Cardiac and renal function are inextricably connected through both hemodynamic and neurohormonal mechanisms, and the interaction between these organ systems plays an important role in adaptive and pathophysiologic remodeling of the heart, as well as in the response to renally acting therapies. Insufficient understanding of the integrative function or dysfunction of these physiological systems has led to many examples of unexpected or incompletely understood clinical trial results. Mathematical models of heart and kidney physiology have long been used to better understand the function of these organs, but an integrated model of renal function and cardiac function and cardiac remodeling has not yet been published. Here we describe an integrated cardiorenal model that couples existing cardiac and renal models, and expands them to simulate cardiac remodeling in response to pressure and volume overload, as well as hypertrophy regression in response to angiotensin receptor blockers and beta-blockers. The model is able to reproduce different patterns of hypertrophy in response to pressure and volume overload. We show that increases in myocyte diameter are adaptive in pressure overload not only because it normalizes wall shear stress, as others have shown before, but also because it limits excess volume accumulation and further elevation of cardiac stresses by maintaining cardiac output and renal sodium and water balance. The model also reproduces the clinically observed larger LV mass reduction with angiotensin receptor blockers than with beta blockers. We further provide a mechanistic explanation for this difference by showing that heart rate lowering with beta blockers limits the reduction in peak systolic wall stress  relative to ARBs. Heart failure (HF) presents a major and growing health problem in developed countries. It is a leading cause of hospitalization with poor long-term survival. From 2013 to 2016, 6.2 million adults in the United States were diagnosed with HF, with estimated annual societal costs of $30.7 billion . Left veThe kidney is the primary controller of blood and interstitial fluid volume homeostasis, and thus plays an important role in determining both the preload and afterload experienced by the heart. The heart remodels in response to changes in loading, and the pattern of hypertrophy depends on the loading condition. Pressure overload usually causes thickening of ventricle wall, which is often observed in HF patients with preserved ejection fraction (HF-pEF). Volume overload, on the other hand, causes ventricle cavity enlargement and thinning of the ventricle wall. This pattern is typical of heart failure with reduced ejection fraction (HF-rEF). These remodeling patterns impact cardiac function, which in turn alters renal function through changes in renal perfusion, leading to changes in blood and/or interstitial fluid volume. Neurohumoral mechanisms including the renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system, and natriuretic peptides regulate the integrated function of these organs.A large number of cardiac therapies act by primarily reducing the workload on the heart, rather than by directly altering cardiac contractile function. This reduced workload is achieved by reducing heart rate, reducing peripheral resistance, and decreasing blood volume. This reduced workload translates into slowing or reversal of cardiac remodeling and improvement in overall cardiac function. Nearly all HF therapies, e.g., drugs modulating the RAAS and/or natriuretic peptides , beta blComputational models in which physiology, pathophysiology, and pharmacology are described mathematically with sufficient level of mechanistic details and fidelity [an approach called quantitative systems pharmacology (QSP) modeling ] are incIn this article, we present an integrated cardiorenal model that builds on the Guyton and Bovendeerd models to link a detailed mechanistic representation of kidney function and volume homeostasis with the dynamics of cardiac function and remodeling. We adapted the model to allow myocyte remodeling in response to changes in cardiac loading. We then applied the model to propose a mechanistic explanation for observed differences in left ventricular hypertrophy regression between two therapies, the angiotensin receptor blocker losartan and the beta blocker atenolol, that was observed in the LIFE clinical trial .The major functional modules and mechanisms of the mathematical model are shown schematically in Plv to myocardial fiber stretch and strain is the ratio of LV wall volume Vw and chamber volume Vlv.The ventricular mechanics portion of the model was adapted from a previously published model by fσ and m,rσ are mechanical stresses in myocardium along the fiber and radial directions, respectively. This assumption allows the mathematical representation of cardiac dynamics to be substantially simplified to a set of ordinary differential equations with a limited number of parameters, without the need for finite element analysis. Right ventricle dynamics was described by the same equation with distinct Vw and Vrv parameters. In our model function of atria was not included and therefore blood was assumed to flow passively from the pulmonary vein to the left ventricle and from the vena cava to the right ventricle. Spatial variations in cardiac geometry and mechanical properties were not considered. Heart valves were modeled as ideal diodes allowing flow only in one direction, except when modeling regurgitation as described later. Detailed description of ventricular model with equations can be found in original publication , interstitial tissue (VIS), and fibrosis (Vf).To describe these remodeling phenomena, the LV chamber wall volume Myocytes are modeled as cylinders, and myocyte volume is determined as,Nmyo, Dmyo, and Lmyo are the number, average diameter, and average length of myocytes.where, Dmyo is the sum of the normal  diameter Dmyo,0 and any change in diameter ΔDmyo resulting from remodeling. Lmyo is the sum of normal  length Lmyo,0 and any change in length ΔLmyo.fσ in the cardiac tissue fiber. The peak systolic stress f,peak,0σ under baseline conditions is used as the reference stress level. When the peak stress along the fiber f,peakσ is greater than f,peak,0σ, myocyte diameter increases, representing the formation of sarcomeres in parallel. When f,peakσ is less than f,peak,0σ, myocyte diameter decreases.As proposed by Grossman, we assume that the heart remodels to maintain a certain level of peak elastic stress Myocytes cannot increase in diameter infinitely. As the diameter approaches the maximum value, the rate constant for the increase in diameter approaches zero:Dmax is assumed to be equal to myo,0D, so that the increase in diameter is limited to 2X normal, based on the upper limit of histologic observations of myocyte diameter  stress under baseline conditions is used as the reference stress level Lmax is assumed to be equal to Lmyo,0, so that the increase in length is limited to 2X normal. Kl0 was determined by fitting clinical data on LV hypertrophy regression, as described later.ΔThe left ventricle cavity volume at zero transmural pressure increases as the myocyte length increases, according to the equation,VLV0 is the cavity volume before any remodeling has occurred.where V as a state variable, and by parameters, hydraulic resistance R, vessel capacitance C and, in case of systemic and pulmonary arterial beds, inertance I.The systemic and pulmonary circulation are described with a lumped parameter model, as illustrated in i, the change in its volume VI is determined by the balance between the blood inflow, QI–1, and blood outflow QI.For each compartment QI between compartments is calculated from eq. 12, in which the inertance II equals zero for all i, except for the systemic and pulmonary arterial beds ; and no flow otherwise (PI–1 < PI). All blood compartments except LV and RV are considered passive and pressure inside them is calculated as,Heart valves control the flow in and out of the LV and RV. They are assumed to be non-leaky, with blood flowing forward when the pressure in the upstream compartment Pi0 is the volume when the system is at equilibrium with environment without cardiac activity. Total blood volume Vb in the system is equal to the sum of all compartment volumes.where V+ and water homeostasis. It describes blood flow, resistance, and pressures through the renal vasculature (Eqs. S1–S4); Starling forces across the glomerulus (Eq. S5); filtration of water, glucose, and Na+ through the glomerulus ; reabsorption of glucose through sodium glucose co-transporters (SGLT) along the proximal tubule  and urinary glucose excretion (Eq. S10); reabsorption of Na+ through SGLT, NHE3, and other mechanisms in the proximal tubule (Eqs. S12–S15) and along the rest of the nephron and urinary Na+ excretion (Eqs. S16–S18); reabsorption of water across osmotic gradients along the nephron (Eqs. S19–S27) and urinary water excretion (Eq. S28); tubular hydrostatic pressures along the nephron (Eqs. S37–S40); whole body balance of Na+ and water, and distribution between blood, interstitial, and peripheral compartments (Eqs. S29–S36).The renal function portion of the model is summarized in + concentration (Eq. S45) that alters collecting duct water reabsorption (Eq. S25). (2) The pressure-natriuresis phenomenon is modeled as a signal from renal interstitial hydrostatic pressure  that alters Na+ reabsorption rates along the nephron . (3) Tubuloglomerular feedback (TGF) is modeled as a signal from macula densa sodium flow (Eq. S48) that signals the afferent arteriole (Eq. S1) to constrict or relax. (4) Myogenic autoregulation is modeled as a function of preafferent pressure  that signals the preafferent arterioles (Eq. S1) to constrict or relax. (5) Whole-body blood flow autoregulation is modeled as a signal from cardiac output that modulates peripheral resistance  (6) Atrial Natriuretic Peptide . (7) To describe the renin-angiotensin-aldosterone System (RAAS), renin