaging with tissue analysis in patients with HCM, AS, DCM, and other cardiomyopathies suggest that a combination of LV echocardiographic imaging parameters can be used to better characterise underlying LV tissue architecture and function.In the study by Cordero-Reyes et al. in patients with DCM , segmentThe left atrium (LA) has three distinct roles in LV filling – in addition to atrial contraction, it acts as a reservoir and a conduit for pulmonary venous return . Atrial Her et al. investigated LA deformation in 50 patients with mitral valve disease undergoing mitral valve replacement or repair, 28 of whom had mitral stenosis (MS) . All patThe association between LA STE strain and LA fibrosis was investigated in another study of 46 patients with MR due to mitral valve prolapse undergoing surgery, all of whom were in sinus rhythm . Cameli No studies were found directly correlating segmental or global right atrial deformation with underlying tissue characteristics.STE deformation imaging can be a powerful imaging modality to investigate many cardiac conditions. However, information on its use as a means to determine local pathological changes remains limited, which is likely related to the scarcity of human tissue samples. Despite this obstacle, the studies discussed in this review establish important links between STE deformation imaging and underlying histopathological changes, which will be valuable for the design of translational cardiac research studies.Traditional echocardiographic global assessments such as LV volumes and LV EF are excellent for detecting global dilatation and dysfunction. Typically, once overt systolic dysfunction (as detected by impaired LV EF) is present, myocardial deformation analysis offers little additional diagnostic or prognostic information. There remain however many patients where differentiating primary cardiomyopathic processes from, for example, diabetes-related fibrosis or infiltrative processes at an earlier stage of their disease would be clinically important. In selected clinical cases, tissue characterisation is performed with CMR, but this technology is difficult to scale up for routine use. Echocardiography therefore will remain the primary imaging tool for most patients.Prior to the advent of CMR, integrated backscatter, which measures the ultrasonic reflectivity of the region of interest, was a major focus of tissue characterisation research . StudiesSTE has a number of well-established limitations: it relies upon good image quality to allow accurate tracking and movement of a region of interest in and out of the image plane will affect strain measurement. This can be overcome using 3D imaging, which has its own limitations. In particular, there can be difficulty optimizing image quality over the whole 3D volume rather than a limited 2D slice, and frame rates are typically lower with 3D imaging. Less experienced sonographers also show lower levels of reproducibility of STE derived strain measures . There aBeyond global assessment of myocardial and atrial function, segmental STE deformation measures have limited, but definite, evidence of providing information on the underlying tissue. These measures should be considered for use as surrogate outcomes in early stage clinical trials, with the aim of translating basic research findings to a stage where they can be tested in clinical outcome-based trials.To move echocardiographic tissue characterisation into clinical utility, we believe the following four steps must be made. First, given the relatively small body of literature available, further research with larger numbers of participants and more in-depth tissue assessment  is required to provide the robust evidence base needed to rely on these surrogate measures. In particular, there is a distinct lack of studies focusing on the atria, which is especially important in the current context of increasing numbers of patients with atrial fibrillation. Second, formal measures of diagnostic accuracy should be reported, rather than simple correlations. Third, a method of integrating information including global function  and segmental measures should be developed to allow more advanced phenotyping . As Capt


Congestive heart failure (CHF) is a debilitating condition that afflicts tens of millions of people worldwide and is responsible for more deaths each year than all cancers combined. Because donor hearts for transplantation are in short supply, a safe and durable means of mechanical circulatory support could extend the lives and reduce the suffering of millions. But while the profusion of blood pumps available to clinicians in 2019 tend to work extremely well in the short term (hours to weeks/months), every long-term cardiac assist device on the market today is limited by the same two problems: infections caused by percutaneous drivelines and thrombotic events associated with the use of blood-contacting surfaces. A fundamental change in device design is needed to address both these problems and ultimately make a device that can support the heart indefinitely. Toward that end, several groups are currently developing devices without blood-contacting surfaces and/or extracorporeal power sources with the aim of providing a