In recent decades, survival of children with complex congenital heart disease has improved considerably. Specifically, children with a variety of congenital heart defects resulting in ‘single ventricle’ physiology can now undergo palliative surgery that allows survival beyond the neonatal period, and in many cases into adulthood, despite having a single functional ventricular pumping chamber supplying both the pulmonary and systemic circulation. Our growing understanding of the functionally univentricular heart has resulted in freedom from Fontan failure of >50% at 25 years post-Fontan. Yet there is still a fair amount of knowledge to be gained, specifically as it relates to the pulmonary circulation in this group of patients. Knowledge gaps relate not only to the pulmonary circulation after Fontan operation, but also at each stage of the single ventricle surgical palliation, including the native physiology prior to any intervention. The pulmonary circulation is affected by multiple issues related to the single ventricle, including specific details of the anatomy unique to each patient, any intervention(s) undertaken, and potential complications such as aortopulmonary collaterals, protein losing enteropathy, plastic bronchitis, venovenous collaterals, pulmonary arteriovenous fistulae, ventricular dysfunction, pulmonary venous stenosis, and more. This chapter will review the current knowledge with regard to the pulmonary circulation in the single ventricle patient, primarily after the Fontan operation. Additionally, it is our hope to help the practitioner assess the pulmonary circulation in the single ventricle patient; we will also discuss the evidence behind and approach to treatment strategies in order to optimize the pulmonary circulation in this complex group of patients. Congenital heart lesions resulting in single ventricle physiology account for up to 3% of congenital heart lesions, and historically were associated with high mortality in infancy. A variety of heart lesions including hypoplastic left heart syndrome, tricuspid atresia, double inlet left ventricle, and many others are characterized as having a single functional ventricular chamber that must supply both the systemic and the pulmonary circulation. By definition, prior to any interventions, the two circuits exist in parallel rather than in series. This results in obligate arterial desaturation due to mixing of blood and chronic overload of the single ventricle that receives and ejects both circulations. In order to address these conditions, a series of staged surgical palliations are now generally performed for patients with single ventricle physiology, with an ultimate goal of separating systemic venous blood via passive drainage to the pulmonary circulation from the systemic circulation that is ejected by the single ventricle .In 1971, Fontan and Bordeaux first described an approach for the operative treatment of the patient with a functional univentricular heart, separating the systemic and the pulmonary circulation. The concept of the ‘Fontan circulation’ creates a circulation in which the systemic venous return is connected to the pulmonary circuit in the absence of an interposed ventricle, and all shunts  are interrupted. This results in near normalization of arterial saturation and elimination of chronic volume overload. This separation of the circulations comes at risk of chronic venous hypertension, congestion of the systemic veins, and decreased cardiac output both at rest and with exercise. Historically, several changes to the ‘Fontan approach’ have occurred over the years, including the routine strategy of a bidirectional cavopulmonary anastomosis  prior to the Fontan operation itself . Further evolution from a ‘classic Fontan’ , has been to what is now considered the optimal approach, the intracardiac lateral tunnel approach, or more recently the extracardiac conduit. There are various reasons for this evolution in strategies and approach. These details will not be discussed in detail but are addressed to some extent later within this chapter.In 1978, Choussat and Fontan described their important patient criteria necessary to result in a successful Fontan operation . These rHaving described the above, unquestionably, the Fontan concept and its evolution has changed the field such that survival for children with a functionally univentricular heart is not only possible but is expected. The concept of passive cavo-pulmonary flow into the lungs in the absence of a pumping chamber is the principle by which adequate systemic and pulmonary circulation is achieved. This principle has resulted in a reliably high survival rate; but we are far from conquering all of the potential medium and long-term complications. Critical to the success of our management strategy is the protection of the pulmonary vasculature. Variation in the initial single ventricle anatomy and physiology makes it difficult to argue for a ‘one size fits all’ strategy. The presence of pulmonary undercirculation vs. pulmonary overcirculation, systemic obstruction, pulmonary obstruction, pulmonary hypoplasia, and/or pulmonary vein abnormalities are each very different entities that must be recognized with timely and appropriate intervention so that the aforementioned protection and optimization of the pulmonary circulation may occur.It goes without saying that Fontan circuit creation cannot be achieved at birth because of the inherent elevation of the pulmonary vascular resistance. Additionally, the caval veins and the pulmonary vascular bed are relatively small. Once the pulmonary vascular resistance has diminished, it is typical to entertain a staged approach whereby the superior and inferior systemic venous systems are connected to the pulmonary vascular bed on separate occasions.In the initial steps of a univentricular anatomy, management must aim for and achieve unrestricted flow from the heart to the systemic circulation, a controlled amount of well-balanced and limited blood flow into the lungs, and an unrestricted blood return to the ventricle. In order to achieve these important entities, interventions in the neonatal period may be necessary. These interventions may include coarctation repair, Damus–Kaye–Stansel, Norwood repair, systemic-to-pulmonary artery shunt, ductal stent, balloon atrial septostomy, or pulmonary artery band. Which of the above interventions are necessary will be dictated by the specific anatomy of the univentricular heart.At 3–12 months of age, and depending upon the anatomy and physiology, most centers will embark upon a bidirectional cavopulmonary shunt. This procedure was first based on experimental work of Haller and colleagues  and firsAt most centers , the Fontan operation will be performed between one and five years of age. The operation is performed by connection the inferior caval venous return to the pulmonary circuit either via a lateral tunnel connection or an extracardiac conduit. A fenestration may be created between the conduit and the pulmonary atrium. This is done routinely at some centers and in ‘high-risk’ patients at other centers and is undertaken to allow for a residual ‘right-to-left’ shunt in order to increase the preload and cardiac output of the systemic ventricle, and perhaps decreasing systemic venous pressure and systemic venous congestion. This maneuver will be at the expense of a degree of cyanosis but has been shown to reduce post-operative morbidity as well as mortality. The fenestration can be managed with closure at a later date, perhaps in the interventional catheterization lab. Alternatively, the fenestration may be maintained indefinitely to afford the advantages described above for an indefinite period of time.In almost all patients with a functionally univentricular heart, the growth and development of the pulmonary vasculature will be abnormal. Decreased pulmonary blood flow may be present and may originate in fetal life. Pulmonary blood flow is most certainly less than normal following the bidirectional Glenn operation except in the presence of significant aortopulmonary collateral flow. It is possible for growth of the pulmonary arterial bed after the initial palliation before the bidirectional caval shunt, but an initial systemic-to-pulmonary shunt may cause pulmonary artery distortion as well as a maldistribution of flow to the pulmonary arteries, causing a combination of pulmonary hypoplasia to some areas and vascular disease to others. This latter concept may actually also occur in the absence of a systemic-to-pulmonary artery shunt in a select number of patients. As Gewillig has pointed out, the pulmonary architecture may be further compromised by mechanical obstruction following abnormal connections, ductal constriction, surgical scarring, or external compression . UnfortuAllowing for optimal growth and development of the pulmonary vasculature is critical and is probably best achieved before the bidirectional cavopulmonary shunt. The initial palliative procedure is likely the most important determinant of future Fontan well-being. As beautifully discussed by Gewillig, our current strategies provide for only a very limited period of time for this controlled pulmonary overflow and catch up growth to occur, and rather replaces this with a strategy of protection of the single ventricle with a small shunt in order to avoid ventricular volume overload. This difficult balance must take into account the fact that the critically important low pulmonary vascular resistance is determined and maintained by a well-developed vascular bed. If flow to the vascular bed is less than optimal, insufficient growth and development of the pulmonary vascular bed will occur with a resultant higher pulmonary vascular resistance . TherefoThe physiology of any particular univentricular heart goes hand-in-hand with the anatomic nuances. Key determinants as alluded to above include obstruction to outflow, inflow, or flow across the atrial septum, systemic and pulmonary venous return, pulmonary vascular resistance, atrioventricular valve regurgitation, and systemic ventricular function. For example, with severe systemic outflow obstruction as in hypoplastic left heart syndrome, the neonate is dependent upon right-to-left shunting through a patent ductus arteriosus in order to maintain and support systemic cardiac output. In contrast, if there were a critical obstruction to pulmonary blood flow, a patent ductus arteriosus is necessary for an obligate left-to-right shunt in order to support adequate pulmonary blood flow. Other important issues that can be assessed as per above include the systolic ventricular function, long axis and radial diastolic function, as well as airway mechanics such as structural lung disease or scoliosis. Any and all of these issues have the potential of making the Fontan circuit less than ideal.On the other hand, if obstruction to pulmonary venous return were present, important pulmonary hypertension may occur. Examples of this scenario could include an atretic or stenotic atrioventricular valve or a restrictive atrial septal defect. Therefore, the optimal physiology of any univentricular heart requires good ventricular function, absence of atrioventricular valve regurgitation, an unrestrictive atrial septal communication, and well balanced systemic and pulmonary blood flow. The latter is determined by the balance of downstream systemic and pulmonary vascular resistances and will be discussed in detail elsewhere.By way of an additional and important brief physiologic review, particularly as it relates to the Fontan circuit, Rychik (The Relentless Effects of the Fontan Paradox) beautifully describes “the imperfect circulatory physiology” associated with the Fontan as well as its inherent potential complications. Specifically as this relates to the pulmonary circulation, it is the absent ventricular thrust and passive cavo-pulmonary flow which leads to an inherently lower cardiac output than normal with a concomitant inability to deliver