secretion is modeled as a function of macula densa sodium flow, with a strong inhibitory feedback from angiotensin II bound to the AT1 receptor (AT1-bound AngII) (Eqs. S52–S55). Renin generates Angiotensin I, which can be converted to Angiotensin II by ACE or chymase, or degraded (Eq. S56). Angiotensin II can bind to the AT1 or AT2 receptor, or can be degraded (Eq. S57). AT1-bound AngII signals efferent, preafferent, and afferent vasoconstriction, proximal tubule sodium retention, and aldosterone secretion . Aldosterone binds to the mineralocorticoid receptor (Eq. S60) and signals sodium retention in the connecting tubule/collecting duct (Eq. S61).The model incorporates multiple intrinsic and neurohormonal regulatory feedback mechanisms. (1) Vasopressin is modeled as a function of plasma Nab (Eq. S29). However, venous bed volume is already defined in the section “Circulation Model” (Eq. 11). In order to reconcile two values of venous volume, its value resulting from Renal Model is now called “target” venous volume Vven,target. It accounts for the mismatch between the total blood volume resulting from the renal model and volume of all the other compartments from the circulation model.The cardiac and renal models are linked together through mean arterial pressure (MAP) and blood volume. MAP is calculated from the arterial pressure wave generated by the cardiac model, and used as an input into the kidney model, to calculate renal blood flow and glomerular hydrostatic pressure . The renal model determines sodium and water excretion rates. The excess of water excretion over water intake decreases the fluid returned through the renal vein into the venous bed, that in turn determines total blood volume VEquation 11 for venous volume is then altered allowing the volume to adjust and reach this target volume:https://bitbucket.org/hallowkm/lv-hypertrophy-model.The model was implemented as a system of ordinary differential equations and all simulations were conducted using the RxODE package  in R verThe normal steady-state outputs of the new combined model were compared with normal ranges previously obtained with the separate cardiac and renal models. We further tested the model to ensure that under normal baseline conditions, the model was in a stable steady state, that all regulatory signals were at their set point, that all hypertrophic signals were zero, and that the model responded appropriately to perturbations including changes in cardiac output (CO) setpoint and altered Na+ intake . Lastly,art, which encompasses the resistance of the valves and larger arteries. Mitral valve regurgitation was simulated by allowing back-leak across the mitral valve when the pressure difference across the valve exceeds a certain value ΔPleak.f,peak,0, σf,ED,0σ and relative values of the rate constants governing changes in myocyte diameter Kd0 and myocyte length Kl0 were determined by fitting the measured values in the study.The stress thresholds The LIFE study reported changes in LV hypertrophy over time in patients with essential hypertension treated with either losartan or atenolol . To simuWe have previously described the calibration and validation of the plasma renin concentration (PRC) as RAAS biomarker and blood pressure response to treatments targeting the RAAS, including losartan . We confThe beta blocker atenolol was modeled as a reduction in heart rate of 8 beats per minute, as observed in the LIFE study, as wells as a reduction in renin secretion sufficient to reduce renin activity by 40% . BecauseModel parameters added or changed from previously published model versions , 2018 arart by five-fold over the course of the simulation. The threshold peak systolic stress, σf,peak,0 above which myocytes increase in diameter was set as the baseline peak systolic stress of 49.2 kPa (369 mmHg), while the threshold end diastolic stress σf,ED,0 above which myocytes increase in length was set at 4.5 kPa (33.75 mmHg). The latter is slightly above the baseline level of 4.3 kPa (32.25 mmHg), since small changes in volume status do not cause irreversible changes in myocyte length. d = 0 and Kl = 0 – solid gray curves), LV peak systolic stress (LV PSS) greatly increased over time. Blood volume began to accumulate as sodium and water were retained, reflected by positive water and sodium balance, in order to maintain cardiac output. This resulted in greatly elevation of ED stress and EDP to physiologically unsustainable levels that would likely result in systemic and pulmonary edema and the signs and symptoms of heart failure.Pressure overload was simulated as a consequence of aortic stenosis, which was modeled by increasing systemic arterial resistance Rd, Kl = 0 – blue curves), LV PSS rose initially but then returned to near normal values. There was a very small rise in blood volume and no change in LV ED stress, as sodium and water balance were maintained. Thus, myocyte thickening appears to be a beneficial adaptive response that not only normalizes cardiac wall stress but also sustains cardiac output and allows the kidney to maintain sodium and water balance.If instead, the myocytes were allowed to increase in diameter , the response was maladaptive: there was additional fluid retention even beyond case 1, as well as greatly elevated LV EDP and ED stress, and further rightward shifting of the pressure-volume (P-V) loop. In this physiologically untenable state, the limits of the model system’s ability to maintain cardiac output were reached.On the other hand, if myocytes were not allowed to increase in diameter, but were allowed to elongate in response to elevated ED stress (Case 3: Kd and Kl – red curves), the response fell between case 1 and case 2. LV peak stress returned near normal, but with some sustained fluid retention, LV ED stress elevation, and rightward shifting of the P-V loop.When both remodeling mechanisms were allowed (Case 4: non-zero Kart (three-fold) was determined to best fit the absolute increase in LV mass index and LV peak systolic pressure. The ratio of the remodeling rate constants Kd to Kl  was decreased over the course of the simulation from 17.5 kPa (131.25 mmHg) to 12.5 kPa (93.75 mmHg). d = 0 and Kl = 0 – solid gray curves), LV EDP and blood volume both greatly increased over time, resulting in an unsustainable state that would likely result in systemic and pulmonary edema and progressive signs of heart failure. This fluid retention occurred because elevated venous pressure reduced renal perfusion and produced a sodium imbalance that caused volume accumulation. Allowing myocyte diameter to change in response to LV PSS  did little to mitigate this. Since LV PSS was initially reduced (as the back leak during systole reduced the peak pressure generated by the ventricle), myocytes decreased in diameter and the ratio of wall thickness to chamber radius (h/R) fell, and LV EDP was slightly reduced, but LV ED stress was actually increased. If myocytes were not allowed to increase in diameter, but were allowed to increase in length in response to elevated ED stress , the increasing chamber volume accommodated the excess preload for a while, and increases in LV EDP, venous pressure, and blood volume were initially limited. However, peak systolic stress was elevated. At the same time, as the heart wall thinned (h/R ratio fell), the pressure generated by the heart during systole fell, and by 30 weeks did not even exceed the pressure necessary to produce regurgitation (2nd panel). As it thinned further, the system entered an unstable state in which cardiac output fell while venous pressure rose dramatically, renal perfusion fell and the sodium imbalance became large, and blood volume rose rapidly. The PV loop shifted dramatically up and to the right, as stroke volume and ejection fraction plummeted. However, when both remodeling mechanisms were allowed , increases in LV EDP and blood volume were limited compared to case 1 and 2, and the rightward shift of the PV loop was limited and stroke volume and ejection fraction were preserved relative to case 3. This suggests that the combined effects of eccentric and concentric remodeling may help to stabilize cardiac wall stress, maintain stroke volume, and mitigate but not prevent volume accumulation.Volume overload was simulated as a consequence of progressive development of mitral regurgitation. To model mitral regurgitation, ΔPleak  was determined to best fit the absolute increase in LV mass index. The ratio of the remodeling rate constants Kd to Kl , but did not permit determination of the absolute time constants, since LV geometry was not measured over time in those studies.d, we fit the LV hypertrophy regression observed with antihypertensive treatment in the LIFE study, under the assumption that both increases and decreases in myocyte diameter in response to changes in load can be described by the same time constant. To determine KThe model predicted similar blood pressure reductions but larger reductions in LV mass with losartan than atenolol, in agreement with findings from the LIFE trial, as well as several meta-analyses of LV hypertrophy regression . The smaWe next sought to understand the reason for this smaller reduction in stresses with atenolol. Losartan acts by blocking the AT1 receptor, preventing angiotensin II from binding. This results in renal vasodilation , reduced tubular sodium reabsorption, and subsequently natriuresis and diuresis that serves to lower blood pressure. Atenolol inhibits the RAAS by blocking renin secretion, but also affects the heart directly by reducing heart rate. As shown in Cardiac and renal function are hemodynamically and neurohormonally linked. The integrated model of cardiac and renal function described here provides a tool for investigating and understanding the impact of dysfunction or intervention in one organ on the function of the other in this critical organ system.The model reproduces different LV hypertrophic patterns observed due to mitral regurgitation and aortic stenosis. The cardiac remodeling rules