safe, tether-free means to support the failing heart over extended periods of time. Congestive heart failure (CHF) is a progressive condition in which cardiac function deteriorates over time. It is most common among people 65 years or older, but practically anyone can be at risk as the causes of heart failure include everything from coronary artery disease, high blood pressure, and congenital heart defects to myocarditis, abnormal heart rhythms, valve disease, diabetes, and obesity. The most common symptoms of the disease include shortness of breath and fatigue, and it is often diagnosed via blood tests, electrocardiograms, echocardiograms, stress tests, coronary angiograms, and chest x-rays  CHF remaCADs are often categorized according to duration of support. If a device lasts from hours to weeks as a means to stabilize patients until longer-term mechanical support can be implemented, it is considered to be a ‘bridge-to-device (BTD)’ . BTDs weCADs may also be used to provide circulatory support to patients on the waiting list for heart transplantation, in which case they are considered to be ‘bridge-to-transplant (BTT)’ devices. While BTT devices do not last longer than 2 years on average, the longevity of CADs is much better today compared to that of the mid-80s where the typical working life of these devices was only about a month . Yet, thIn rare instances that are difficult to predict, some patients recover cardiac function while under CAD support and no longer need heart transplantation. These cases are categorized—more often in retrospect than by design—as ‘bridge-to-recovery (BTR)’ . Currently, the most ambitious unmet goal in the CAD field is to develop a cardiac support system for long-term or permanent use. A safe, reliable, durable, implantable support mechanism leading to the preservation, or even restoration, of cardiac competence and coronary flow that completely frees patients from the need for heart transplantation would be considered an effective device for ‘destination therapy (DT)’ . In ordeThe concept of artificial blood pumps can be traced as far back as 1813 when Le Gallios first performed the task by squeezing rubberized pumping chambers between pairs of wooden planks . The earWhen VADs were first developed, they were designed to replicate the native cardiac cycle and generate pulsatile flow using a diaphragm and unidirectional artificial heart valves A 3]. Th. Th3]. TBecause the left ventricle (LV) and right ventricle (RV) can be supported either separately or in unison, ventricular assistance is commonly separated into LVAD, RVAD, and BiVAD categories . With isThe clinical settings in which RVAD therapy are most commonly employed include acute myocardial infarction, pulmonary embolism, pulmonary hypertension, myocarditis, post-cardiotomy shock, cardiac transplantation, and LVAD implantation. As the frequency of LVAD use continues to rise, this last scenario is becoming increasingly common as nearly half of all CHF patients show right heart failure after LVAD implantation and 4% require RV support within the first two weeks post-operation ,28. BecaWhile the majority of patients retain sufficient RV function throughout the course of LVAD therapy to avoid the need for ancillary support, nearly 48% of LVAD recipients experience sufficient levels of postoperative RV dysfunction to warrant the use of a biventricular assist device . BiVAD iTotal artificial hearts (TAHs) are designed to entirely replace native heart function over extended periods to treat end-stage CHF. The first human TAH implantation was performed in 1969 by Denton Cooley using the Liotta artificial heart as a bridge to cardiac transplantation. The patient was supported on this pneumatic device for three days during which time hemolysis and deteriorating renal function prompted surgeons to replace the pump with a donor heart that failed 36 h later ,19. It wBecause first generation pulsatile pumps were limited by their large size, high noise emission, and durability issues leading to frequent malfunction and morbidity, research to develop smaller and more reliable devices were initiated and continued through the 1990s . As a reThe third generation LVADs are continuous flow centrifugal pumps designed with magnetic and/or hydrodynamic levitation of the impeller with non-contact bearings and its outflow directed perpendicular to the axis of rotation ,34. ThesAfter five-plus decades of dedicated research aimed at developing blood pump technologies to support the failing heart, a cadre of devices capable of delivering different levels of support at different levels of invasiveness are now available to treat different varieties and severities of cardiac malfunction. These range from acute catheter-based interventions used for partial univentricular support to long-term implantable pumps designed to restore normal perfusion levels in both systemic and pulmonary circulations ,18,20. AExtracorporeal membrane oxygenation (ECMO) A is a foAbioMed’s Impella catheter B is an iPneumatic intra-aortic balloon pumps (IABP) C, which Thoractec’s CentriMag acute circulatory support system D, a tempAlthough the Heartmate II axial flow pump remains the world’s most widely used and extensively studied