normal blood flow into the pulmonary bed. As a result there is decreased ventricular filling and low stroke volume and a chronic state of systemic ventricular volume depletion . This chAlso, as elucidated in Rychik’s review, the specific univentricular substrate may not work in favor of the perfect passive cavo-pulmonary flow state. Complexities related to the specific anatomic substrate may also lead to a progressive worsening of the pulmonary circulation over time. Thus, the pulmonary vascular bed may not only be abnormal because of altered pulmonary flow patterns in utero, but can be subjected to deterioration over time after birth either related to surgical interventions or otherwise. What is absolutely clear is that the pulmonary vascular bed is critical in the optimal functionality of passive cavo-pulmonary flow and optimal cardiac output in the Fontan patient. It is also important to note that changes over time, as discussed above, can result in further impairment of the pulmonary circulation. These changes can be etiologically complex and may be related to a previous aorto-pulmonary shunt (pulmonary artery distortion with impairment of pulmonary blood flow and hence impairment of pulmonary vascular bed development), aortopulmonary collateral due to chronic hypoxia, and low cardiac output further impeding passive pulmonary blood flow and adding to ventricular volume overload as well as the factors mentioned above. Potential additional contributing—and perhaps poorly understood—factors include a chronic elevation in venous pressure with passive congestion (a pro-inflammatory state) as a result. Also important are an increased risk for thromboembolism as a result of passive congestion with or without liver dysfunction as well as lymphatic abnormalities which may be related to all of the above. Without question, all of these interrelated issues are important in the Fontan patient. Perhaps inherent is the effect of all these issues on the pulmonary circulation and the untoward effects of a less than optimal pulmonary circuit. The vicious cycle that often perpetuates itself must be broken in order to prevent ongoing and worsening cardiac output, end-organ perfusion, and functionality.Various forms of collateral vessels can develop in the single ventricle patient. Included are venovenous collateral vessels, aortopulmonary collaterals and pulmonary arteriovenous collateral connections. Venovenous collaterals can develop most commonly after the bidirectional cavo-pulmonary shunt. It is typically a result of the higher venous pressure and the opening of existing small connections or the development of new connections. The concerning result of venovenous connections is cyanosis as a result of venous blood being carried away from the cavopulmonary circuit, away from the lungs and to the heart itself. The typical venovenous connection is a left superior vena cava which becomes larger after the bidirectional caval pulmonary connection and then creates a right-to-left shunt. Venovenous connections can also create cyanosis via a direct connection to the pulmonary veins or left atrium. Aortopulmonary collateral blood vessels cause pulmonary overcirculation. They are likely the result of chronic hypoxia that is present in the majority of single ventricle patients. The degree of aortopulmonary collateral blood vessels are variable and of debatable significance. The benefit of the elimination of these blood vessels, usually by catheter intervention, is also debated frequently. Finally, the development of pulmonary arteriovenous fistulae is another a potential source of cyanosis. It typically is diagnosed in the single ventricle patient with a long-standing cavopulmonary connection but without connection of inferior vena caval blood flow into the pulmonary circuit . It is believed that a factor within the hepatic circulation will prevent the development of these fistulous connections once the Fontan connection adds the ‘factor’ to the pulmonary circulation.So as an ideal, a low pulmonary vascular resistance is critical and mandatory for an optimally functioning Fontan circuit. In general, as noted above, the pulmonary vascular resistance will control the cardiac output . GewilliTherefore, based on much of what is elucidated above, in order to stack the deck in our favor, management of the single ventricle patient prior to the Fontan itself must be aimed the perfect growth of the pulmonary vasculature. It is the opinion of some that initial pulmonary overcirculation may actually augment the growth of the pulmonary vasculature. As Gewillig has suggested, for example, the optimal balance between a short-lived small shunt in order to minimize ventricular volume overload and preserve cardiac function, and a large longstanding shunt to augment pulmonary growth, is yet to be determined . What isOptimizing the pulmonary vascular resistance in the univentricular heart through anatomic strategies from the outset are critical as described above. It is recognized that patients with single ventricle physiology who do not fulfill classic criteria for pulmonary hypertension (mean PAP > 25 mmHg and PVRI > 3) can still have important alterations in pulmonary vascular resistance that place them at risk for poor outcome and may be amenable to pulmonary vasodilatory therapy . PulmonaPulsatile flow is important for shear stress-mediated release of endothelium-derived nitric oxide and for the lowering of the pulmonary vascular resistance by the passive recruitment of capillaries ,13 Obviop < 0.05) after nitric oxide inhalation [Both animal and human studies have evaluated the effects of non-pulsatile flow on pulmonary vascular resistance and vasoreactivity ,14,15. Ahalation . For exaA recent review by Snarr et al. reviewed the limitations of the Fontan physiology and reported on a number of studies that have attempted to characterize molecular level changes responsible for abnormal pulmonary vascular resistance in patients with single ventricles . These sIt will be important to understand the molecular mechanisms involved in the Fontan pulmonary hemodynamics, including and especially the pulmonary vascular resistance.Understanding both the short-term and long-term consequences of this physiology is needed to improve outcomes.Most importantly, identifying the molecular targets that will modulate the abnormal physiology may allow for treatment of a frequent cause of failed single ventricle palliation.Interestingly and importantly, these studies suggest some important concepts:On the basis of the above information, there seems to be a rationale for attempts at pharmacologic manipulation of the pulmonary vascular resistance in single ventricle patients, with either superior cavopulmonary anastomoses or Fontan, in order to optimize both short-term symptoms and long-term outcomes. Unfortunately, widespread use of pulmonary vasodilators in this population has occurred with only anecdotal success and results from small studies guiding their use.Pulmonary vasodilator therapy has been used immediately following bidirectional superior cavopulmonary anastomosis in patients with low oxygen saturations immediately post-operatively with some reported success. Agarwal et al. reported on the use of iNO in the post-operative period in patients with elevated Glenn pressure >20 mmHg and showed that most patients were responsive to 20–40 ppm iNO with improvement in Glenn pressure, lower inotrope score and improved oxygenation index . In thosExogenous nitric oxide has been used acutely in post-operative Fontan patients; other pulmonary vasodilator agents have been also used in a more chronic fashion. Use of iNO in the immediate post-operative period following Fontan completion in patients with favorable pre-operative hemodynamics but elevated TPG and CVP following surgery has been shown to significantly reduce TPG and CVP while improving systemic blood pressure . Case reThis responsiveness to iNO would certainly support the possibility that sildenafil, which limits the breakdown of cGMP produced in response to nitric oxide and has vasodilatory and anti-proliferative effects upon vascular smooth muscle cells, could be a strategy in this patient population.Sildenafil is the most widely studied pulmonary vasodilator in patients following Fontan palliation. The initial study into its utility to decrease pulmonary vascular resistance and improve exercise capacity in children with Fontan physiology was performed by Giardini et al in 2008 . This stThe longer-term response to sildenafil therapy in this population was evaluated in a randomized, double-blind, cross-over trial to evaluate the effect of six weeks of sildenafil on exercise performance and echocardiographic indices of myocardial performance ,30. WhilAnother pathway for therapeutic intervention could be the endothelin-1 pathway. Endothelin-1 is a peptide that is produced by the endothelial cells and plays an important role in vasoconstriction and cell proliferation and acts through a balance of two endothelin receptors, type A and type B. As discussed above, there has been suggestion of increased levels of endothelin-1 and its receptors in the pulmonary arteries of failed Fontan patients, as well as published reports of elevated plasma levels of endothelin-1 levels in Fontan patients with increased central venous pressure ,32. TherThe prostacyclin pathway may also offer a potential therapeutic benefit to the Fontan patient. Prostacyclin is endothelial cell generated and increases production of cyclic AMP which results in vasodilation and also inhibits smooth muscle cell proliferation. Prostacyclin analogues have been used to modulate pulmonary vascular reactivity in pulmonary hypertension. Very few studies have been performed in the Fontan population although a randomized, double-blinded, placebo-controlled trial of inhaled iloprost was undertaken to assess the effect of exercise in Fontan patients . This stAn additional interesting and important concept is the role of systemic-to-pulmonary artery collateral flow in the Fontan patient in general, and most certainly in the failing Fontan patient. There is considerable debate on the role of this vasculature in the failing Fontan patient, whether these vessels should be closed, and in what circumstances should that occur ,39. We wThere is little question that the Fontan concept (and its evolution over the years) has been an incredible success, and has enabled the survival of a large number of patients that previously had much less hope. We have learned tremendous amounts from both anatomical and physiological standpoints. In that the group of patients with a functionally univentricular heart represents a very diverse population, with many anatomic variations, there are some important anatomic principles—with regard to inflow to the heart, outflow from the heart, as well pulmonary artery size and distortion—that affect outcomes. In addition to optimizing all of the above to the best of our abilities, protection of the pulmonary vasculature and ensuring a very low pulmonary vascular resistance throughout the lifetime of the Fontan physiology is absolutely critical to our success for every individual patient. Achieving this is challenging in the face of the inherent anatomic challenges of any given patient, the by-definition non-pulsatile flow within the pulmonary vasculature resulting in lack of sheer stress-mediated release of endothelium-derived factors to maintain a low pulmonary vascular resistance, and the likely extensive network of systemic-to-pulmonary artery collaterals. The role of these very complicated and intertwined factors, including the changes at the molecular level, are not entirely clear. In any case, however, a low pulmonary vascular resistance in the Fontan patient is critical. The role of pulmonary vasodilator agents may turn out to be very important in the further palliation of this group of patients. Which agents, when to begin therapy, and how long to treat are yet to be determined.