utilized are similar to those proposed by In response to mitral regurgitation, the simulations indicate that eccentric remodeling may initially help mitigate volume overload, but because this type of remodeling is not self-limiting , as the ventricle expands and is unable to maintain a normal output, fluid begins to accumulate at an accelerated rate  to days/weeks  to months (LV remodeling) with relatively low computational complexity. Complexity of the model does not go beyond ordinary differential equations, and simulating 6 months in model time can be completed in 3 min of real time. This model is adequate to describe the data considered, but further refinements may be needed to more fully represent the pathophysiological processes of hypertrophy and heart failure. The current model does not account for changes in cardiac tissue mechanical properties  that likely occur due to cardiac fibrosis that accompanies hypertrophy. In addition, the model does not attempt to describe the biochemical processes by which mechanical signals are sensed and translated into cellular level changes in structure and function. Efforts to develop such models have recently been reviewed by The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.KH wrote the manuscript, designed and performed the research, and analyzed the data. CV, SA, and SE designed and performed the research, analyzed the data, and revised the manuscript. All authors contributed to the article and approved the submitted version.SE was an employee of Amgen, Inc. KH has received funding from AstraZeneca, Pfizer, Merck, and Takeda within the last 2 years. The authors declare that this study received funding from AstraZeneca, Pfizer, and Merck. The funder was not involved in the study design, collection, analysis, interpretation of data, writing of this article, or decision to submit it for publication. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In fetal aortic stenosis (AS), it remains challenging to predict left ventricular development over the course of pregnancy. Myocardial organization, differentiation and fibrosis could be potential biomarkers relevant for biventricular outcome. We present four cases of fetal AS with varying degrees of severity and associate myocardial deformation on fetal ultrasound with postmortem histopathological characteristics. During routine fetal echocardiography, speckle tracking recordings of the cardiac four-chamber view were performed to assess myocardial strain as parameter for myocardial deformation. After pregnancy termination, postmortem cardiac specimens were examined using immunohistochemical labeling (IHC) of key markers for myocardial organization, differentiation and fibrosis and compared to normal fetal hearts. Two cases with critical AS presented extremely decreased left ventricular (LV) strain on fetal ultrasound. IHC showed overt endocardial fibro-elastosis, which correlated with pathological fibrosis patterns in the myocardium and extremely disturbed cardiomyocyte organization. The LV in severe AS showed mildly reduced myocardial strain and less severe disorganization of the cardiomyocytes. In conclusion, the degree of reduction in myocardial deformation corresponded with high extent to the amount of pathological fibrosis patterns and cardiomyocyte disorganization. Myocardial deformation on fetal ultrasound seems to hold promise as a potential biomarker for left ventricular structural damage in AS. Fetal aortic stenosis (AS) is a rare congenital heart disease comprising 0.2–0.5 of 1000 live births. It is known for its wide spectrum of clinical severity and difficulty to predict the clinical course in pregnancy and after birth. Even the mildest forms, characterized by only a subtle flow acceleration across the aortic valve at mid-gestation, may develop into a life-threatening critical AS at birth, carrying a high risk of morbidity and mortality ,4,5,6. FMahtab et al. demonstrated that borderline left ventricles (BLV) with similar macroscopic appearances can show great variety in microscopic ventricular organization and differentiation. In particular, a subset of BLV hearts resembled normal hearts, containing a well-organized cardiomyocyte alignment and proper organized intercalated disks with a normal expression pattern of important myocardial differentiation markers such as cardiac troponin-I, N-cadherin, and Connexin43 (Cx43). In contrast, the remaining BLV hearts presented histologic abnormalities similar to HLHS hearts, showing disturbed cardiomyocyte and intercalated disks organization along with an almost completely absent expression of myocardial differentiation markers. Ventricular organization and differentiation could therefore be a predictor of biventricular outcome . In fetaNormal myocardial organization and differentiation allows a coordinated contraction of the myocardium via effective cell–cell coupling, which is necessary for optimal cardiac function. Endocardial damage, such as endocardial fibro-elastosis, also affects myocardial contraction. A non-invasive tool to assess myocardial wall motion in vivo comprises the novel echocardiographic technique speckle tracking. Speckle tracking quantifies the deformation of the myocardial tissue by following the motion of certain myocardial regions, the so-called speckles, over sequential ultrasound frames .We hypothesized that ultrasonographic myocardial deformation corresponds with the level of myocardial organization, differentiation and fibrosis and is therefore an in vivo marker of ventricular damage in fetal AS. Studies assessing the correlation between prenatal imaging and histology are extremely rare. Here, we present four cases of aortic stenosis diagnosed in utero with varying degrees of severity and compare the myocardial deformation based on prenatal ultrasound to postmortem histopathologic characteristics.This study was performed in accordance with the Dutch regulation for the proper use of human tissue for medical research purposes and conducted according to the principles of the Declaration of Helsinki  and Dutch Fetal Tissue Act. The protocol was approved by the local Ethics Committee (NL66978.058.18).An overview flowchart of the methods is depicted in n = 3) gave signed written informed consent to donate cardiac tissue for immunohistochemical analysis. Two women donated the entire heart specimen and one woman gave permission to obtain heart biopsies taken from five segments . The whole cardiac specimens were fixated in formaldehyde followed by storage in ethanol until use and the cardiac biopsies were immediately embedded in paraffin according to standard protocols. Two normal heart specimens (one entire heart specimen and one left ventricle (LV)) of similar gestational age served as immunohistochemical control cases, obtained from legal abortion material.Written informed consent was received from the women to perform speckle tracking recordings during routine fetal echocardiograms. The recordings were analyzed offline, weeks after the initial examination and therefore did not influence clinical decision-making. All women who decided to terminate the pregnancy  using the Canon Aplio i-800 ultrasound machine with abdominal PVI475BX and PVT674 High Frequency convex transducers. For speckle tracking recordings, cine loops of the apical or basal cardiac four chamber-view with an insonation angle of <30° were stored in B-mode setting. We optimized settings by adjusting sector width, depth, gain and zoom box to achieve framerates between 60–120 frames/s. Each clip contained at least 4 cardiac cycles in absence of maternal and fetal movements and was repeated 3 times. A measurement software package  was used for offline analysis; detailed methods of the analysis have been described previously [eviously . In brieImmunohistochemical Analysis. All cardiac specimens were embedded in paraffin according to standardized protocols. Frontal sections of 5 μm from whole hearts and 5 μm sections from the segmental biopsies were mounted on KP-Silane adhesive glass slides (Klinipath). Immunohistochemical and immunofluorescence staining was performed as described previously on the sections comprising the cardiac four chamber view and long-axis view  [ct view) . All useCase 1 was diagnosed with a fetal critical AS at 20 + 3 weeks of gestation that met the international criteria for in utero aortic valvuloplasty  11]. Th. Th11]. Case 2 presented at our fetal cardiology service at 19 + 5 weeks of gestation, revealing a critical AS with postvalvular dilatation . The LV Case 3 presented with a severe fetal AS showing seriously increased flow velocity (350 cm/s) across the aortic valve at 20 + 1 weeks gestation. The international criteria for in utero aortic valvuloplasty were not met  as the fCase 4 was referred to our fetal cardiology service with an abnormal three vessel view, based on an enlarged aorta, at 21 + 1 weeks GA. We diagnosed a severe AS with an adequate size of the aortic annulus showing increased forward flow across the valve (300 cm/s) and postvalvular dilatation with turbulent flow . As the Speckle tracking values of all cases are depicted in The two cases with severe AS (case 3 and 4) had normal LV appearance by eyeballing, but the left ventricular myocardial wall deformation showed a mild reduction . Right ventricular myocardial deformation was overall normal with a GLS of −17.6% and −21.2%. Again, in all severe AS cases the lateral side of the RVs showed slightly increased SLS values (SLS between −15.3% and 30.0%) and the septal side an overall mild reduction (SLS between −6% and −29.3%).In normal hearts, the cardiomyocytes of both the LV and RV were well-aligned and showed a proper banding pattern. Cx43 and N-cadherin were found as a diffuse pattern in the cytoplasm and were also expressed with more intensity at the lateral borders of the cardiomyocytes, illustrating the presence of gap and adherence junctions. Furthermore, some early intercalated disks were present at the longitudinal ends, mostly solely expressing