VAD to date with over 26,000 patients implanted for periods up to 10 years and beyond, third-generation centrifugal pumps like the HeartMate III (Thoratec) and HeartWare HVAD (HeartWare) are currently poised to become the device of choice as either BTT or DT for end-stage CHF patients. HeartMate III  was builHeartWare HVAD is a small CF-LVAD with a displacement volume of 50 mL and an output capacity of 10 L/min . It is cSynCardia CardioWest TAH (SynCardia) is the world’s first and only commercially approved total artificial heart that is currently in use today . The mecConventional continuous flow VADs were designed specifically to treat adult patients, who comprise the vast majority of the end-stage CHF population and so tend to be too large for use in pediatric patients weighing less than 25 kg (55 lbs.) . Berlin In spite of the increasing number of VAD options currently available to patients due to revolutionary advances in cardiac support technologies, numerous challenges still persist. Ventricular arrhythmia, right heart failure, infection, pump thrombosis, and bleeding are still areas of concern, as are issues of long-term patient management and a lack of clear guidelines regarding patient eligibility criteria for VAD therapy . DifficuIndeed, given that heart failure has now risen to pandemic proportions across the globe while the availability of donor hearts remains woefully inadequate to meet the rising demand, continued expansion of mechanical circulatory support for use as long-term BTT or DT is considered a clinical necessity. But despite decades of development most VAD therapies are limited to short-term BTT applications due to three longstanding complications. One is bacterial infection from percutaneous drivelines, which is the most frequent LVAD-associated problem . AnotherDevice malfunction, bleeding, thrombosis, and inadequate aftercare all contribute to VAD failure in the clinical setting, but percutaneous driveline infection (DLI) A is one Another significant cause of LVAD complications is thromboembolism B associaThe reported incidence of gastrointestinal bleeding (GIB) C after cThe rate of DLI, thromboembolic incidents, and bleeding problems must be curtailed if long-term cardiac support is to become a viable treatment option for end-stage CHF patients. Toward that end, there have been numerous attempts to eliminate these predominant failure modes and develop an untethered, non-blood-contacting VAD as a destination therapy.To provide long-term CAD patients better quality-of-life, various powering methods have been proposed to minimize or eliminate extracorporeal power requirements that limit patient autonomy and contribute to patient stress over potential power delivery failures  and DLI risk. One of the most interesting attempts was a nuclear-powered device from the 1980s that used Plutonium-238 as a power source. The potential was in the nuclear radioisotope Plutonium that offered the highest possible energy density and long half-life without requiring any energy storage. However, the critical problems of heat dissipation and safety concerns regarding nuclear element leakage eventually led to termination of the project ,87. Another attempt to develop a permanently implanted circulatory support system was based on a small, lightweight spring decoupled C-core solenoid that was first introduced in the early 1980s. This solenoid drive system was used to actuate a pair of preloaded beam springs that directly coupled to a dual pusher-plate blood pump, producing high starting forces and constant pump pressures through repeated ejection strokes. With this technology operating in combination with external plug-ins that included portable and rechargeable lithium-ion, nickel metal hybrid, or lead acid gel batteries, a level of patient mobility similar to that afforded by battery-powered devices available today was achieved ,89. HoweTranscutaneous energy transmission (TET) technology A that trThe inductive electromagnetic TET system B used inThe use of electrically stimulated skeletal muscle as an endogenous power source to drive circulatory support systems is another alternative that is currently under study. An internal muscle energy converter that operates by converting the contractile energy of a muscle into a hydraulic power source would greatly simplify cardiac implants by eliminating electromechanical components and avoiding the need to transmit energy across the skin ,103. A dThe concept of muscle-powered cardiac support is not new. The use of untrained skeletal muscle to aid the failing heart dates way back. In 1935, Beck and Tichy employed static muscle grafts to revascularize the myocardium . And in The recent development of a functional muscle energy converter (MEC), which operates by converting endogenous muscle energy into hydraulic power, may ultimately provide CAD developers with the means to harness the body’s own energy to assist the failing heart over the long term ,103. Amocopulsation) or diastole (counterpulsation). Copulsation enhances cardiac output by increasing pulse and arterial pressure during systole, while counterpulsation boosts heart function by reducing aortic pressures as the heart fills thereby providing lower cardiac