The physiological factors which affect left ventricular (LV) long-axis function are not fully defined. We investigated the relationships of resting heart rate and body size with the peak velocities and amplitudes of LV systolic and early diastolic long axis motion, and also with long-axis contraction duration.Two groups of adults free of cardiac disease underwent pulsed-wave tissue Doppler imaging at the septal and lateral mitral annular borders. Group 1 (n = 77) were healthy subjects <50 years of age and Group 2 (n = 65) were subjects between 40–80 years of age referred for stress echocardiography. Systolic excursion (SExc), duration (SDur) and peak velocity (s') and early diastolic excursion (EDExc) and peak velocity (e') were measured.SExc was not correlated with heart rate, height or body surface area (BSA) for either LV wall in either group, but SDur was inversely correlated with heart rate for both walls and both groups, and after adjustment for heart rate, males in both groups had a shorter septal SDur. Septal and lateral s` were independently and positively correlated with SExc, heart rate and height in both groups, independent of sex and age. There were no correlations of heart rate, height or BSA with either e` or EDExc for either wall in either group.Heart rate and height independently modify the relationship between s` and SExc, but neither are related to EDExc or e`. These findings suggest that s` and SExc cannot be used interchangeably for the assessment of LV long-axis contraction. The longitudinally oriented myocardial fibres of the left ventricle provide substantial contributions to both left ventricular (LV) ejection and filling –3, and e2) )0.725 and BMI was calculated as weight in kilogram per square metre in height (kg/m2). Blood pressure was measured during the echocardiographic study with the patient in a supine position. Study group 1 comprised 77 healthy adult subjects <50 years of age. Subjects were eligible if they had no history of cardiac disease, diabetes or hypertension, were on no medication, had a BMI < 30 kg/m2 and had a systolic blood pressure (BP) ≤140 and a diastolic BP ≤90 mm Hg at the time of the study. All subjects also had normal LVEF (≥55%) and no more than mild valvular disease as assessed by echocardiography. Study group 2 comprised 65 adult subjects selected from a consecutive population referred for stress echocardiography to investigate for possible ischaemic heart disease. Exclusion criteria included diabetes, renal failure, morbid obesity (BMI > 40 kg/m2), preceding beta blocker medication (even if ceased for the study), known myocardial infarction or symptomatic ischaemic heart disease, a LVEF <55%, a regional wall motion abnormality, more than mild valvular disease or a positive test for inducible ischemia.The study design was approved by the Monash Health Human Research and Ethics committee and all clinical investigation was conducted according to the principles expressed in the Declaration of Helsinki. Written informed consent was obtained prospectively from Group 1 subjects, but as Group 2 subjects were identified retrospectively the requirement for consent was waived. Height and weight were measured immediately prior to the echocardiographic study, BSA was calculated using the formula: 0.0001 x 71.84 x (weight [kg])Echocardiography was performed on a Sonos 5500 machine  in Group 1 and a Vivid 7 machine  in Group 2. Studies were stored digitally and measured offline using Xcelera V1.2 L4 SP2  by one of 2 investigators (LD or BC). Four- and two-chamber 2-dimensional loops of left ventricular contraction were recorded in both groups and used for measurement of LV end-diastolic volume (LVEDV), end-systolic volume and the calculation of the ejection fraction (LVEF) using the biplane method of discs. The length of the LV at end-diastole (LVEDL) from the plane of the mitral annulus to the apical endocardium in the 4- and 2-chamber views was recorded during the measurement of the LVEDV, and the longest dimension from these 2 views has been used . Pulsed-2) and used to estimate the degree of variability in a dependent variable explained by a multivariate model. Apart from decisions regarding inclusion of variables in multivariate models, a p value of <0.05 was considered significant.Statistical analysis was performed using Systat V13 . Continuous variables are presented as mean ± SD. Univariate linear regression analysis was performed to assess the relationships of age, heart rate and measures of body size with TDI variables. Multivariate regression analysis was performed with selected variables to assess the independence and extent of contributions to the observed relationships. Sex was included in multivariate models as a dummy variable . The partial correlation coefficient (β) value is provided in multivariate analyses. The coefficient of determination has been adjusted for the number of terms in the model  SDur was inversely and independently correlated with heart rate, (2) there was no relationship of SExc with heart rate, height or BSA, (3) s` was only moderately correlated with SExc, and was positively correlated with heart rate and height, independent of SExc, age and sex, (4) IVRT` was inversely and independently correlated with heart rate, and (5) there were no correlations of EDExc or e` with heart rate, height or BSA. The above findings suggest that both resting heart rate and height need to be taken into account when interpreting s` as a measure of LV long axis contraction, whereas, and despite the inverse correlation between heart rate and IVRT`, neither heart rate nor height require consideration for the interpretation of e`.Our finding of inverse linear correlations between heart rate and LV long axis SDur was not unexpected as inverse correlations of resting heart rate with the duration of the ejection time and LV electromechanical systole have been reported previously in normal subjects with heart rates varying between 40 and 100/min ,38,55. FInterpretation of the finding of a positive correlation of s` with resting heart rate requires consideration of the Bowditch staircase phenomenon, also known as the treppe effect or the force-frequency relationship ,58. WhilThe absence of a relationship between heart rate and SExc does not necessarily exclude an inotropic effect of an increase in heart rate because the amplitude of contraction will also be affected by concomitant changes in loading conditions . Thus, iDespite the lack of a relationship of SExc with either height or BSA in either group, a positive and independent correlation of s`with height (and less convincingly with BSA) was evident in both groups. The lack of any relationship of SExc with body size in our study groups was not expected and there is currently no satisfactory explanation for this observation. The lack of relationship did not appear to be related to a divergence between body size and heart size as LVEDL was positively correlated with height and BSA, and LVEDL was also not related to SExc. Loading conditions also require consideration, but there was no relationship evident between body size and BP or between SExc and BP, and thus no evidence for a positive relationship between body size and afterload as an explanation for the lack of a positive relationship between body size and SExc. With regard to preload, we are not aware of any evidence to suggest a relationship between body size in non-obese subjects and either left atrial pressure or LV end diastolic pressure. On the other hand, it is possible that LV long axis preload may not be directly related to either left atrial pressure or LV end diastolic pressure, particularly if it is considered to be the extent of stretch of the LV wall just prior to contraction. While atrial long axis contraction is an important component of LV long axis stretch , the ampHeight has recognized cardiovascular associations, including variations in heart rate and of the ascending aortic pressure waveform, and these effects also need to be considered when attempting to explain the lack of relationship of body size with SExc and the positive correlation of height with s`. Thus, an inverse relationship between height and heart rate has been described ,69, but Sex was considered in our analysis of TDI variables as not only is male sex recognized to be a determinant of a shorter duration of electromechanical systole , but sexBoth s` and mitral annular plane systolic excursion (which is likely to be closely related to SExc) have been used in previous studies to evaluate LV long axis contraction ,12,71,72There were no correlations of age with s` or indeed, with any of the measures of LV long axis systolic motion in Group 1 in our study. By contrast, there were inverse correlations of age with both s` and SExc in Group 2. That there was no independent effect of age on s` in Group 2 after including SExc in the models indicates that the mechanism underlying the reduction in s` with age in that group was a decrease in the amplitude of mitral annular excursion. The relationship of aging with mitral annular or basal LV s` has been investigated in a number of previous studies and there is evidence for ,27–31 anStudies in isolated myocardium show an acceleration of relaxation with increased frequency of contraction , and a s0.5 rather than BSA did not improve the correlation with any of the TDI variables shown in An important limitation of our study is that it was observational, therefore preventing any definite conclusions regarding causality. Nevertheless, the finding of inverse relationships of heart rate with the duration of long axis contraction was expected based on previous experimental and observational studies, and the main findings were similar in two complementary groups. There were some small differences between the septal and lateral LV walls, and whether these represent genuine differences or the play of chance cannot be determined by a single study. However, there is some evidence for the former given that differences between the behaviour of these walls have also been observed in other studies ,31,43,78In conclusion, in adult subjects with a normal LVEF, resting heart rate is an inverse and independent correlate of LV long axis SDur and a positive and independent correlate of LV long axis s`. These observations regarding heart rate are consistent with previous descriptions in humans of the “velocity staircase” effect, which is directly related to the force-frequency relationship ,60,62. IS1 File(XLSX)Click here for additional data file.


The second objective was to compare a conventional Multi Breath Hold (MBH) protocol to a Single Breath Hold (SBH) SMS protocol and evaluate the respective repeatability in healthy volunteers.Quantitative measurements of left ventricular (LV) rotational mechanics can be estimated from cardiac tagged images and provide early insight into LV dysfunction. Current clinical protocols acquire tagged images at the LV apex and the LV base in two separate breath-held scans, which can contribute measurement bias due to differences in cardiac loading conditions. The first et al. MRM 67, 1210-1224). Conventional MBH grid tags were also acquired. Each method was repeated twice. LV twist measurements were calculated using the FAST method . Both MBH and SBH acquisitions were repeated in random order. Repeatability results were compared using a t-test and Bland-Altman analysis.A cardiac tagging sequence, which uses non-selective RF pulses to generate grid tag patterns throughout the heart, was modified to support SMS. The sequence was evaluated in an IRB approved study after obtaining consent from ten (N = 10) healthy human subjects with 15 heartbeat acquisition using the following parameters: 330-400 × 330-400 mm FOV, 6 mm slice thickness, TE/TR = 4.5/5.3 ms, 12° flip angle, 1.8 × 1.8 mm resolution, 250 Hz/pixel bandwidth, 8 phase encode lines per segment on a 1.5T scanner (Siemens Avanto). Simultaneous basal and apical images were acquired through mid-diastole (~750 ms). SMS images were reconstructed using a Matlab toolbox (Setsompop, K. Figure Since the tagging preparation pulses are non-selective, SMS and cardiac tagging can be combined into a single breath-held acquisition. The SBH SMS approach resulted in similar estimates of peak LV twist with improved repeatability in half the scan time compared to the MBH approach.