N-cadherin but co-expression of N-cadherin and Cx43 was also found a–d.In contrast, the LVs of the two cases with critical AS  staining exposed a homogenous pattern of interstitial fibroblasts, without signs of pathological fibrosis a–d. The Strikingly, in contrast to normal hearts, the subepicardium of both LV and RV was significantly thickened in all AS cases, suggesting epicardial activation. The subepicardium contained marked dilated coronary vessels which were surrounded by large TUBB3 positive nerves, while only a few nerve cells were seen in areas without vasculature . Next toFetal AS remains a challenging CHD considering its difficulty to predict left ventricular development over the course of the pregnancy and with that, the postnatal outcome. Myocardial organization, differentiation and fibrosis could be potential biomarkers, relevant for biventricular outcome . The keyMyocardial wall deformation in relation to histopathology. In the current study, fetal AS cases with the most pronounced disturbance of the cardiomyocyte network and endocardial fibrosis patterns showed the utmost impairment of myocardial wall deformation on fetal ultrasound , which changes gradually towards complete localization at the lateral borders and intercalated disks during prenatal and postnatal development . One couPathophysiology of endocardial fibro-elastosis in aortic stenosis. Altered hemodynamics in AS trigger the formation of endocardial fibro-elastosis via myocardial hypoxia [ hypoxia ,42. In t hypoxia . This suThe origin of the accumulated fibroblasts in endocardial fibro-elastosis is still debated, where both endocardium-derived cells (EndMT) or epicardial-derived cells (EMT) have been proposed ,24. EndMRelation to development of HLHS. Remarkably, the degree of cardiomyocyte disorganization in the critical AS cases was identical to the HLHS specimens described by Mahtab et al. [b et al. , which cb et al. . Of noteRight ventricular involvement in a left ventricular disease. The RV has long been neglected in this typical left-sided heart disease. However, there is growing evidence that typical one-sided CHDs are in fact biventricular diseases [diseases . The RV Although the current study material is unique and provides relevant insights in the pathophysiology of fetal AS, the number of studied specimens is too limited for statistical evidence. However, this case series shows that prenatal myocardial function associates to high extent with myocardial histology as the degree of the reduction in myocardial wall deformation on echocardiography corresponded with the histological amount of pathological fibrosis patterns and disorganization of the cardiomyocyte network. Therefore, fetal echocardiography, in particular GLS, seems to hold promise as a potential biomarker for structural myocardial damage. Current promising sophisticated genetic techniques, such as spatiotemporal single-cell RNA sequencing , may pro


ObjectiveTo evaluate the impact of successful percutaneous balloon mitral valvuloplasty (BMV) on left atrial (LA) reservoir function and LA volume in patients with severe mitral stenosis (MS) using peak atrial longitudinal strain (PALS).MethodThis was a prospective, non-randomized observational study conducted at the Laxmipat Singhania (LPS) Institute of Cardiology, Kanpur from August 2018 to February 2020 among patients with severe rheumatic MS undergoing BMV to assess LA reservoir function and its volume after BMV using PALS. Inclusion criteria were symptomatic severe rheumatic MS (NYHA ≥II), normal ventricular systolic function, and suitable valve morphology. Exclusion criteria were the coexistence of aortic valve involvement, left atrial appendage clot, mitral leak more than mild, pregnancy, hypertension, diabetes, and coronary artery disease. To assess LA reservoir function and its volume after BMV, PALS was used. LA was divided into six regions of interest and longitudinal strain curves of individual segments together with global strain were recorded. PALS was calculated at baseline 24 hours following the intervention, and at three months of follow-up.Result2 vs. 1.83±0.3 cm2; p<0.001). The mean age of patients was 26.7±4.7 years; 214 (82.3%) patients were in normal sinus rhythm (NSR) while 46 (17.7%) had atrial fibrillation (AF).Successful BMV was performed in 260 patients , resulting in significant improvement in mitral valve area (MVA) , and at three months of follow-up . Those with AF had lesser improvement in PALS in comparison to those with NSR  at three months of follow-up. At three months, the increase in PALS was also lower in patients with a history of stroke as compared to those without it . Both LA volume and indexed LA volume reduced significantly immediately at 24 hours and during follow-up.Significant improvement in PALS was noted immediately following the procedure  and it continued to improve at three months of follow-up , which was 24% and 74% improvement from baseline respectively. Significant reduction in indexed left atrial (LA) volume was observed immediately following the procedure (56.8±14.3 ml/mConclusionLA reservoir function, as assessed by PALS, is reduced in patients with severe MS. It improved significantly within 24 hours following BMV and continued to improve at three months of follow-up. It is an underutilized modality among patients of MS for decision-making prior to intervention and to assess the effect of the intervention. The left atrium (LA) acts as a reservoir, conduit, and pump ,2. It acIn patients with mitral stenosis (MS), the function of the LA gets disrupted because of increased afterload, which leads to its enlargement and pressure overload which further gets aggravated with the onset of atrial fibrillation as its pump function completely ceases -7. With This was a prospective, non-randomized observational study, which was conducted at the Laxmipat Singhania Institute of Cardiology (LPSIC), GSVM Medical College, Kanpur from August 2018 to February 2020 among patients with severe rheumatic MS to assess LA reservoir function and its volume after BMV using PALS. The study was approved by the LPSIC ethical committee. The inclusion criteria were symptomatic severe rheumatic MS (NYHA ≥II), normal left ventricular systolic function (ejection fraction ≥55%), right ventricular systolic function (annular velocity ≥9.5 cm/s), and suitable valve morphology by echocardiography (presence of dark zone on commissures). Exclusion criteria were coexistence of aortic valve involvement, poor echo window, left atrial appendage clot, moderate or severe mitral regurgitation, pregnancy, hypertension, diabetes, and coronary artery disease. All patients were subjected to detailed clinical evaluation, including an electrocardiogram, weight, height, and transthoracic echocardiography using Vivid6 GE echocardiography machine . All measurements of ventricular parameters  were recorded using the leading-edge technique as per recommendations laid down by the American Society of Echocardiography . The sevAtrial strain imagingLA regional function and deformation properties were studied using 2D speckle strain imaging. Apical four and two-chamber views of LA were obtained at relatively high frame rates (60-80 fps). Region of interest (ROI) was adjusted following tracing its endocardial border in both views. In regions of discontinuities (pulmonary veins and LA appendage), extrapolation of LA endocardial and epicardial surfaces at the junction of these structures was performed to obtain the ROI. The ROI was divided into six segments and a total of 12 segments were analyzed with the software generating the individual segmental longitudinal strain curves together with global strain in each view  and considered successful when post-procedural MVA was >1.5 cm2, abolition of transmitral gradient (<5 mm Hg) and degree of mitral regurgitation < 2+ . Tissue Statistical analysisAll statistical analysis was performed using SPSS Statistics v. 20 . Numerical results were expressed as mean ± SD while categorical data were expressed as number and percentage. Pre- and post-BMV analyses were done using the paired t-test and Wilcoxon signed-rank test. The correlation between two variables was analyzed using the Pearson correlation coefficient. P-value < 0.05 was considered statistically significant.2.Baseline parameters are shown in Table 2 vs. 1.83±0.3 cm2; p<0.001). PALS improved significantly immediately following the procedure  and continued to improve at three months of follow up  which corresponded to 24% and 74% increase from baseline respectively. LA dimension also reduced immediately after BMV  and at three months of follow up a significant reduction was noted . Similarly, a significant reduction was observed in LA volume, and LA volume index (56.8±14.3 ml/m2 vs 48.4±12.5 ml/m2) immediately post BMV and (56.8±14.3 ml/m2 vs. 45.4±13.3 ml/m2) at three months of follow-up. Whereas MVA increased significantly post BMV from 0.89±0.11 cm2 to 1.83±0.3 cm2, and at three months after BMV MVA was 1.89±0.2 cm2 (Figure Following balloon dilatation, a significant increase in MVA was noted (0.89±0.11 cmOur study demonstrated that the LA reservoir function assessed by PALS is abnormal in patients with mitral stenosis, which showed a significant increase within 24 hours after BMV, and this trend continued at three months of follow-up. Using the onset of atrial contraction as a reference may lead to a greater physiological strain curve, allow easier measurement of the contractile phase, and has been reported to be more predictive of outcome in patients with new-onset heart failure -20. HoweThe left atrium enlarges as a result of pressure and volume overload and undergoes remodeling in patients with mitral stenosis. A wide range of LA pressure exists in rheumatic MS despite similar MVA because an important determinant of LA pressure is LA compliance. Despite similar MVA, patients with rheumatic MS have a different grade of depressed left atrial compliance and hence different stiffness . AbnormaThe findings of our