afterload for the failing heart [Despite innumerable CAD designs and material modifications made over the decades in an attempt to eliminate chronic pump thrombosis, the situation still persists while the precise dosage and frequency of long-term antithrombotic therapies remain ambiguous ,21. Consng heart . These tng heart . But, abA normal heart with a ventricular ejection volume of about 71.5 mL per beat (CO = 5 L/min and HR = 70 bpm) has a ventricular ejection fraction (EF) of 60%. While a healthy heart’s EF ranges from 55% to 70%, anything less than that is considered mild (<54%) to severe (<35%) heart failure. One way to boost the EF of a defective heart is by applying pulsatile pressure to the epicardial surface in synchrony with the natural ventricular contraction. Copulsative biventricular compression devices have been around for decades. The Anstadt Assistor Cup became the first successful direct cardiac compression sleeve (DCCS) in 1991 and Dr. DeBakey’s pneumatic LV compression cup was first implanted in 1996 ,21,109. Recently, researchers have turned to emerging soft robotic technologies to improve the long-term functionality of DCCSs. In 2017 for example, a silicone molded sleeve A that emAnother form of circulatory support for CHF patients that provides effective cardiac unloading and patient stabilization is displacement of blood from the aorta during the diastolic phase of the cardiac cycle. This technique is most often performed clinically using an IABP that is implanted and inflated inside of the descending aorta as previously described. This mechanical support augments diastolic pressure and coronary circulation via balloon inflation and reduces the resistance to systolic output via the presystolic deflation of the balloon ,59,115. Passive periventricular restraint, which involves wrapping the entire epicardial surface with a sleeve-like prosthetic to provide circumferential diastolic support to the failing heart, is an approach that evolved from a surgical procedure known as cardiomyoplasty (CMP) in which the ventricles were wrapped with the latissimus dorsi (LD) muscle flap and stimulated to contract in synchrony with the systolic portion of the cardiac cycle. While CMP was effective in reducing wall stress, myocardial oxygen consumption and adverse ventricular remodeling, these benefits were found to persist in some patients even after the muscle flap stopped contracting, which suggested that these same effects might be produced via passive ventricular restraint alone. Toward that end, several passive prosthetic devices were developed to produce the same effects without resorting to the surgical complexities and post-surgical complications involved with LD flap isolation and subsequent transplantation into the chest. Corcap  and Paracor HeartNet were two such devices that were designed to act more like the passive LD flap insofar as pressure was applied uniformly across the ventricular free walls. The Acorn sleeve was a flexible, polyethylene-terephthalate mesh that was placed around the heart through a median sternotomy to provide end-diastolic support and reduced wall stress . The ParKey characteristics of the large and expanding family of cardiac assist devices developed in the past, used in the present and slated for the future are summarized in Since 2001 when the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial became the landmark study that established the benefits of implantable, pulsatile, and permanent VAD therapy in patients with late stage CHF, survival rates have improved to nearly 80% one-year after primary implantation due to a combination of refinements in patient selection strategy, surgical techniques, and peri-operative management ,131,132.Since its inception in the early 1960s, a remarkable amount of research and development has been performed in an effort to improve and expand the field of cardiac assist devices. As a result, a wide array of cardiac assist technologies is available to clinicians today, each with their unique set of strengths and weaknesses, but all designed with one common goal in mind: to provide safe, reliable circulatory support however and whenever it is needed. Of course, these challenges grow larger as rising levels and durations of support are required and it is important to continue to seek solutions that will free these patients from persistent physical risks and psychological distress. Toward that end, reducing device-related complications and eliminating the loss of freedom imposed by percutaneous tethers will be key factors in developing CADs that are truly suitable for long-term or permanent use. In addition, replacing current patient management practices with physician–patient interface systems that are more systematic, convenient, and effective will likely play a big role in improving the lives of CHF patients who must rely on life-sustaining devices for years on end. Fortunately, there is reason to expect that many of these improvements will be implemented in the not-too-distant future as steps to meet these challenges are currently being taken by several groups working to develop effective destination therapies with longer patient survival times and improved quality-of-life.