Current modifications required for metabolic cart measures of oxygen consumption in the MRI environment present clinical challenges in widespread application. Using the Fick principle we sought to quantify and compare non-invasive MRI derived Chronic heart failure (CHF) is the leading hospital discharge diagnosis in patients over age 65 [1]. Emerging techniques in cardiovascular magnetic resonance (CMR) have resulted in unique opportunity for improvement of non-invasive assessment of the physiologic and anatomic effects of CHF. We have previously demonstrated the accuracy and feasibility of 2 (ml O2/100ml blood) from quantitative T2 mapping of the left and right ventricle blood pools. The Fick principle was used to quantify 2 for comparison with measured VO2. Lin's Concordance Correlation Coefficient (ρc) and the 95 percent lower confidence level (95% LCL) were used to evaluate agreement between two techniques MRI-Eight subjects underwent CMR exam with in-magnet c was 0.9669, while the 95% LCL was 0.8815.Mean 2 saturation. The combination of VO2 and CMR will potentially enhance non-invasive estimation of oxygen extraction, and when combined with exercise stress may be helpful in determining whether cardiac function or peripheral oxygen extraction, are the primary cause of heart failure related symptoms in individual patients.Non-invasive MRI derived


This review aims to highlight the general and specific strengths and limitations of intraoperative 3D echocardiography. This article explains the value of real-time three-dimensional transesophageal echocardiography (RT 3D TEE) during cardiac surgery and cardiac interventions.Recently published recommendations and guidelines include the use of RT 3D TEE. RT 3 D TEE provides additional value particularly for guidance during cardiac interventions , assessment of the mitral valve in surgical repair, measurement of left ventricular outflow tract area for transcatheter valvular replacements, and estimating right and left ventricular volumes and function. The exact localization of paravalvular leakage is another strength of RT 3D TEE. The major limitation is the reduced temporal resolution compared to 2D TEE.Three-dimensional echocardiography is a powerful tool that improves communication and accurate measurements of cardiac structures. Since the first use of transesophageal echocardiography (TEE) during cardiac surgery in 1979 .Three-dimensional transesophageal echocardiography 3D TEE) was first available as an offline model after acquisition of multiple 2D examinations D TEE was. Real-tiThis article highlights the strengths and limitations of RT 3D TEE in daily clinical practice during cardiac surgery and interventional cardiac procedures. This article is divided into two parts. The first discusses the strengths and the limitations of 3D echocardiography in comparison to 2D echocardiography (2DE), and the second outlines the specifics of RT 3D TEE looking at different cardiac structures.Two-dimensional echocardiography to visualize the 3D structure of the heart requires cognitive reconstruction from multiple 2D images. This is no longer required in 3D echocardiography. Further, while 2D echocardiography only reveals cross-sectional views of the heart, 3D echocardiography is more akin to a Cartesian coordinate system ••, enablBecause ultrasound propagation is equal in both 2D and 3D echocardiography, the use of more Cartesian coordinate-like data to improve spatial orientation leads to reduced temporal resolution. Practically, the echocardiographer using 3D echocardiography has to decide between the optimal temporal and spatial resolutions when imaging specific cardiac structures.Both temporal and spatial resolutions play a role in the quality of images produced by 3D echocardiography. Images need to be of adequate quality to allow qualitative and quantitative assessment. Temporal resolution is displayed as volumes per time unit (volume rate), and this can be increased by decreasing the volume size (sector) imaged. Spatial resolution can be improved by reducing the volume acquired or by increasing the number of scan lines through the volume. Increasing the number of scan lines for a specific volume will reduce its temporal resolution.Different 3D modalities are available  mode with and without color Doppler). The technical aspect of these different modalities will not be discussed in detail in this article, but it is explained elsewhere ••.The inherent physical properties of ultrasound and with that the limitations of ultrasound imaging in general are equally applicable to 3D and 2D echocardiography. Additionally, there are specific 3D-based artifacts such as stitching artifacts, dropout, “blurring” or thickening, blooming, and rail road artifacts –10. DropAnother limitation comes with displaying 3D echocardiographic images on a 2D screen. In doing so, colors are used to give a sense of depth and reality ••. ThereSimultaneous multiplane mode allows the recommended biplane measurement for ejection fraction of the same heartbeat, whereas in 2D TEE assessment, it can only be performed in two different heartbeats .Table 1SWith FV mode and multiple beat acquisitions, the left ventricular volume and function can be more accurately determined by 3D than by 2D echocardiography when compared to other image modalities like multidetector computed tomography (MDCT) or cardiac magnetic resonance imaging (CMRI) ••. ThreeImage acquisition time to assess LV function and volume is equally between both 3D and 2D. But, analysis of the 3D data set takes on average 2 min longer . In addiEspecially advantageous in the perioperative setting, nearly all left ventricular dimensions can be measured based on a single FV data set when using 3D TEE. This may be important in cardiac surgery when the patient is either unstable or there is not enough time for a comprehensive 2D TEE examination . MultislThe complex geometry of the right ventricle makes it impossible to evaluate right ventricular ejection fraction (EF) using 2D TEE. For experienced echocardiographers with access to special software, it is recommended to use 3D-derived right ventricular EF . Good acThe non-planar anatomy of the mitral valve (MV) complex lends itself to 3D assessment. It is more intuitive to assess the MV using 3D echocardiography than to reconstruct this three-dimensional structure using multiple 2D views , 22. TheThree-dimensional MV assessment especially for MV repair surgery can be used to predict the probability of successful MV repair and to assess the result after repair ••, 27, bColor flow Doppler in FV mode can be used to measure the VC area (VCA) and the proximal isovelocity surface area (PISA) by planimetry ••, 29, oThree-dimensional TEE is remarkable in its ability to assess commissural fusion  in rheumParavalvular leaks can be exactly located  and quanThree-dimensional echocardiography can accurately display the anatomy of the aortic valve in most patients and simplify communication between physicians , but in Subvalvular aortic membranous structures as well as dynamic left ventricular outflow tract (LVOT) obstruction can be diagnosed by 3D echocardiography , but lowAssessment of left ventricular outflow area with 3D echocardiography has been shown to correlate better with multislice computed tomography (MSCT) compared to 2D echocardiography , 39 and Pathology can be assessed by 2D and additionally by 3D TEE before aortic root, valve-sparing aortic, or valve repair surgery ••, 41.In aortic stenosis, 3D TEE can be used to measure left ventricular outflow area and diameter ••. Semi-The use of 3D color flow is not recommended in quantification of aortic regurgitation due to the low temporal and spatial resolutions, except in patients with multiple jets . In thesThe assessment of the tricuspid valve (TV) and its pathology has to include assessment of the right ventricle and right atrium. Three-dimensional echocardiography allows accurate evaluation of right ventricle function and volumetric assessment with specialized and costly software.Using biplane 3D TEE mode at different levels of the esophagus and stomach makes it possible to accurately identify the different leaflets •.Color flow Doppler (CFD) can be added to the FV set to more accurately assess insufficiency or stenosis of the valve , 44. VenThe greater distance between the probe and the TV and the non-perpendicular alignment make imaging of the TV by RT 3D TEE difficult ••.The thin leaflets of the pulmonary valve (PV) are situated in the far field from the TEE probe, and an echo dropout artifact is frequently encountered. Therefore, RT 3D TEE has no advantage over 2D TEE in the clinical evaluation of the PV.Three-dimensional echocardiography is more accurate in measuring left atrial (LA) and right atrial (RA) volumes and compares well with CMRI measurements . Using RThree-dimensional TEE is more sensitive and detects cases of aortic aneurysms and dissections that are missed with 2D TEE. The dissection flap appears in 3D TEE as a tissue flap. The linear image of the dissection membrane can be mistaken for an artifact in a 2D examination. The involvement of the right coronary artery ostium in aortic dissections is more accurately diagnosed by 3D TEE .The complexity of cardiac surgery and interventional procedures is increasing, and intraoperative and intraprocedural three-dimensional imaging is necessary to guide these , 50.While MSCT is the gold standard for sizing the aortic valve, 3D TEE is an accurate alternative in units where MSCT is not available or in situations where it is contraindicated –52. The Live 3D zoom TEE images can be used to correctly localize paravalvular leaks. Care should be taken not to mistake echo dropout artifacts as paravalvular leaks. The size of the dehiscence can be determined by acquiring a FV set with CFD to confirm leakage and to measure its size .Guidance RT 3D TEE and simultaneous multiplane mode are strongly recommended for guidance of transcatheter edge to edge MV repair with the MitraClip® –58.The Cardioband® direct annuloplasty MV repair is done with fluoroscopic and 2D/3D TEE guidance. Simultaneous biplane and 3D TEE are used for transseptal puncture and RT 3D TEE (wide-sector zoom) to assess anchoring position and final adjustment .RT 3D TEE can be used in addition to 2D TEE and fluoroscopy to help with coronary sinus identification during the indirect coronary sinus annuloplasty technique .Mitral stenosis can be treated by balloon valvotomy if found suitable for the procedure. Three-dimensional TEE can be used to assess the mitral commissural fusion to further determine suitability for this procedure. Three-dimensional TEE with its simultaneous biplane mode is used for correct transseptal puncture , 61.Intra-atrial Septum and Left Atrial Appendix Three-dimensional TEE is superior to 2D TEE in the spatial information that it provides to delineate the variant anatomy of a patent foramen ovale (PFO) and of atrial septal defects (ASD). The en-face image of the intra-atrial septum allows for spatial orientation and counting of defects. RT 3D TEE is also very suitable to guide the intervention. Offline MPR is useful for correct measurement of ASD size through precise alignment, can indicate rim deficiencies, and allows measurement relationships to important structures like the aorta •.The sizing of the left atrial appendix (LAA) can be done by RT 3D TEE . Two-dimInfective endocarditis (IE) and its complications can readily be diagnosed and further clarified by the use of intraoperative 2D TEE. Three-dimensional TEE FV and real-time modes reveal pathology that is not readily seen with 2D echocardiography . There iThree-dimensional and multiplane imaging are suggested to confirm or exclude cardiac masses in the cardiac chambers .Volumetric assessment of cardiac masses can be performed with 3D echocardiography, and further detailed assessment is possible: looking at attachment and detailed morphology .Thromboembolism from the thoracic aorta and atheromatous plaque in the aortic arch should be visualized in 3D and multiplane images .More complex percutaneous and transapical valve procedures are attempted and periprocedural 3D TEE guidance may also be useful in upcoming interventions –73.Automated or semi-automated software for quantification of the MV, for example, is feasible , 75, butHybrid imaging techniques with the different imaging modalities merged and used at the same time will also improve the capabilities of 3D imaging . CombineThree-dimensional strain and strain rate as parameters of myocardial deformation for the assessment of the left ventricle, right ventricle, and left atrium will play an important role in chamber quantification in the future , 78•.For the first time, RT 3D TEE allows for the anatomical display of most cardiac structures and pathologies, therefore facilitating improved communication between physicians. It additionally allows for more accurate quantification of some stenotic as well as regurgitant pathologies. Further development in 3D technology and the definition of normal values are the next steps to increase the clinical value of RT 3D TEE.