study, i.e. significant improvement of PALS, are in line with other studies published. Rohani et al. documented the acute effect of BMV and MVR in patients with mitral stenosis. Positive peak LA strain improved significantly after BMV .Change in LA volume was concordant with findings reported by Rohani et al.  and AnsaIn our study, left atrial volume and systolic strain were inversely related and helpful in the assessment of left atrial remodeling and predictive of atrial fibrillation, which was concordant with findings reported by Tsang et al.  who alsoRegarding the reduction in trans-mitral mean pressure gradient and systolic pulmonary artery pressure, our findings were concordant with the report by Vijayvergia et al. . AlthougIt has been demonstrated that the left atrial dimension assessed by M mode doesn´t reduce significantly at 24 hours after BMV but reservoir function certainly changes when assessed using peak atrial longitudinal strain. This can be explained as changes in the LA dimension are the long-term change which follows, usually evident at the six-month follow-up, while reservoir function improved immediately following the procedure as shown in our study. This was coherent with findings reported by Ansari et al.  and VijaPALS is one of the best predictors for maintenance of sinus rhythm among patients with lone atrial fibrillation as reported by Di Salvo et al. . They obIn a study by Liao et al., women had higher PALS than men, and aging deteriorates it in both sexes although more prominent among women in advanced age . In our In our study, we documented that the successful BMV leads to the improvement of LA function, LA dimensions, and improvements in these parameters continue at three months of follow-up. The PALS is an important method to evaluate the LA reservoir function and it should be used in patients with mitral stenosis for decision-making before intervention and to see the effect of the intervention.Limitations of the study We followed the patients only for three months; a longer follow-up would have given a better understanding of the effect of BMV on LA function in patients with mitral stenosis.The LA reservoir function can be better assessed by PALS. It is independent of rhythm and is better at predicting changes in atrial function. It is reduced in patients with severe mitral stenosis. PALS improves significantly within 24 hours following BMV, and improvement continues in the months following the procedure. PALS should be evaluated in patients with mitral stenosis for decision-making before intervention and to see the effect of the intervention. The improvement in PALS after BMV increases the probability of continuing to have sinus rhythm and lower cardiovascular events in the future.


A correlation between RV and LV SRe was found in TOF patients  as well as between RV and LV GLS . Two-dimensional speckle-tracking echocardiography reveals subclinical RV and LV diastolic dysfunction in adults with repaired TOF. A correlation is observed between RV and LV diastolic dysfunction as well as between RV and LV systolic dysfunction.Several studies have reported a correlation between right ventricular (RV) and left ventricular (LV) systolic dysfunction in adults with repaired tetralogy of Fallot (TOF). However, data are lacking regarding the relationship between RV and LV diastolic dysfunction assessed by 2-dimensional speckle-tracking echocardiography. We studied 69 adults with repaired TOF  who had been regularly followed up and had routinely undergone echocardiography. In addition to conventional echocardiography, global longitudinal strain (GLS) and early diastolic strain rate (SRe) of both ventricles were assessed using 2-dimensional speckle-tracking echocardiography. Results were compared with 30 age- and sex-matched controls. RV and LV GLS were decreased in TOF patients compared with controls . RV and LV SRe were also decreased in TOF patients compared with controls (1.22 ± 0.34 sec Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease . Early sHowever, recent studies have found that left ventricular (LV) systolic dysfunction is also associated with impaired clinical status in patients with repaired TOF  and is aLV diastolic dysfunction in patients with repaired TOF have also been investigated –19; howeThis was a single-center, retrospective, cross-sectional study. The study included asymptomatic adults (age ≥ 15 years) with repaired TOF, who had received regular follow-up at Congenital Heart Disease Center, Tenri Hospital  and had routinely undergone echocardiography between January 2012 and August 2018. We used an echocardiographic database to screen for eligible patients with repaired TOF. Only echocardiography performed with Vivid 7 or Vivid E9 machine  was included to avoid variability in strain measurements between different vendors. For those who had undergone several echocardiographic examinations with the GE machines during this period, the most recent one was used for analysis. Exclusion criteria were as follows: echocardiography without the entire RV free wall in the apical 4-chamber view, poor image quality for speckle-tracking analysis, and patients who were not in sinus rhythm. Echocardiographic data were compared with those of 30 age- and sex-matched normal controls.This study was conducted in accordance with the Declaration of Helsinki. The institutional ethics committee at Tenri Hospital approved the protocol . Written informed consent was waived because of the retrospective nature of the study.All echocardiography was performed by experienced sonographers according to standardized protocols using Vivid 7 or Vivid E9 machines . Images were acquired from standard parasternal and apical views and digitally stored. Measurements included RV end-diastolic and end-systolic area, RV fractional area change, right atrial end-systolic area, LV end-diastolic and end-systolic dimeter, LV ejection fraction (using biplane Simpson’s method), LV wall thickness, left atrial volume, and tricuspid annular plane systolic excursion (TAPSE). Severity of pulmonary regurgitation (PR) was graded by jet width, length, and duration using Doppler echocardiography according to the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging recommendations . SeveritRV and LV strain and strain rate were analyzed offline using 2-dimensional speckle-tracking analysis software . The LV algorithm was used for both ventricles. The endocardial border was traced in the apical 4-chamber view and the width of the region of interest was adjusted. Myocardial tracking was confirmed visually and verified with the software. The endocardial border was retraced if myocardial tracking was inadequate. Peak systolic longitudinal strain was defined as the peak negative value on the curve. As in LV global longitudinal strain (GLS) analysis, RV GLS was defined as the average of peak systolic longitudinal strain of all segments of the right ventricle including the ventricular septum . RV and t-test or Wilcoxon rank sum test based on their distributions. Relationships between two continuous variables were assessed using Pearson’s correlation analysis. Variables which were not normally distributed were log transformed. Intra- and interobserver reproducibility for conventional and speckle-tracking echocardiographic parameters of both ventricles were assessed by calculating interclass correlation coefficient in 20 randomly selected patients with repaired TOF by the same observer and two different observers, respectively. All statistical analyses were conducted with SPSS software version 22.0 . All reported p values were two-tailed, and p < 0.05 were considered statistically significant.Categorical variables were presented as numbers and percentages and compared using the chi-squared test. Continuous variables were expressed as mean and standard deviation or median and interquartile range and compared using the Student's A total of 113 adult patients with repaired TOF were identified to be potentially eligible for enrollment using the echocardiographic database. Among them, RV speckle-tracking analysis was not feasible in 44 patients because the entire RV wall was not recorded in the apical 4-chamber view or image quality was too poor to perform adequate myocardial tracking. LV speckle-tracking analysis was not feasible in 21 patients because of poor image quality. The feasibility of RV speckle-tracking analysis was 61%, which was lower than that of measuring TAPSE  and tricuspid E′ . The feasibility of LV speckle-tracking analysis was 81%, which was also lower than that of measuring LV EF  and mitral E′ . This study finally included 69 TOF patients in which biventricular speckle-tracking analysis was feasible. Sixty-three patients had undergone intracardiac repair at our hospital; the remaining 6 patients had undergone this surgery at other hospitals.Demographic and clinical characteristics are presented in Table Conventional echocardiographic findings are presented in Table RV and LV GLS were significantly decreased in patients with repaired TOF compared with controls  or log-transformed age at repair . RV and LV GLS were not significantly different between TOF patients with and without moderate to severe PR  and between those with and without moderate to severe PS . RV and LV GLS correlated with QRS duration in patients with repaired TOF . RV GLS correlated with TAPSE  and LV GLS correlated with LV EF  in patients with repaired TOF.A correlation between RV GLS and LV GLS was found in patients with repaired TOF  and log-transformed age at repair . RV and LV SRe were not significantly different between TOF patients with and without moderate to severe PR  and between those with and without moderate to severe PS . RV and LV SRe correlated with QRS duration in patients with repaired TOF . RV SRe correlated with tricuspid E′  and LV SRe correlated with mitral E′  in patients with repaired TOF.A correlation between RV SRe and LV SRe was found in patients with repaired TOF  and 0.86 (95% CI 0.55–0.95) for