RESULTS/ANTICIPATED RESULTS: Of the 205 patients identified, 59 had been lost to follow-up. Of the 146 patients  actively followed 18 (12%) had died at a median (IQR) age of 27 (21–34.3); in patients alive as of 10/2016 the median age was 26 years (22–34). Fontan types were lateral tunnel (LT) , extracardiac (EC) , right atrial to pulmonary artery (RV-PA) , and Fontan with Bjork modification . Systemic left ventricle  was more common than systemic right ventricle . Of the 146 patients, 101 (69%) had significant morbidity or mortality: 86 (59%) were diagnosed with arrhythmia, 18 (12%) died, and 11 (8%) underwent heart transplants. Frequent procedures included: Fontan revisions/cryoablation in 28 (19%), electrophysiology studies with ablation in 73 (50%), and pacemakers in 53 (36%). Of the arrhythmia diagnoses, 57 (64%) were atrial tachyarrhythmias. RV-PA Fontan procedures were associated with significantly more atrial arrhythmia than all other Fontan types . There was no statistical difference in occurrence of atrial arrhythmia in adults with LT Versus EC Fontans (p=0.3). While patients who had undergone RV-PA and Bjork Fontans were older with median age 34 years, there was no significant difference in age between LT and EC (median 24.0 and 24.5). DISCUSSION/SIGNIFICANCE OF IMPACT: Adult survivors of the Fontan procedure suffer from significant morbidity and mortality. The single most prevalent morbidity is atrial arrhythmia. We conclude that RV-PA Fontans, now obsolete, have the highest prevalence of arrhythmia and that there is no difference in arrhythmia burden between LT and EC Fontans. Given the high prevalence of morbidity and mortality in this population, it is imperative that they be followed by cardiologists with expertise in congenital heart disease.OBJECTIVES/SPECIFIC AIMS: The morbidity and mortality in adults with single ventricular hearts who have undergone Fontan palliation is poorly defined. These patients have a high burden of arrhythmia, heart failure, and re-operation. We hypothesized that age and type of Fontan predict occurrence of arrhythmia. METHODS/STUDY POPULATION: In total, 205 patients aged 18 years who had undergone a Fontan procedure were identified. Those with incomplete data were excluded. Demographic, anatomic, pharmacologic, imaging, hemodynamic, and electrophysiologic data were collected. The χ


We believe that dynamic quantitative iodine perfusion imaging may be a highly sensitive tool for the precise functional assessment and monitoring of early myocardial ischemia.Ischemic heart disease is the globally leading cause of death. When using coronary CT angiography, the functional hemodynamics within the myocardium remain uncertain. In this study myocardial CT perfusion imaging using iodine contrast agent demonstrated to strongly improve the assessment of myocardial disorders. However, a retrieval of such dynamics using Hounsfield units from conventional CT poses concerns with respect to beam-hardening effects and low contrast-to-noise ratio (CNR). Dual-energy CT offers novel approaches to overcome aforementioned limitations. Quantitative peak enhancement, perfusion, time to peak and iodine volume measurements inside the myocardium were determined resulting in 0.92 mg/ml, 0.085 mg/ml/s 17.12 s and 29.89 mg/ml*s, respectively. We report on the first extensive quantitative and iodine-based analysis of myocardial dynamics in a healthy porcine model using a dual-layer spectral CT. We further elucidate on the potential of reducing the radiation dose from 135 to 18 mGy and the contrast agent volume from 60 to 30 mL by presenting a two-shot acquisition approach and measuring iodine concentrations in the myocardium  Thereby ischemic heart disease is the most common cause of death (7.249 million deaths worldwide in 2008) accounting for 12.7% of the total global mortality2. Further myocardial ischemia is responsible for angina, unstable angina as well as cardiac arrhythmias.In 2015 approximately 15.9 million myocardial infarctions occurred worldwide3. Consequently, the number of invasive coronary angiography and revascularization procedures is considered higher than necessary5. To overcome these shortcomings and assess myocardial hemodynamics in a functional, i.e. not purely anatomic manner, dynamic imaging techniques such as cardiac perfusion CT and cardiac magnetic resonance imaging (CMR) perfusion have evolved. While perfusion CMR is a well-established technique for the detection of myocardial ischemia without radiation exposure for patients, CT offers several advantages compared to MR. First, a CMR examination of the myocardium takes 45 to 60 minutes, whereas CT of the heart including calcium scoring, CCTA and perfusion analysis can be performed within 10 minutes. Especially in an emergency setting this is of special importance. Short scan time in CT also helps to avoid movement artifacts. In general, a main advantage of CT is its high resolution. Considering the relatively small thickness of the myocardium, this has a high potential to improve the detection of even small regions of subendocardial ischemia. Multiple studies showed evidence that myocardial perfusion imaging can significantly increase the accuracy of assessing flow limiting coronary artery diseases or areas of prior infarction8. Especially in the case of moderate coronary artery disease, where an anatomical evaluation of the stenosis is ambiguous, perfusion imaging is considered helpful for diagnosis.While coronary computed tomography angiography (CTA) shows high sensitivity towards the anatomical detection of destructive coronary artery disease - which is the most frequent reason for