Asymmetric wall thickening has been described in patients with aortic stenosis. However, it remains poorly characterized and its prognostic implications are unclear. We hypothesized this pattern of adaptation is associated with advanced remodelling, left ventricular decompenzation, and a poor prognosis.2) and 37 age and sex-matched healthy volunteers underwent phenotypic characterization with comprehensive clinical, imaging, and biomarker evaluation. Asymmetric wall thickening on both echocardiography and cardiovascular magnetic resonance was defined as regional wall thickening ≥ 13 mm and > 1.5-fold the thickness of the opposing myocardial segment. Although no control subject had asymmetric wall thickening, it was observed in 26% (n = 43) of patients with aortic stenosis using magnetic resonance and 17% (n = 29) using echocardiography. Despite similar demographics, co-morbidities, valve narrowing, myocardial hypertrophy, and fibrosis, patients with asymmetric wall thickening had increased cardiac troponin I and brain natriuretic peptide concentrations (both P < 0.001). Over 28  months of follow-up, asymmetric wall thickening was an independent predictor of aortic valve replacement (AVR) or death whether detected by magnetic resonance  or echocardiography .In a prospective observational cohort study, 166 patients with aortic stenosis (age 69, 69% males, mean aortic valve area 1.0 ± 0.4 cmAsymmetric wall thickening is common in aortic stenosis and is associated with increased myocardial injury, left ventricular decompenzation, and adverse events. Its presence may help identify patients likely to proceed quickly towards AVR.https://clinicaltrials.gov/show/NCT01755936: NCT01755936. Aortic stenosis is not only characterized by progressive valve narrowing but also by the hypertrophic response of the left ventricle (LV) that ensues.,Echocardiography is the most common imaging technique to assess patients with aortic stenosis and can provide assessments of wall thickness that can be used to calculate left ventricular mass index. Cardiovascular magnetic resonance is less widely employed but provides the gold standard assessment of left ventricular mass and wall thickness with the unique ability to identify myocardial fibrosis. Asymmetric wall thickening is most commonly associated with hypertrophic cardiomyopathy.In this study, we sought to assess asymmetric wall thickening in patients with aortic stenosis using both cardiovascular magnetic resonance and echocardiography. In particular, we aimed to investigate in depth the factors associated with an asymmetric pattern of wall thickening, its relationship with other markers of left ventricular remodelling and decompenzation and to assess its prognostic implications.2. Coronary artery disease was defined as previous myocardial infarction, documented evidence of myocardial ischaemia or a > 50% stenosis of the coronary artery lumen. The blood sampling and analysis protocols are described in the We performed a prospective observational cohort study of stable subjects with mild, moderate, and severe aortic stenosis recruited from the Edinburgh Heart Centre. All patients who attended the institution between March 2012 and August 2014 were invited to participate. We excluded patients with other forms of valvular heart disease (moderate or severe in nature), end-stage heart failure, advanced malignancies or other comorbidities with a life expectancy < 2 years, cardiomyopathies (including previous myocarditis), and contraindications to gadolinium-enhanced magnetic resonance, such as ferromagnetic foreign bodies and estimated glomerular filtration rate < 30 mL/min/1.73 mBoth the clinical and imaging assessments were carried out at the Clinical Research Facility and the Clinical Research Imaging Centre, Edinburgh. The study was conducted in accordance with the declaration of Helsinki and approved by the local research committee. Written informed consent was obtained from all enrolled patients.Cardiovascular magnetic resonance was performed using a 3T scanner . A balanced steady-state free precession sequence was used for short-axis cine imagine of the LV and assessment of left ventricular volumes, mass and ejection fraction . LV longitudinal function was determined by measuring the difference in mitral annular displacement between end-systole and end-diastole. On short-axis cine images, epicardial and endocardial contours were carefully identified and planimetered in end-systole and end-diastole for left ventricular volume quantification. The left ventricular mass was calculated from the total myocardial volume (excluding trabeculations and papillary muscles) multiplied by the density of the myocardium (1.05 g/mL). All volumes and mass values were indexed to body surface area . The left ventricular mass/volume ratio (M/V) was calculated by dividing the left ventricular mass by the left ventricular end-diastolic volume. This parameter indexes the left ventricular mass to cavity size, with M/V values > 1.16 g/mL identifying patients with a relative increase in wall thickness.Late gadolinium enhancement (LGE) was used for detection of focal replacement fibrosis. Acquisition was performed between 8 and 15 min after gadobutrol  administration using an inversion recovery fast gradient-echo sequence and a phase-sensitive inversion recovery sequence in two phase-encoding directions in order to distinguish true enhancement from artefact. The inversion time was optimized to achieve adequate nulling of the myocardium. The presence of LGE was evaluated visually by two experienced operators . Where present, it was quantified using QMASS software  as an area of myocardium with a signal intensity exceeding the threshold of two standard deviations above the mean value of normal myocardium. All areas of inversion artefact or myocardial regions contaminated by blood pool or epicardial fat were excluded.myocardium/ΔR1blood-pool] and ΔR1 = (1/post-contrast T1 − 1/pre-contrast T1). In order to evaluate the total amount of interstitial fibrosis in our study cohort, we calculated the indexed fibrosis volume in each patient using the following equation: ECV × left ventricular myocardial volume corrected for the body surface area.T1 mapping was performed using the Modified Look-Locker Inversion recovery sequence for the assessment of diffuse myocardial fibrosis. Short-axis T1 maps of the mid-cavity were acquired in diastole before and 20 min after the administration of 0.1 mmol/kg of gadobutrol  using a dedicated 32-channel anterior-posterior cardiac array. T1 maps were analysed using OsiriX 4.1.1 software . For diffuse fibrosis, we calculated the extracellular volume fraction (ECV) derived from pre- and post-contrast myocardial T1 values corrected for blood-pool T1 and haematocrit. The ECV was calculated according to: ECV = partition coefficient ×  [1 − haematocrit], where partition coefficient = . Among patients that underwent aortic valve replacement, perioperative complications were also more frequently observed in individuals with asymmetric wall thickening than subjects without .Patients were followed up for a median of 28  months and 86 events occurred . Using the magnetic resonance analysis, the primary end-point was higher in patients with asymmetric wall thickening (P = 0.021). In patients that underwent aortic valve replacement, perioperative adverse outcomes were also more frequently reported in subjects with asymmetric wall thickening on echocardiographic .Based upon the echocardiographic assessments, there were 23 outcome events  in the 29 patients (79%) with asymmetrical wall thickening. This compared with 48 events in the 105 patients (46%) with concentric wall thickening. Using our combined primary outcome measure the asymmetric group on echo again had worse outcomes independent of age, sex, left ventricular mass index, coronary artery disease and the mean aortic valve gradient  of patients with mild-to-severe aortic stenosis when assessed using magnetic resonance. Echocardiography is less sensitive missing a third of these cases so that asymmetric wall thickening was only identified in 17% (n = 29). Irrespective of the imaging modality used, patients with asymmetric wall thickening had evidence of more advanced left ventricular decompenzation with elevated myocardial injury and increased BNP concentrations compared to those with concentric wall thickening. This was despite the two groups having similar co-morbidities, valve narrowing, myocardial fibrosis, and left ventricular hypertrophy. Moreover patients with asymmetric wall thickening (on both magnetic resonance and echocardiography) were found to have an adverse prognosis, with this form of remodelling acting as an independent predictor of aortic valve replacement or death after correction for age, sex, left ventricular mass index, coronary artery disease, and aortic stenosis severity.We here provide a comprehensive multimodality imaging assessment of asymmetric wall thickening in 166 patients with aortic stenosis. In a prospective consecutive cohort, we demonstrate that asymmetric wall thickening is common, affecting a quarter , and characterized by advanced wall thickness measurements .,Echocardiography is less well suited to measuring wall thickness and limited by the availability of acoustic windows. In this study, it missed 14 cases of asymmetric wall thickening detected by magnetic resonance. In eight patients, this was because short-axis echocardiographic images were not interpretable. Overall our prevalence of asymmetric wall thickening on echocardiography is similar to that previously reported,Why do some patients develop asymmetric rather than concentric wall thickening in response to increased afterload? The explanation for this observation remains unclear. In this comprehensive evaluation, we did not observe any clear differences in patient demographics, co-morbidity, bicuspid aortic valve prevalence, or aortic stenosis severity between these two groups. Asymmetric wall thickening did appear reversible following surgery suggesting that it represents an adaptive response to an increased afterload. One potential theory relates to the bending radius of the septum and posterior wall of the LV. It has been suggested that the larger radius of the septum leads to greater myocardial tensions during contraction, promoting a more pronounced hypertrophic response.During follow-up, a total of 14 patients died, limiting our mortality assessments, the outcome data are therefore predominantly driven by aortic valve replacement. A large multicentre study with longer follow-up is desirable. Further attention should also be paid to the mechanism underlying asymmetric wall thickening formation, including the underlying genetics and the explanation for the associated adverse prognosis.Asymmetric wall thickening is a common adaptation pattern in patients with aortic stenosis, which can be detected using both cardiovascular magnetic resonance and echocardiography. Despite similar demographics, comorbidities, valve narrowing, myocardial hypertrophy, and fibrosis patients with asymmetric wall thickening have increased evidence of myocardial injury (with elevated cardiac troponin I) and BNP levels. Moreover, asymmetric wall thickening was associated with adverse outcomes acting as an independent predictor of aortic valve replacement or death in this population.European Heart Journal—Cardiovascular Imaging online.Supplementary Tables and FiguresClick here for additional data file.