TAPSE, respectively, and 0.97 (95% CI 0.92–0.99) and 0.91 (95% CI 0.79–0.96) for LV EF, respectively. Reproducibility of tricuspid and mitral E′ could not be investigated because video clips of tissue Doppler imaging are not routinely stored at our hospital. The interclass correlation coefficient for GLS and SRe of both ventricles are presented in Table This study investigated subclinical RV and LV systolic and diastolic dysfunction in adults with repaired TOF using 2-dimensional speckle-tracking echocardiography. The main results were as follows: (1) 2-dimensional speckle-tracking echocardiography was able to reveal a decrease in RV and LV SRe in asymptomatic adults with repaired TOF compared with controls; (2) a correlation was observed between RV and LV SRe as well as between RV and LV GLS.Recently, SRe has been proposed as a more accurate marker of myocardial relaxation than conventional tissue Doppler echocardiography , 24. StrThere are no established parameters regarding assessment of RV diastolic dysfunction in patients with repaired TOF. In our study, tricuspid E′ was decreased in patients with TOF. However, previous studies have reported that conventional parameters using tricuspid flow velocities and tricuspid annular velocities were not associated with RV end-diastolic pressure in children with repaired TOF , 29. FurThe mechanism of LV diastolic dysfunction in adults with repaired TOF is not fully understood; in particular, data on its relationship with RV diastolic dysfunction assessed by 2-dimensional speckle-tracking echocardiography are lacking. A previous study investigated RV and LV diastolic dysfunction in children (mean age 12 years) with repaired TOF using speckle-tracking echocardiography . This prOur study suggests that ventricular interaction plays a role in diastolic dysfunction, as has previously been reported for systolic dysfunction. Recent studies with cardiac magnetic resonance in patients with repaired TOF found a correlation between RV and LV extracellular volume fraction  and betwThe mechanism of ventricular interaction remains unclear. Mechanical coupling may provide an explanation. The right and left ventricles share a continuous myocardial band . ImpaireThis study has several limitations. First, this is a retrospective study, therefore there is a potential for selection bias. Not all echocardiographic images of eligible patients from the echocardiographic database could be analyzed due to the inability to track the RV myocardium. Second, this study has demonstrated low feasibility of speckle-tracking echocardiography for the assessment of RV function in patients with repaired TOF. However, this limitation may be resolved if more attention is paid to acquisition of good-quality images of the entire right ventricle. Third, all patients in the study were clinically stable and did not undergo cardiac catheterization around the time of echocardiography; therefore, we could not directly compare the accuracy of SRe and E′ using catheter-derived references such as relaxation time constant (Tau), peak negative dP/dt, or end-diastolic pressure. Fourth, RV assessment by 2-dimensional speckle-tracking echocardiography did not include RV outflow tract function. Previous studies have suggested that RV outflow tract systolic dysfunction is related to impairment of RV performance in patients with repaired TOF , 38. RV Two-dimensional speckle-tracking echocardiography reveals subclinical RV and LV diastolic dysfunction in adults with repaired TOF. A correlation is observed between RV and LV diastolic dysfunction as well as between RV and LV systolic dysfunction in adults with repaired TOF.


The use of anthracycline-based chemotherapy is associated with the development of heart failure, even years after the end of treatment. Early detection of cardiac dysfunction could identify a high-risk subset of survivors who would eventually benefit from early intervention. Cardiac magnetic resonance feature-tracking (CMR-FT) analysis offers a practical and rapid method to calculate systolic and diastolic strains from routinely acquired cine images. While early changes in systolic function have been described, less data are available about late effects of chemotherapy in diastolic parameters by CMR-FT. The main goal of this study was to determine whether left ventricular (LV) early diastolic strain rates (GDSR-E) by CMR-FT are impaired in long-term adult survivors of non-Hodgkin lymphoma (NHL). Our secondary objective was to analyze associations between GDSR-E with cumulative anthracycline dose, systolic function parameters and myocardial tissue characteristics.This is a single center cross-sectional observational study of asymptomatic patients in remission of NHL who previously received anthracycline therapy. All participants underwent their CMR examination on a 3.0-T scanner, including cines, T2 mapping, T1 mapping and late gadolinium enhancement imaging. Derived myocardial extracellular volume fraction was obtained from pre- and post-contrast T1 maps. CMR-FT analysis was performed using Trufi Strain software. The data obtained were compared between anthracycline group and volunteers without cardiovascular disease or neoplasia.2). Compared with controls, anthracycline group showed impaired LV global early diastolic circumferential strain rate (GCSR-E) , early diastolic longitudinal strain rate (GLSR-E)  and early diastolic radial strain rate (GRSR-E) . Impaired LV GCSR-E, GLSR-E and GRSR-E correlated with increased anthracycline dose and decreased systolic function. There were no correlations between GDSR-E and myocardial tissue characteristics.A total of 18 adult survivors of NHL, 14 (77.8%) males, at mean age of 57.6 (± 14.7) years-old, were studied 88.2 (± 52.1) months after exposure to anthracycline therapy (median 400 mg/mLeft ventricular early diastolic strain rates by CMR-FT are impaired late after anthracycline chemotherapy in adult survivors of non-Hodgkin lymphoma. The use of anthracycline chemotherapy is associated with the development of heart failure (HF) among survivors of non-Hodgkin lymphoma (NHL), even years after the end of treatment . DetectiWe conducted a cross-sectional observational study in a tertiary care center, with asymptomatic patients in remission of NHL who previously received anthracycline therapy and had finished their treatment at least 1 year before the enrollment. Patients were excluded if they had active cardiac disease, symptoms consistent with congestive HF, renal insufficiency or usual contraindications for CMR as implantable devices, cerebral aneurysm clips and cochlear implants. Subjects with no evidence of cardiovascular disease or neoplasia, recruited by open invitation, were included in the control group.This study complied with the Declaration of Helsinki and was approved by the Research Ethics Committee of the Paulista Medical School—UNIFESP  and Botucatu Medical School—UNESP . All participants provided witnessed, written, informed consent.All participants underwent their examination on a 3.0-T Magnetom Verio Scanner  with a phased array chest coil, according to study protocol. A cardiac cine steady-state free precession (SSFP) sequence was acquired using retrospective cardiac gating. Typically, 25 phases were acquired in 2-, 3-, and 4-chamber long axis views and a stack of short axis views. Scan parameters: field of view (FOV) 37-cm, repetition time (TR) 43.54 ms, echo time (TE) 1.38 ms, flip angle 50°, slice thickness 6 mm, in-plane image resolution 1.6 × 1.6 mm. Late gadolinium enhancement (LGE) with a single-shot phase-sensitive inversion recovery (PSIR) sequence was acquired in a stack of short axis, 2- and 4-chamber long axis views, 8 to 15 min after intravenous injection of 0.15 mmol/kg of a gadolinium-based contrast agent . Scan parameters: FOV 37-cm, TR 600 ms, TE 1.07 ms, flip angle 40°, slice thickness 5–8 mm, in-plane resolution 2.2 × 1.9 mm.Quantitative T2 mapping was performed using a T2-prepared SSFP sequence with the following imaging parameters: FOV 36-cm, TR 254.32, TE 1.07 ms, flip angle 35°, slice thickness 8 mm, in-plane image resolution 2.5 × 1.9 mm, acquisition in late diastole on every fourth heartbeat; T2 preparations: 0 ms, 25 ms and 55 ms.Quantitative T1 mapping was performed with a Modified Look-Locker Inversion-Recovery (MOLLI) sequence in mid-cavity short axis, pre-contrast (Native T1) and again at least 15 min after administration of gadolinium, according to previous published consensus . Pre-con2.The biventricular end-diastolic volume (EDV) and end-systolic volume (ESV) were measured by manual segmentation of the short axis cine images, using Argus function software . The endocardial borders were traced at end-diastole and end-systole, including trabeculations and papillary muscles in the blood pool. EDV and ESV were calculated for each ventricle using the method of disc summation. Ventricular stroke volume (SV) was calculated with the difference between the EDV and ESV, and ventricular ejection fraction (%) was (SV/EDV) × 100. LV epicardial borders were draw only at end-diastole to calculate LV mass (M). All volume measurements were indexed for the body surface area (BSA) and expressed in ml/mStrain analysis by feature-tracking was performed processing cine images with dedicated software  as previously described . CircumfT1 and T2 maps were automatically generated on the MR scanner with motion corrected images using a novel non-rigid registration algorithm –27. A remyocardium/ΔR1blood), where Δ R1 = R1 post-contrast – R1 pre-contrast and R1 = 1/T1.The ECV was calculated as (1-hematocrit) ×  and compared by Student's t test or Wilcoxon signed-rank test, whereas qualitative variables were expressed by their frequencies and percentages, and compared by the chi-square test or Fisher's exact test. Considering a mean difference in diastolic strain rates of 20 ± 20%/s, the alpha error of 0.05 and power of 0.8, for this study we calculated a number of 17 subjects per group. Spearman’s correlations were used to examine the