myocardial infarction - the diagnosis of myocardial ischemia itself is rather unspecific, contingent on the lower positive predictive value of obstructive lesions detected by the latter9. The major advantage of static perfusion imaging is that myocardial blood-flow can be rapidly assessed, and that the underlying radiation dose is comparatively low. Using rest/stress protocols, especially in combination with CTA, a good assessment of suspected coronary artery disease has been reported11. However, static CTMP only provides a (semi-)qualitative analysis, while also being highly susceptible to temporal perfusion artifacts and thereby heavily reliant on the correct timing. In comparison, dynamic CTMP is performed by constantly acquiring scans within a 20–40 seconds timeframe and hence imaging the complete first pass of contrast agent through the heart12. While this technique is rigid and allows for a quantitative analysis of hemodynamics, the underlying Hounsfield-based assessment is susceptible to beam-hardening effects induced by the iodine contrast agent13. Further physiological models must be considered which relate Hounsfield units to the actual blood or iodine flow14. Finally, the continuous acquisition mode poses concerns with respect to an increased radiation dose.Among CT myocardial perfusion (CTMP) imaging two approaches have been developed. With the static technique a single scan is performed when the enrichment of iodine within the myocardium is considered maximal, so that an optimal contrast between healthy, under-perfused and infarcted myocardial tissue is achieved. To ensure correct timing, the (test) bolus has to be tracked and the enrichment within the aorta determinedet al. showed that by using rapid kVp switching DECT a higher reproducibility of dynamic myocardial perfusion measurements in comparison to a Hounsfield units based evaluation can be assured15. Further Sánchez-Gracián et al. demonstrated, that iodine quantification in myocardial perfusion stress DECT is beneficial for the differentiation of healthy and ischemic or necrotic myocardium16. Finally, Fahmi et al. reported on quantitative myocardial perfusion images and thereby demonstrated a superior assessment of myocardial infarcts in comparison to a conventional measurement17. Sellerer et al. showed an improved root mean square deviation (RMSD) of observed iodine concentrations  for different measurement configurations using a modern clinical DLCT system18. This is of particular importance, as the quantification accuracy of iodine densities in regions of low contrast agent accumulation like in the myocardium plays a crucial role in the generation of our results.Here the introduction of dual-energy CT (DECT) in clinical routine offers potential to overcome the aforementioned limitations. Different technological approaches have been established for acquiring dual-energy data. Mainly three technical implementations are used in clinical CT scanners: Dual-source CT (DSCT), rapid kVp switching CT (KVSCT) and Dual-layer CT (DLCT). A DSCT system consists of two X-ray tubes and two associated detectors, whereas the KVSCT machines use one detector and a source with two alternating kVp settings during the scan. To acquire spectral information in DSCT and KVSCT systems a scan must be designed accordingly before its start. As the photon energy separation takes place in the detector, in DLCT conventional and spectral data are obtained simultaneously without the necessity of a spectral scan pre-setting. Spectral data provides strongly increased contrast and sensitivity  and iodine density image channels) towards soft-tissue and iodine-based imaging, thereby opening up new perspectives for a reduction of radiation dose and volume of injected contrast agent. In 2012 So. 18.In this study, we report on the very first extensive quantitative and iodine-based analysis of myocardial dynamics in a healthy porcine model in rest, using a dual-layer spectral CT. We include the presentation of iodine perfusion, time to peak, peak enhancement and volume maps. In a first step, we show in congruence with previous studies, that low-energy virtual MonoE-keV images and iodine density maps are superior in comparison to conventional images in the depiction of temporal opacification of the myocardium with respect to relative signal enhancement and contrast-to-noise ratio. Afterwards the temporal uptake of iodine is modelled using a gamma-variate function and corresponding dynamics deduced from the model in a pixel-wise manner. Further, we elucidate on the possibility and performance of quantitatively assessing the myocardial peak enhancement map using a semi-static two-shot approach. Based on the accuracy and consistency of determining low iodine densities with modern dual-energy systems, we suggest that dynamic quantitative iodine perfusion imaging may be a highly sensitive tool for the precise functional assessment and monitoring of early myocardial ischemia, if a valid database for stress and/or rest can be established20. This is also well reflected in the temporal contrast-to-noise ratio  was scanned using a state of the art dual-layer spectral CT system from Philips with a detector coverage of 4 cm and a peak voltage of 120 kVp. An overall volume of iodine contrast agent of 40 ml  was injected into the ear vein, which corresponds to a concentration of 154 mg/kg-bodyweight. Within this animal study, scans were immediately acquired after injection to track the bolus and enable hemodynamics analysis throughout the whole thorax. Electrocardiographically (ECG)-triggered dynamic axial scans were adjusted to the cardiac cycle with an