Supratentorial pilocytic astrocytoma (PA) may mimic pleomorphic xanthoastrocytoma (PXA) on conventional MR imaging, and a differentiation is clinically important because of distinct recurrence rate and anaplastic transformation rate. The purpose of this study was to investigate the diagnostic potential of diffusion-weighted imaging (DWI) in differentiating supratentorial PA from PXA.mean) and minimum ADC values (ADCmin) were calculated from the ROIs containing the contrast-enhancing lesion on DWI. ADCmean values and ADCmin values were compared among all supratentorial PA and PXA as well as between the subgroup of lobar PA and PXA by using an unpaired Student’s t test. The optimum threshold, sensitivity, specificity, accuracy, and the area under the receiver operating characteristic curve (AUC) were determined.We retrospectively reviewed DWI and conventional MR imaging of 16 patients with supratentorial PA and 8 patients with PXA. Variables of mean ADC values  and ADCmin values  were significantly higher in supratentorial PA compared with PXA. The ADCmean values and ADCmin values were also significantly higher in lobar PA than those in PXA. The ADCmean values were useful for differentiating supratentorial PA from PXA, with a threshold value of > 1189.8 × 10−6 mm2/s . The optimal threshold values of > 1189.8 × 10−6 mm2/s for ADCmean values provide sensitivity and specificity of 85.7 and 100%, respectively, for discriminating lobar PA from PXA. The optimum threshold value for ADCmin was > 1063.5 × 10−6 mm2/s.Both ADCDWI is helpful in characterization and differentiation of supratentorial PA from PXA.The online version of this article (10.1007/s00234-018-2036-y) contains supplementary material, which is available to authorized users. Pilocytic astrocytoma (PA) is classified as World Health Organization (WHO) grade I tumor, which occurs most commonly in children and young adults . This tuPA could be reliably differentiated from PXA when PA occurs in the cerebellum on conventional MR. Unfortunately, when PA occurs in the supratentorial brain, differential diagnosis of supratentorial PA and PXA can be challenging on conventional MR imaging due to their similar neuroradiological presentations, typically appearing as a large cystic mass with a mural-enhancing nodule . Given tTo date, DWI studies in low-grade glioma and on glioma grading have not reported ADC values of PA separately from PXA –17. The This retrospective study was approved by the institutional review board of our hospital, and written informed consent was waived due to its retrospective nature. From March 2010 through October 2017, potentially eligible patients with pathologically confirmed supratentorial PA and PXA were identified. For the selection of appropriate patients, those with obvious hemorrhagic lesions, previously treated, or incomplete DWI raw data were excluded. The patients with pathologically confirmed anaplastic PXA were also excluded. Pretreatment MR images of consecutive patients were reviewed retrospectively, and DWI was requested in addition to conventional MRI.All patients underwent surgical resection after MR examination. Tumor specimens were fixed in 10% phosphate-buffered formalin, embedded in paraffin, and representative slides were stained with hematoxylin-eosin reagent for standard histological diagnosis based on the histologic features by a neuropathologist (8 years of experience in histology) according to the 2016 WHO classification of tumors of the central nervous system (revised 4th edition) .Imaging was performed with a 3.0 T MR system  or another 3.0 T MR system  using a head coil. The conventional MR imaging sequences were performed by using axial T2WI, axial and sagittal T1WI, axial FLAIR, and contrast-enhanced T1WI in 3 orthogonal planes. FOV at 220 mm, section thickness of 5 mm, and intersection gap of 1 mm were uniform in all sequences.b = 0 and 1000 s/mm2. Acquisition parameters for the DWI sequence were as follows: repetition time (TR)/echo time (TE), 8200/102 ms; FOV, 220 mm; section thickness, 5 mm; intersection gap, 1 mm; NEX, 2.0. DWI was performed before administration of contrast material. Processing of the ADC map was generated automatically on the MR unit.Echo-planar DWI was acquired in the transversal plane with b = 1000 s/mm2.An experienced neuroradiologist  who was blinded to histopathologic results retrospectively interpreted all MR images. The reader evaluated each lesion and recorded the following MR findings: (a) tumor location, (b) predominant radiologic pattern , (c) peritumoral edema, (d) contrast enhancement pattern (mild enhancement or marked enhancement), (e) presence of adjacent leptomeningeal involvement , and (f) presence of inner tables scalloping. The tumor location was defined as the main lobe when more than one lobe was involved by the lesion. For evaluation of DWI sequence, qualitative assessment of the DWI signal intensity in the contrast-enhanced solid portions of the lesion was performed. The signal intensity of the lesion was classified as hyperintense, isointense, or hypointense compared with the contralateral normal-appearing white matter on DWI map with min), a maximum of 6 ROIs depending on tumor size  were positioned without any overlapping inside the tumors on ADC maps. To obtain mean ADC values (ADCmean), freehand ROI was delineated along the border of the contrast-enhancing solid regions of each tumor. Cystic, necrotic, hemorrhagic, or apparent vessel regions that might interfere with ADC values were avoided.Another two experienced neuroradiologists  independently and manually placed the region of interest (ROI) on ADC maps to encompass the contrast-enhancing solid portion of the tumors at the representative slice. For each tumor, the contrast-enhancing solid part was identified on contrast-enhanced T1-weighted images and matching ADC maps. The representative slice was defined as containing the largest area of the contrast-enhancing solid portion of each lesion and was selected independently by each observer. To obtain minimum ADC values . If the interobserver variability for ADC parameters has an excellent agreement (ICC > 0.75), the opinions of these two readers were intergraded through taking the average of values. The ADCmean values and ADCmin values were compared using the unpaired Student’s t test in all supratentorial PA and PXA and then between lobar PA and PXA.All statistical analyses were performed with Statistical Package for the Social Sciences  and MedCalc software . Results with Z test.The receiver operating characteristic (ROC) analysis curves were constructed to determine the diagnostic accuracy and optimum threshold value of each ADC parameter for discriminating supratentorial PA, especially lobar PA, from PXA. The optimum threshold value defined was those that provided highest sensitivity and specificity jointly and maximized Youden index based on the decision plot. The sensitivity, specificity, positive predictive value, negative predictive value, accuracy, and area under the curve (AUC) based on optimum cut-off values for each ADC parameter were further calculated. Furthermore, comparisons of AUCs for different ADC parameters were made with a Twenty-four pathologically proved cases, including 16 cases with supratentorial PA and 8 cases with PXA, were enrolled in this study. The demographic data and conventional MRI manifestations of supratentorial PA and PXA are summarized and compared in Table mean values and ADCmin values calculated for supratentorial PA, lobar PA, and PXA are shown in Table n = 4), isointense (n = 10), and hypointense (n = 2) relative to the contralateral normal-appearing white matter. Conversely, the signal intensity of PXA was hyperintense (n = 6), isointense (n = 2), and hypointense (n = 0). The signal intensity in the solid contrast-enhancing portions of PA was significantly higher than that of PXA (P = 0.02). Interobserver agreement of two readers for the semiquantitative analysis of all ADC parameters was excellent . Both ADCmean values  and ADCmin values  were significantly higher in supratentorial PA compared with PXA, respectively. In addition, Both ADCmean values  and ADCmin values  were also significantly higher in lobar PA compared with PXA, respectively. The results of the ROC curve analysis are given in Table mean values seemed to account for the higher AUC (0.977) in differentiating supratentorial PA from PXA, with a cut-off value of 1189.8 × 10−6 mm2/s and sensitivity and specificity of 93.8 and 100%, respectively. But there were no significant differences in AUC between ADCmean and ADCmin for differentiating supratentorial PA from PXA using Z test . The ADCmean values were also useful for discriminating lobar PA from PXA  with a cut-off value of 1189.8 × 10−6 mm2/s . The decision plot for ROC analysis is shown in Supplementary Figs. The ADC parameters including ADCense n = 0, and hyense n = 0, and hyense n =  relativemean and ADCmin values based on contrast-enhancing portions of the tumor in supratentorial PA group were significantly higher than those in PXA group.In this study, we used ADC values derived from DWI to discriminate supratentorial PA and PXA, which is frequently indistinguishable with conventional MRI. Our preliminary results suggested that both ADCBoth PA and PXA belong to low-grade astrocytoma and gross total resection without adjuvant treatment including radiotherapy or chemotherapy is considered as the preferred treatment. However, the surgical planning of supratentorial cystic PA may slightly differ from cystic PXA. The surgical procedures for removal of cystic components of PA and PXA include radical resection of cyst wall, biopsy of cyst wall, or no resection at all. Previous studies have reported that the cyst wall of PA was free from tumor tissues even if it was enhanced on MRI , and remPA typically occurs in the cerebellum, whereas the overwhelming majority of PXA arises from the supratentorial brain. With the typical location and appearance of a well-delineated cerebellar cystic mass with mural nodule, the diagnosis of PA is easy. However, when located in the supratentorial region, PA shares its typical “a supratentorial cystic mass with enhancing mural nodule” appearance with PXA . As pres−6 mm2/s in the 7 PXA tumors. In the present study, we found that the signal intensity in the contrast-enhancing areas of PXA tended to be hyperintense or isointense relative to normal white matter on DWI. Furthermore, the mean ADC values of PXA in this study were comparable to previous findings [−6 mm2/s) [mean of 1542 ± 186 × 10−6 mm2/s, which was consistent with that in previous studies [−6 mm2/s) in 3 patients with PA, while 1 PXA had relatively lower ADC value of 1009 × 10−6 mm2/s . In this study, we found that all ADC values of supratentorial PA were significantly higher than those of PXA. Furthermore, we also performed a subgroup analysis of lobar PA and found that all ADC values of lobar PA were also significantly higher than those of PXA. This finding could be explained by different histopathological features of PA and PXA. Histologically, PA is a tumor of low-moderate cellularity within markedly loose myxoid background [DWI is a reliable and practicable MR technique and has been widely used to evaluate intracranial tumors –13, 15. findings , 30. Sevfindings , 31–33. 