relationship between continuous variables. Univariate linear regression analysis was used to evaluate the influence of clinical and CMR parameters in global circumferential early diastolic strain rate (GCSR-E), GLSR-E and global radial early diastolic strain rate (GRSR-E). Univariate variables with a significant correlation were entered into a stepwise multiple regression analysis to determine independent predictors of GCSR-E (model 1), GLSR-E (model 2) and GRSR-E (model 3). Data were analyzed using SAS Studio 3.8 and considered significant if 2 (IQR: 225–400 mg/m2), 14 (77.8%) males, between 32–81 years old (mean 57.6 ± 14.6 yo) that were studied 88.2 (± 52.1) months after exposure to therapy. Two (11.1%) patients received mediastinal radiotherapy at the time of treatment. The control group was composed of 17 subjects from the staff of the hospital or their relatives, without previous history of cardiovascular disease or neoplasia. There were no significant differences on clinical variables including cardiac risk factors between groups, except for age, marginally lower in controls (p = 0.047). The main clinical characteristics of the study population are shown in Table We selected 20 adult survivors of non-Hodgkin lymphoma from the hospital records. One patient declined in participating and another one had claustrophobia during the CMR examination. So, the anthracycline group comprehended 18 adult survivors of non-Hodgkin lymphoma, treated with the same chemotherapy scheme , median cumulative anthracycline dose of 400 mg/mp = 0.012), with a mild raise in LVESV . Focal, non-ischemic LGE was present in at least 01 myocardial segment in 03 patients (16.7%). Native T1, ECV and T2 were similar between anthracycline and control groups , and in a multivariate analysis reduced systolic strain was an independent predictor of impaired early diastolic strain rates, even when age was considered as confounder. Similar to us, Stoodley et al.  reportedThis study is limited by the small sample size and cross-sectional design, so further corroboration of these findings in prospective larger-scale multicenter studies is required. Likewise, we cannot say whether the impairment in GDSR-E occurred previously or concomitantly with the reduction in systolic strain. As anthracycline patients were marginally older than controls we cannot exclude some influence of the age in the observed difference of GDSR-E measures between the two groups. Also, longer follow-up is necessary to determine if GDSR-E measured by CMR-FT will predict the development of symptomatic heart failure or will be helpful in guiding therapy. We studied only long-term survivors instead of all patients treated with anthracycline-based chemotherapy in our institution, therefore some bias of selection has to be considered.In this study we demonstrated that left ventricular GDSR-E by CMR-FT are impaired late after anthracycline chemotherapy in adult survivors of NHL. Impaired GDSR-E were associated with cumulative anthracycline dose and systolic function parameters. There were no correlations between GDSR-E and myocardial tissue characteristics.


The non-invasive quantitative evaluation of left ventricle (LV) function plays a critical role in clinical cardiology. This study proposes a novel ultrasonic biomechanics method by integrating both LV vortex and wall motion to fully assess and understand the LV structure and function. The purpose of this study was to validate the ultrasonic biomechanics method as a quantifiable approach to evaluate LV function.Firstly, B-mode ultrasound images were acquired and processed, which were utilized to implement parameters for quantifying the LV vortex and wall motion respectively. Next, the parameters were compared in polyvinyl alcohol cryogen (PVA) phantoms with different degree of stiffness corresponding to different freezing and thawing cycles in vitro. Finally, the parameters were computed in vivo during one cardiac cycle to assess the LV function in normal and abnormal subjects in vivo.In vitro study, the velocity field of PVA phantom differed with stiffness (varied elasticity modulus). The peak of strain for wall motion decreases with the increase of elasticity modulus, and periodically changed values. Statistical analysis for parameters of vortex dynamics  based on different elasticity (E) of phantom depicted the good viability of this algorithm. In vivo study, the results confirmed that subjects with LV dysfunction had lower vorticity and strain (S) compared to the normal group.Ultrasonic biomechanics method can obtain the vortex and wall motion of left ventricle. The method may have potential clinical value in evaluation of LV dysfunction. There is an increasing risk of sudden death from cardiac diseases among survivors of acute myocardial infarction with reduced left ventricular (LV) systolic function . QuantifDuring early diastolic filling, the transmitral blood flow is directed towards the left ventricle, which leads to formation of a vortex. Vorticity (W) is an essential parameter of the fluid structure, defined as the curl of velocity field, which can be calculated by the gradient component of velocity in different directions . The preHowever, vortex dynamics seeded by particles  primarilSimultaneously, strain (S) and strain rate (SR), directly reflect regional myocardial deformation with novel indexes that are building blocks in assessing LV wall performance –16. HereFrom all the aforementioned works, it is observed that the S and SR are playing an important role in assessing and evaluating the myocardial function. However, few studies attempt to take the vortex dynamics and the myocardial motion of left ventricle into account for integrated assessment of LV function. This study proposes a novel ultrasonic biomechanics method by integrating both LV functions  to fully assess and understand the mechanisms in LV structure and function. Compared with conventional processes, We improved the resolution, accuracy, and operation rate in our method by employing numerical techniques including: cross-correlation calculation, Gaussian multimodal fitting, pseudo-vectoring and zero-vector processing, Taylor expansion and multiple iterations in window deformation, and the simplification of the diagnostic window matrix. This method serves as a useful application to analyze the vortex and regional wall motion of LV. It will guide individuals to obtain two-dimensional LV indices and to assess LV function precisely. The purpose of the present study is to validate the ultrasonic biomechanics method as a quantifiable approach to evaluate LV function.In this study, we propose a novel method for analyzing and evaluating the ventricular vortex and wall motion from B-mode echocardiograms. B-mode ultrasound images were obtained and then analyzed with Matlab software, using the cross-correlation calculation that has been described and validated by Niu et al.  in our tFigure Once the velocity field was acquired, the computed results were then rearranged in terms of LV fluid dynamics and wall motion parameters such as vorticity  and strain that gives a description of ventricular myocardial deformation. Generally, the parameters were measured by calculating the mean value in each interrogation window.ω is defined by the curl of velocity fieldx (m), y (m), vx (m/s), and vy (m/s).Mathematically as presented by , vorticiThen, based on , the totRS) of pulsatile contribution with respect to the time-average flow is a measure of flow “vitality”, a global measure generated by [ω0 and ω1 represent the vorticity strength of the first and zeroth order Fourier harmonic, respectively. The first order is the main pulsatile contribution, while the zeroth order is the steady contribution.The relative strength (rated by :\documenL) is the instantaneous maximum width of the left ventricle, while L0 is the original length, and ∆L is the difference in length.In general terms, strain represents relative deformation and strain rate represents the rate of deformation. Therefore, they can be defined as:v2 − v1means the change in instantaneous myocardial v1 and v2 at two points, distance d means change in velocity points at specific time.And where −1, and the pump provided a waveform that simulates the realistic ventricular behavior. The waveform reproduced an output phase ratio of systole and diastole of 35/65. A 10 MHz linear array transducer (L14-5W/60) was connected to the Sonix RP ultrasound system  laterally, scanning the left ventricular PVA phantom. Pairs of B-mode images, separated by a short time interval, were obtained with a frame rate of 97 Hz, and about 112 frames in one cycle. We captured images of the simulated blood flow by injecting ultrasound contrast microbubbles (UCAs) into the system and seeding them, which are supposed to faithfully follow the dynamics of fluid flow, into upstream chamber that are necessary for measure of displacement and related properties in fluids. To track the wall motion, scatters were mixed in the PVA when phantom was made. All the above mentioned presents the investigated working conditions for phantom experiments, as shown in Fig. To accomplish this study, a LV pulsed flow simulator system was established. It comprised a LV phantom container with different stiffness, made from polyvinyl alcohol cryogen (PVA). PVA phantoms were made by two metal molds of different diameters, as shown in Fig. This study was performed using a number of subjects including four patients with LV dysfunction  and five healthy volunteers . This study was approved by the Ethical Committee of the Third Affiliated Hospital of Sun Yat-sen University with waiver of informed consent. In this study, 1 MHz transducer was used to image all volunteers and patients at a frame rate of 30 to 60 Hz. Flow dynamics and myocardial contours were manually traced in different levels of view, and the echocardiography with contrast agent imaging was performed on volunteers to calculate LV blood flow dynamics in the apical 4-chamber views during one