increment of zero, with the scanning area covering the mid part of the left ventricular myocardium. A total of 36 consecutive scans were acquired. Finally, no  automatic motion-correction algorithm for the heart was available as the entire heart volume was imaged only fragmentary. Therefore, data points with extensive motion in heart or other thorax structures were manually abandoned, resulting in a non-equidistant sampling of the curve with 15 scan points. Figure tio Fig.  and relatio Fig. , where t22. Using a two-step fitting routine, only the first pass of contrast agent was considered so that artifacts arising from recirculation were excluded. Figure 2 being close to 1), even in case of a non-equidistant temporal sampling. The corresponding transversal thorax slices obtained from the model  within the iodine density map, this channel was used for further iodine-dynamics analysis. Figure del Fig.  are of s23. A peak enhancement value , gives additional information on the overall blood intake capacity, its storing as well as the flush out behaviour.The simultaneous analysis of all perfusion parameters allows for a specific diagnosis of myocardial disorders: a reduced peak enhancement with a normal time-to-peak value indicates scarred/fibrotic myocardium, limiting the absolute capacity of the myocardium, while in presence of a delayed peak value an ischemic disorder is consideredA major drawback of a precise flow dynamics analysis is the necessity of a sufficient temporal sampling of the iodine density curve. This implies acquisitions before and during iodine contrast enrichment until myocardial saturation is reached, which poses concerns with respect to radiation dose. For an initial assessment of the myocardial blood flow , we propose to derive the quantitative, iodine peak enhancement map from a semi-static two shot approach in stress and/or rest without the need of modelling/fitting the data. For this, two scans are obtained in the myocardial saturation phase (in this case at 23.3 and 24.9 seconds). To obtain a homogeneous pattern within the myocardium, the corresponding two iodine densities are averaged and smoothed by a minor Gaussian-blur (to mimic the fitting routine). Finally, to directly calculate the peak enhancement, an offset value from literature or a scout scan/control measurement is subtracted. Note that in a conventional HU-based assessment an arterial curve must be obtained in order to normalize data, which however is obsolete in case of quantitative, absolute iodine density values. Figure Within this study, we showed that by using a state-of-the-art dual-energy perfusion CT imaging technique, it is possible to deduce absolute iodine-based flow dynamics of the heart, arteries and myocardium. This allows for an assessment of functional properties of the latter in a quantitative manner. Thereby, major advantages arise in comparison to conventional HU-based diagnosis: first of all, the increase in image contrast during perfusion is most pronounced in the iodine density map, helping with a better visual assessment of the myocardium and potential ischemic or infarcted regions. This allows for a more rigid fit of the imaging data as well as the potential to reduce the amount of contrast agent and radiation dose. Secondly, the image values examined by the radiologist are not affected by beam hardening artifacts and hence are independent from factors such as patient size and variations between different CT platforms, facilitating a value-based assessment. Finally, the obtained image data is quantitative, which renders an acquisition and consequent normalization with an arterial curve unnecessary, provided that the concentration of contrast agent with respect to patient characteristics is reliably controlled. Given the establishment of an extensive clinical database comparing iodine-based dynamical indicators for various myocardial dysfunctions, in both stress and rest, we believe that DECT may allow for a fast, rigid, highly sensitive and specific assessment of heart diseases.in-vivo concentration of 154 mg/kg-bodyweight, is well below volumes typically applied in clinical routine. In a very recent study comparing various dual-energy scanners Sellerer et al. demonstrated, by using an abdominal phantom and mimicking various patient sizes, that even low iodine concentrations below 1 mg/ml  can be reliably measured with a relative error around 10% only18. Older studies reported on similar values, i.e. a constant absolute error of 0.1 mg/ml in case of iodine concentrations below 1 mg/ml25. Given a relative increase of iodine density within the healthy myocardium of 575% (0.16 mg/ml to 1.08 mg/ml) during contrast uptake within our study, the accuracy of modern systems can be considered as sufficiently high.However, an essential requirement for the establishment of such a database and using data without normalization is that the quantitative iodine densities present in the human myocardium can be measured precisely and in a reproducible manner. In the here presented animal study, a volume of 40 ml of Ultravist 300 was injected and an offset adjusted iodine density of 0.92 mg/ml found within the myocardium. Note that the corresponding iodine 16. Further, previous studies on quantitative iodine perfusion implied the usage of 60 mL of Ultravist 370 (approximate iodine concentration of 317 mg/kg-bodyweight) resulting in an iodine density of 2.56 mg/ml within the healthy myocardium16. As we found a value of approximately 1 mg/ml in the myocardium (iodine concentration of 154 mg/kg-bodyweight) which can be reliably measured with modern DECT systems and allows for a meaningful modelling