6 mm2/s) , 30, 31. studies , 30, 34.ckground , whereasckground . As prevckground , ADC valckground , 38. Takmean values and ADCmin values were significant for the contrast-enhancing portion of the tumor to discriminate supratentorial PA from PXA. Although ROC classification could only be used to illustrate the performance of a binary classifier system and AUC from ROC may be misleading if the ROC curves of two diagnostic tests intersect, ROC analysis is still a widely accepted method for evaluating the diagnostic accuracy of radiological tests [mean values in distinguishing supratentorial PA from PXA , as well as in distinguishing lobar PA form PXA . Therefore, our findings suggest that DWI with ADC values may aid in the differential diagnosis of supratentorial PA and PXA, which is frequently challenging in clinical practice.Recently, a histogram analysis based on whole-tumor has been used to indicate the heterogeneity of high-grade glioma and minimize ROI sampling errors , 39. Howal tests . In thisBesides the intrinsic limitations of the retrospective study, several other potential limitations of this study should be mentioned. Firstly, the number of the patients with PXA was rather small. Future investigations that include more patients are recommended to strengthen the statistical power. Secondly, because ADC values were not used to guide the biopsy in this retrospective study, it was not possible to evaluate the correlations between regions of lower ADC in PXA and hypercellularity point to point. These correlations should be performed in our future study. Thirdly, we could not excluded the presence of tiny hemorrhage within the tumor that may generate susceptibility blooming, hence influencing DWI evaluation, though there was no noticeable evidence of hemorrhage on conventional MRI. Fourthly, the diagnostic accuracy of DWI in our study refers only to the binary comparison of supratentorial PA and PXA, which may indicate these results cannot be used among PA, PXA, and other supratentorial young adult contrast-enhancing lesion, such as gangliocytoma, ganglioglioma, and high-grade glioma. However, the purpose of this study was to differentiate supratentorial PA from PA, which may be distinguishable on conventional MRI. And several conventional radiological features may be indicative of other supratentorial adult contrast-enhancing lesion. For instance, the presence of intratumoral calcification was a consistent feature for gangliogliomas and gangliocytomas. And the infiltrative growth pattern, heterogeneous enhancement, and the presence of hemorrhage and necrosis should indicate high-grade gliomas. Finally, supratentorial PA and PXA are not amenable for a surgical excision despite of preoperative accurate differential diagnosis. However, the surgical strategies for cystic components of these two tumors may be different in order to reduce postoperative disability and mortality without increasing the recurrence rate. Further prospective studies are needed to confirm the value of differential diagnosis of these two tumors in guiding the surgical plans.In conclusion, our results suggest that DWI is helpful in characterization and differentiation of supratentorial PA from PXA.ESM 1(PDF 1160 kb)


The cardiac system compensates for variations in physiological and pathophysiological conditions through a dynamic remodeling at the organ, tissue, and intracellular levels in order to maintain function. However, on longer time scales following the onset of ventricular pressure overload, such remodeling may begin to inhibit physiological function and ultimately lead to heart failure. This progression from compensatory to decompensatory behavior is poorly understood, in particular owing to the absence of a unified perspective of the concomitantly remodeling subsystems. To address this issue, the present study investigates the evolution of compensatory mechanisms, in response to overload, by integrating diffusion-tensor MRI, echocardiography, and intracellular and hemodynamic measurements within consistent computational simulations of aortic-banded rat hearts. This approach allows a comparison of the relative leverage of different cardiac properties  to affect cardiac contraction. Measurements indicate that, following aortic banding, an ejection fraction (EF) of 75% was maintained, relative to control rats, despite significant remodeling of the left-ventricular wall thickness (increasing by ~90% over 4 weeks). Applying our framework, we identified the left-ventricular wall thickness (concentric hypertrophy) and the intracellular calcium dynamics as playing the dominant roles in preserving EF acutely, whereas the significance of hypertrophy decreased subsequently. This trend suggests an increasing reliance on intracellular mechanisms (average increase ~50%), rather than on anatomical features (average decrease ~60%), to achieve compensation of pump function in the early phase of heart failure. The heart is a dynamic system that adapts to changes in external loading conditions to maintain its physiological function. In cases of ventricular pressure overload, where the ejection of blood from the ventricle is hindered by elevated aortic pressure, the maintenance of this function requires an increase in the generated stress to maintain systemic blood flow , we seek to isolate the impact of AB on the cardiac system, to effectively probe two different stages of compensation. For each case, we integrate echocardiography, diffusion-tensor MRI (DT-MRI), hemodynamic, and calcium-stimulus measurements into computational models designed to quantify and compare different contributions to compensation. We then apply an The AB rat hearts used in this study display concentric hypertrophy, when compared to the control (sham-operated) rats, without however showing symptoms of decompensation or heart failure. An additional feature is that, despite the magnitude of the imposed change of physiological conditions, the overall cardiac performance, as measured by the left-ventricular ejection fraction EF (the ratio of the stroke volume SV to the end-diastolic volume EDV), remains remarkably constant. This constancy in EF, together with the absence of symptoms of decompensation, underpins our characterization of this phase as a phenomenological manifestation of compensation, i.e., before the onset of decompensation. Having replicated the measured principal features of the cardiac cycle using the computational models, we calculated and compared the partial sensitivities of EF to the functional parameters of each heart model. We thus interpret these sensitivities as reflecting the overall capacity of the heart to respond dynamically under pathologically induced stress to maintain normal function. Taken as a whole, this computational modeling approach provides a theoretical framework for unifying the experimental datasets, which conceptually represent separate time points in the evolution of compensation.The workflow of the model characterization is outlined in Figure ex vivo fixation process, performed prior to DT-MRI, resulting in an overestimate of the LV dimensions in diastasis, and hence precluding reliable model parameterization. Those hearts were therefore discarded. In total, one SHAM heart and three AB hearts were successfully simulated and considered for further analysis.In some instances, it was not possible to reproduce the measured diastolic and contractile properties using any choice of model parameters because the diameter of the segmented heart was too similar to the measured end-diastolic diameter. An analysis of these hearts indicated the likely presence of residual LV pressure during the U with coordinates that describe the cardiac system:Having thus parameterized the heart models, we investigated the impact of aortic banding on cardiac function. Conceptually, our methodological approach associates the remodeling process with a hypothetical trajectory through a multidimensional parameter space 2+]50 is the calcium-binding sensitivity of troponin, pa is the aortic pressure, z is the aortic-valve impedance, PCa and DCa are respectively the peak and diastolic intracellular calcium concentrations, and ugeom and ufiber are generalized coordinates representing the geometrical and fiber configurations. From this perspective, the end points of the trajectory represent the real heart models , while the trajectory represents the continuous evolution from a “healthy” heart (SHAM) to the remodeled heart, as a result of aortic banding. At each intermediate state considered along the trajectory, a new hypothetical heart model was fitted again using the process outlined in Figure where ugeom and ufiber, which represent the geometrical and fiber structures, are defined as continuous variables bounded by ugeom and ufiber, representing hypothetical heart structures generated by linear interpolation of, respectively, the node coordinates or the fiber angles of the end-point models.The geometrical and fiber parameters U:Within this formalism, we quantified the “compensatory ability” of a given model, with respect to each variable, in terms of the sensitivity of EF, considered as a function over S and considers changes in a given parameter u in proportion to the phase-space distance spanned by the overall trajectory. The derivatives ∂EF(u)/∂u were calculated by applying changes to u that were sufficiently small to remain in the local linear regime around the model considered. As discussed below, we interpret S as a measure of the ability of each parameter u to control EF and maintain the heart in a compensated state.This formulation ensures the non-dimensionality of An initial cohort of 20 Sprague-Dawley rats was initially considered for echocardiography . Eight weeks (±4 days) after birth, 10 of the rats were applied an AB on the transverse aorta with a 0.5 mm clip, while the other 10 underwent a sham surgery. All animal use followed NIH guidelines and was approved by the Institutional Animal Care and Use Committee (IACUC) at the University of California, San Diego.2 by nose cone. M-mode echocardiographic images were acquired using a GE vivd/I imaging system. The entire procedure took approximately 15–20 min per animal. The animals were transferred to their cages and quickly regained full consciousness.The heart rate of each rat was monitored every 7 days post intervention. Echocardiograms were measured immediately prior to the operation, and subsequently after 2 and 4 weeks. The rats were rested on an IACUC-approved heating pad and anesthetized with 1.5% isoflurane in 100% OFour weeks post operation, the rats underwent a hemodynamic study to determine the maximum aortic pressure during LV ejection using a manometer-tipped catheter . A subset of six rats from the initial cohort were then imaged by diffusion-tensor MRI (DT-MRI). Two of the SHAM and four of the AB hearts were extracted and fixed in diastasis by arrest using a high-potassium solution, followed immediately by fixation to approximate the relaxed state. Following a method described elsewhere 2h − πr2h, where r = LVD/2. Hence,The EF for each heart was estimated by treating the M-mode echocardiography images as cross sections through a cylindrical LV slice Figure . The chaTo validate this approach, we compared the result of Equation (4) with a more explicit measurement of the rat LV volume using MRI data available in the literature  using a DTI-EPI sequence. A gradient insert allowed for a 1 T/m maximum gradient strength and maximum slew rate of 11,250 T/m/s. Imaging parameters were as follows: FOV 20 × 20 × 20 mm, isotropic 200 μm resolution, gradient duration 2 ms, gradient separation 11 ms, nominal b-value 500 s/mm2, number of non-diffusion weighted images 1. The total scan time was approximately 1 h. This scan protocol was repeated five times and the resultant images were manually averaged in AFNI .Diffusion-weighted images were acquired The resulting image stacks were segmented (ITK-SNAP) and used to reproduce the LV geometry and muscle-fiber configuration in the computational model, as explained below.We complemented the above imaging results with measurements of intracellular calcium stimuli, performed in separate experiments at physiological temperature (37°C) in single myocytes derived from sham and aortic-banded Wistar rat hearts 6 weeks following the the placing of a constriction on the ascending aorta  , was fitted to a finite-element cubic-Hermite single-cavity mesh template comprising 6 elements along the longitudinal direction, 8 in the azimuth, and 2 across the wall thickness Figures  Lamata , 2014. TThe diffusion tensor in the muscle tissue was reconstructed from the DT-MRI images at each voxel contained within the mesh domain, taking the primary eigenvectors as specifying the fiber directions. The projection of each fiber vector onto the local geometrical basis vectors yielded the elevation (α) and imbrication (β) angles , also governed by Hill dynamics h(λ)fxb, assuming Tref = 120 kPa as a scale prefactor consistent with experiments  expresses the length dependence for a local extension ratio λ, while g encapsulates the stretching-velocity dependence, based on a “fading memory” model  = 9.5 mmHg·s/ml], keeping all other parameters unchanged.The pressure boundary conditions were defined by the imposed aortic pressure l Figure . The Winl Figure : periphepa, the Windkessel model governed blood ejection from the LV until volume flow