of the data, we believe that a reduction of applied iodine volume/concentration by a factor of 2 is possible.We further demonstrated that a semi-static two-shot approach yields a deviation of 5–15% in the iodine peak enhancement value in comparison to one derived from the full scan. Ensuing from previous studies showing that ischemic and infarcted regions of the myocardium exhibit a by 23% and 47% decreased mean iodine density, we believe that the quantitative semi-static approach may not be highly specific, however may be a good first indicator for myocardial malfunction  in an initial assessmentFinally, in this animal study 15 scan points were used for the analysis, in order to model early enrichment of arteries and ventricles, accounting to a computed tomography (CT) dose index (CTDIvol) of 15 × 9 mGy equalling 135 mGy. In a clinical setting when only the myocardium is of interest early scan times after the injection can be neglected and an equidistant sampling of myocardial perfusion slope and saturation with 8–12 points is generally sufficient. Correspondingly a CTDIvol of 72–108 mGy can be expected, being well below a critically considered value of 250 mGy.The purpose of this experiment is considered a proof of principle investigation. As the DECT technique offers several advantages regarding quantitative image results using iodine contrast agent, the main point of our manuscript focuses on a initial investigation of quantitative perfusion measurements. The added value of this study is to show the advantage of quantitative iodine density maps in comparison to conventional CT images. In terms of the improved contrast-to-noise ratio and the relative signal enhancement using contrast agent density maps in DECT perfusion imaging, our results are relevant to several clinical perfusion use cases with animals or even humans. Indeed, the improvement of clinical diagnosis should be considered in further statistically meaningful studies with the benefit of various patient groups and myocardial disorders in rest and stress condition. This will permit the establishment of a valid database of quantitative iodine-based hemodynamical parameters. Hereby it will be of essential importance to clarify which of the quantitative hemodynamical indicators are of major diagnostic importance. Further, within this study a dual-layer IQon Scanner from Philips was used, providing a detector coverage of 4 cm only. A spatially limited examination of the heart  however bears the risk of overlooking locally confined flow defects. Under these circumstances, vendors are obligated to increase detector coverage in order to screen the entire myocardium at once.Animal care and all experimental procedures were performed in strict accordance to the German and National Institutes of Health animal legislation guidelines and were approved by the Bavarian Animal Care and Use Committee (AZ 55.2.-1-54-2532-62-13).mm2. The ECG triggered temporal resolution aggregates to 1.08 scans per second or a full acquisition of the specified range every 0,92 second. Firmware version on the scanner was 4.1.0.0. The perfusion scan was conducted in stationary mode with 120 kVp and a mean tube current of 100 mAs. Scans were reconstructed with a Philips B-kernel and a slice thickness of 3 mm. Within 26 seconds 36 scans were recorded, so that the full first pass of contrast bolus was imaged. Hereby the scans were electrocardiographically (ECG)-triggered and adjusted to the cardiac cycle with an increment of zero. Each scan was conducted with a CTDIvol of 9 mGy, resulting in a CTDIvol of 135 mGy and 18 mGy for the extensive analysis of myocardial dynamics (15 scan points) and the two-shot approach, respectively. The perfusion scan was conducted using 40 ml of contrast agent  at a flow rate of 4 ml/s. The contrast agent was injected into the ear vein via an 18-gauge catheter using a dual syringe injection system .CT images of the healthy pig  were acquired with a 64-slice single source dual-layer spectral CT IQon scanner with a detector coverage of 4 cm and a rotation time of 0.27 seconds . The spatial resolution is 2.47 pixels per mm resulting in a pixel size of 0.40 × 0.40 2) were directly obtained from the Philips IntelliSpace Portal. The relative increase in signal  were calculated based on the maximal slope method23:A certain slice within the thorax was determined for further processing and 15 data points in time, with minor structural movement, were selected from the iodine density images. In order to model the first pass of contrast bolus through the heart, arteries and myocardium, gamma variate functions were used, as proposed in literature for both magnetic resonance imaging (MRI) and CTFinally, aforementioned maps were filtered with a median-filter with a 3 × 3-kernel to reduce noise arising from the pixel-wise assessment. Note that data was not normalized or scaled with respect to arterial input functions, hemocrit-scale, cerebral blood volume (CBV) factor or other physiological models for multiple reasons: first of all, within this animal study corresponding values and models are not available. Secondly, we wanted to provide absolute and quantitative, i.e. unscaled, values to the readers, which are independent from assumptions made in underlying physiological models. Correspondingly the iodine volume map presented here does not represent iodine volumes in the sense of millilitres, but rather gives quantitative measure on the area under the curve of the temporal iodine density in the unit of mg/ml*s. The latter is thereby related to the tissues overall blood intake capacity, its storing as well as the flush out behaviour.