was reversed. Fixing the LV volume again in this state, isovolumetric relaxation was then initiated, terminating when the LV pressure attained the chosen diastolic pressure (1 kPa). Diastolic filling was then reactivated and the process was repeated until the pressure-volume loop converged to a steady-state limit cycle.The cardiac cycle was simulated using the protocol described in detail elsewhere , and EF (determined from the echo data using Equation 4). Each of these quantities can be compared directly with the simulation output (section 2.7).To minimize the reliance of the simulation on unmeasured parameters, we limited the analysis to consider a simplified phenotype space defined by three variables: the mean LV diameter at end diastole , the maximum pressure pa; and (3) the dissociation constant [Ca2+]50 between Ca2+ ions and troponin C, which controls the extent of the contraction  the effective tissue stiffness ped = 1 kPa throughout the filling phase. Consequently, the parameter c1 (Equation 5) and the assumed ped, i.e., In the absence of experimental data relating to diastolic filling, we assumed a constant diastolic pressure dia, a conventional marker of overload-induced concentric hypertrophy, calculated directly from the echo data, as illustrated in Figure R[LVWTdia] (see Equation 3) in the SHAM and AB hearts, rather than the final LVWTdia values, to mitigate the natural variability observed between individual hearts.The absence of exterior symptoms of heart failure, in any of the rats considered, implies either that the AB had negligible effect on the hearts on the time scales considered, or that any effect of the AB was compensated by remodeling %/week (s.d.) is significantly greater than the corresponding SHAM rate (3 ± 2)%/week (p = 5 × 10−5)  and −1.3%/week for the AB hearts , suggesting that AB in these rat hearts had an insignificant effect on EF. This is further supported by the similarity in the mean EF values , 4 weeks post intervention  Figure . In conto Figure , with avn Figure . We thert = 4 weeks, the echo data characterize the cardiac dynamics shortly before the hearts were extracted from the animals to perform the ex vivo DT-MRI analysis. This characterization allows the subsequent simulations to reproduce the in vivo contractions with maximum fidelity (section 2.8). Table t = 4 weeks) for these hearts.The echo measurements of specific rat hearts were used to parameterize the computational models for the simulations , the ejection fraction EF, and the maximum pressure Figure 2+]50, and pa that simulated the measured phenotypes with good accuracy  for each coordinate in parameter space U (see Equation 1), in both the SHAM [u = u(SHAM)] and AB [u = u(AB)] cases. As explained in section 2.1, we examined three different trajectories in U, linking the available SHAM heart model to either of three AB models. Each bar in Figures u at one of these trajectory end points. Figure 2+]50, and geometry. In Figure 2+]50, for each heart pair. This change suggests a systematic decrease in the ability of hypertrophy to contribute toward the maintenance of the ejection fraction following aortic banding.Partial sensitivities z artificially, S is relatively insignificant in both the SHAM and AB regimes, suggesting that the impact of the aortic constriction affects cardiac function only indirectly through cardiac remodeling. Similarly, S, S are consistently small. It is therefore unlikely that the large differences in parameter values between the AB hearts  that straddled the measured SHAM phenotype  to −50° (epi). The fitted values are plotted in Figures To test the hypothesis that this evolution results from the increase in LV wall thickness LVWT specifically, we repeated the simulations, this time using canonical semi-ellipsoidal heart meshes, constructed with arbitrary LVWT, instead of the meshes derived from actual hearts. The analysis procedure is outlined in Figure pe Table , i.e., 7S, S, and S50] as functions of LVWT. In all the cases, S decreases with increasing LVWT, while S and S50] both increase, mimicking the trends observed in Figure S and S50], despite the changes in the absolute values of [Ca2+]50 required to reproduce the phenotypes , the opposite tendency is observed here: [Ca2+]50 must increase with LVWT to yield the correct phenotypes. Yet, S50] mirrors S in the same manner as in Figure S with increasing LVWT is again observed, albeit at a smaller rate when applying the AB—rather than the SHAM—calcium transient. These results, taken together, emphasize the particular role played by LVWT in governing the qualitative evolution in compensatory properties.Figure s Figure  for a co S as fThe aim of the present study was, firstly, to apply a data-driven model of the rat heart that reproduces the principal mechanisms by which the heart can compensate for changes in its environmental conditions to preserve its physiological function. Secondly, we sought to identify how this compensatory capacity may evolve in rats as a result of aortic-banding-induced ventricular pressure overload, which is known to instigate cardiac remodeling on various spatial scales. This was done by integrating electrophysiological, echocardiography, and DT-MRI measurements into heart-specific computational models, to allow the isolation and comparison of individual compensatory effects. The models, constructed using the available data, aimed to be as rat-specific as possible to reproduce the measured phenotypes. The variation in model parameters between the different hearts is comparable to variations reported in other studies. For example, Borbély et al.  report sWe considered three broad classes of cardiac properties: the heart geometry , the muscle-fiber configuration, and the intracellular electrophysiological mechanisms, the output of which is the calcium transient that initiates muscle contraction. Although none of the examined rats displayed exterior symptoms of heart failure at the time of the measurement (as displayed by their constant EF), those rat hearts that had been subjected to aortic banding showed clear signs of LV-wall hypertrophy, indicative of the compensatory phase of cardiac remodeling. Intracellular calcium transients measured in LV myocytes derived from aortic-banded rats, albeit of a different breed, also showed significant remodeling. Further, we found that despite these changes, the EF was conserved following aortic banding. Using Equation (2), we therefore quantified the compensatory ability, in the aortic-banded and control hearts, in terms of the partial sensitivities of the EF to individual cardiac parameters. We interpreted these sensitivities as reflecting the capacity of the cardiac system to adapt to changes in physiological conditions in order to maintain its function, as characterized by the EF.2+ binding to troponin C) are of similar magnitude in the hearts with no aortic banding, the latter sensitivities increase significantly at the expense of the former following aortic banding. In other words, a healthy heart can be expected to compensate better for the onset of hypertension by a thickening of its cavity wall, than a heart in an advanced state of concentric hypertrophy; at that stage, remodeling of calcium signaling becomes a more effective compensatory mechanism. The complementary simulations summarized in Figure Our main results, summarized in Figure Another natural concern for this interpretation is that the hypertrophic process necessarily occurs much more slowly than the sudden impact of aortic banding. However, our simulations probed only the experimentally accessible end points of the overall remodeling process. Therefore, insofar as aortic banding serves as an experimental model for the more gradual onset of hypertension, our interpretation remains independent of the evolution of the rat hearts between these end points.2+]50, 6 weeks after the intervention, marks a qualitative transition in the heart's capacity to achieve compensation. The peak calcium level PCa encapsulates the underlying electrophysiological machinery of the muscle cells, which expends energy at every heart beat. The increase in S in the AB hearts can be explained by the lowering of PCa   was increased in the extreme. We deduced that this failure to achieve the expected dynamics resulted from the nominal LV size in diastasis (derived from the DT-MRI measurements) being almost identical to the diastolic diameter (to within 10% or less). In contrast, the successfully simulated hearts had an equilibrium size that typically amounted to 60–70% of the end-diastolic volume, which provided scope for sufficient contraction. One potential cause of error in the erroneous DT-MRI measurement is the possibility of even a small intramyocardial pressure being exerted during perfusion with the high-K+ arrest solution and fixative. The near coincidence of the LV diameter in this state with the measured end-diastolic size is consistent with an unintended inflation of the LV. We therefore considered these anomalies as artifacts and discarded those hearts from the analysis, retaining one SHAM and three AB hearts.DT-MRI is a costly and delicate technique that affords a considerably lower throughput than echocardiography. Thus, whereas the latter experiments provided statistically significant samples of geometric measurements, only a small proportion of those hearts underwent DT-MRI processing. As explained above, the main appeal of performing both experiments successively on the same hearts was to increase the consistency of the models with the biological systems. One performance criterion for the computational simulations was their ability to reproduce the morphological dynamics inferred from the echocardiograms (see section 2.8). Of the initial cohort of hearts (ten SHAM and ten AB), two SHAM and four AB hearts proceeded to DT-MRI. Within this subgroup, only one SHAM heart and three AB hearts successfully simulated the expected diastolic size and EF. In both of the unsuccessuful cases, blood ejection into the aorta stalled at a fraction of the expected EF, even when the strength of contraction  and found no systematic trend distinguishing the SHAM and AB hearts. The available measurements thus provide no evidence that this is a significant parameter for the present purpose.S decreasing with increasing LVWT while S and S50] both increasing. Taken together, these results demonstrate the general pattern that, as LVWT increases, EF becomes less sensitive to variations in LVWT and more sensitive to those of [Ca2+]50 and PCa.To increase confidence in the validity of our conclusions despite the paucity of available hearts, the complementary simulations of Figure To our knowledge, the present work constitutes a first attempt to provide a global view of cardiac compensation, within the context of ventricular pressure overload, by considering the anatomical shape and the passive and active mechanical behavior on an equal footing. We conclude that intracellular behavior becomes a more efficient compensatory mechanism than organ-level remodeling as the rat heart responds to the onset of pressure overload. This phenomenon was observed with regard to EF, a traditional indicator of cardiac dysfunction routinely measured in clinical protocols. Although other metrics of cardiac function  directly reflect cardiac efficacy, those metrics are notoriously dependent on temporal and biological factors, and may vary significantly among healthy subjects of the same species, or even, over time, in a given individual (Haxhe and Lammerant, AL performed the computational analysis, analyzed the experimental data, wrote most of the manuscript. SL wrote the software code for the computational simulations. EC, LF, JO, and AM provided the MRI images of the rat hearts. PL wrote the software code for creating the finite-element meshes used for the simulations. SN and NS contributed significantly to the conceptual design of the work, the analysis of the results and the writing of the manuscript.AM and JO are co-founders, equity holders and scientific advisors to Insilicomed Inc., a licensee of UCSD software used in this research. This relationship has been disclosed to the University of California San Diego and is overseen by an independent conflict of interest management subcommittee appointed by the university. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.