cardiac cycle. B-mode images were recorded from the left ventricular short-axis view (papillary muscle level) over three cardiac cycles to estimate LV myocardial motion. Note that the resolution in the direction that is perpendicular to the propagation direction of ultrasound beam tends to be low, so the direction of LV long axial ought to be parallel to the ultrasound beam for accurate strain measurements. All these echocardiography were stored in format of cine loop for succeeding offline proceeding and analysis. Images were processed using our proposed biomechanics algorithm as mentioned above.p value less than 0.05 was accepted as indicating statistical significance. Parametric data were expressed as mean ± standard. The analysis of covariance (ANOVA) was used to examine the difference of four parameters of vortex dynamics  based on different elasticity of phantom. The t test of independent samples was used to compare the vorticity and wall shear stress between the normal and patient subjects.All statistical analyses were performed using the Statistical Package for Social Sciences statistical software package, version 17.0 . A The velocity field of PVA phantom with different stiffness, which corresponds to the distinct elasticity modulus, was obtained by our biomechanics algorithm  as shownFor the evaluation of strain of wall motion, displacements were calculated along the axial direction that are parallel to the direction of propagation of ultrasound beam, as represented by our algorithm. The calculation results of the tracking wall segments in studies is shown in Fig. −1 versus 0.1 ms−1, which correlates to the strong versus weak elasticity of their left ventricle.The same ultrasonic biomechanics algorithm is implemented to process the images captured from human left ventricle. The average and maximum values of W and WSS of patients with LV dysfunction were larger than that of the control group, though the differences were not statistically significant Table . Figure To further optimize the detection of LV myocardial motion, it is recommended to capture the images when the ultrasound beam is parallel to the interventricular septum. As a result, the longitudinal strain equates to the axial component strain in the ultrasound coordinate system, as illustrated in Fig. This study proposed a novel ultrasonic biomechanics method to simultaneously measure LV vortex and ventricular wall motion to assess LV function, which exhibits potential clinical value. For potential validation and suitability of real echocardiogram, the proposed algorithm was first tested in a phantom experimental set-up as a mean to access LV function. The measurement of these function parameters can contribute to characterizing LV related performance in normal subjects versus patients with LV dysfunction.Previous studies focused merely on investigations to evaluate LV behavior from the aspect of either fluid dynamics or myocardial in left ventricle , 27. In In vitro study, the calculated velocity vector distribution could show the vorticity and wall shear force distribution at the moment of the vortex. The peak occurred at the central position of the vortex, and the peak showed a significant trend of increasing, which corresponded to the different elasticity modulus. The peak of strain for wall motion decreased with the increase in elasticity modulus and periodically changed values. Statistical analysis for parameters of vortex dynamics at various E of phantom depicted good viability of this algorithm.In vivo study, the results confirmed that subjects with LV dysfunction had lower vorticity and S compared to the normal group. The peak of the vorticity and wall shear force occurred at the central position of the vortex in both groups, and the data in the patients with LV dysfunction showed larger values. The measured wall displacement of healthy volunteer was larger than that of patients with LV dysfunction. Also the W and WSS of patients with LV dysfunction were larger than that of the normal individuals, yet the difference was not statistically significant.The potential for quantifying left ventricular function by eddy dynamics and wall motion was investigated in vitro. The current results show that eddy flow dynamics and wall motion characteristics are greatly affected by elasticity, and can be utilized as quantitative parameters in future analysis. It is verified that the two parameters are greatly affected by chamber elasticity, so as to quantify the difference of left ventricular eddy current and wall motion between the left ventricular dysfunction and control group. From the current results, we may speculate that the left ventricular dysfunction will be directly manifested in these two characteristic parameters, which tell noticeable discrepancies, and provide a reference tool for the diagnosis, prognosis and treatment of left ventricular dysfunction.There were several limitations of this study: (1) Compared to the perpendicular-to-axial direction, this method is more accurate in axial direction to calculate wall motion, parallel to the direction of ultrasonic beam. The reason might be the low resolution of the ultrasonic probe in this direction. (2) Given the small number of vivo cases, our findings must be regarded as preliminary. Future research with larger sample sizes are needed to verify these results.This work proposes a novel algorithm to examine LV function from echocardiogram that is adapted to both vortex dynamics and wall motion. In vitro phantom study demonstrated the potential of our new method to detect abnormal vortex and wall motion. The current data in vivo have shown the difference in parameters of both vortex dynamics and wall motion between normal subjects and patients with LV dysfunction. The deviation in vorticity and strain is correlated with LV’s mechanical performance and this method may have potential clinical value in evaluation of LV dysfunction.


Pediatric heart failure (HF) is an important clinical condition with high morbidity, mortality, and costs. Due to the heterogeneity in clinical presentation and etiologies, the development of therapeutic strategies is more challenging in children than adults. Most guidelines recommending drug therapy for pediatric HF are extrapolated from studies in adults. Unfortunately, even using all available treatment, progression to cardiac transplantation is common. The development of prospective clinical trials in the pediatric population has significant obstacles, including small sample sizes, slow recruitment rates, challenging endpoints, and high costs. However, progress is being made as evidenced by the recent introduction of ivabradine and of sacubitril/valsartan. In the last 5 years, new drugs have also been developed for HF with reduced ejection fraction (HFrEF) in adults. The use of well-designed prospective clinical trials will be fundamental in the evaluation of safety and efficacy of these new drugs on the pediatric population. The aim of this article is to review the clinical presentation and management of acute and chronic pediatric heart failure, focusing on systolic dysfunction in patients with biventricular circulation and a systemic left ventricle. We discuss the drugs recently approved for children and those emerging, or in use for adults with HFrEF. Pediatric heart failure (HF) can be defined as a clinical syndrome resulting from ventricular dysfunction, and volume or pressure overload, alone or in combination , 2. The The etiologies of congenital heart disease associated with HF in children are also well-described: there is added complexity in this situation however, since the patient may have a single or biventricular “circulation,” and the systemic ventricle may be a morphologic left or right ventricle. In general terms the “rules” of management for these situations cannot be directly extrapolated from that of a biventricular heart with a systemic left ventricle. Furthermore, in HF with a biventricular heart and a systemic left ventricle, although LV dilation is common, EF may actually be preserved: this is usually the case with left to right shunt lesions, such as a persistent patent arterial duct, a ventricular septal defect. Here, the presentation that is recognized as HF syndrome in infants and young children is commonly associated with a normal LV EF.Additionally, there is some evidence that the genetic architecture of congenital heart disease (which is polygenic) overlaps with that of cardiomyopathy  . CertainAlthough well-recognized, and an important acute and chronic disorder worldwide, the global incidence and prevalence of pediatric HF is unclear , 10. In Given all of this complexity, management of HF in children can be challenging, due to limited guideline availability and considerable practice variation. We will briefly review the clinical presentation and pharmacologic management of acute decompensated and chronic pediatric HF. We will emphasize recently approved therapies, and those still on the horizon for children, which are emerging or currently in use for adults with HFrEF. We will limit the scope of this review to left ventricular failure in children with biventricular physiology, and a systemic left ventricle, since there are very few studies, and no compelling evidence to support the use of chronic heart failure therapies for patients with the Fontan circulation, or with a systemic morphologic right ventricle.de novo or as a deterioration of pre-existing symptoms, commonly with no identifiable precipitating event or illness. Patients demonstrate some degree of fluid retention (congestion) which can be offset by vomiting and poor feeding in infants and young children. Most will also have poor perfusion, permitting the broad categorization of patients into a simplified matrix of congestion/no congestion and underperfusion/no underperfusion  is characterized by an abrupt presentation, either erfusion .The presence of congestion and/or hypo-perfusion, and whether the left or right ventricle are both involved in the dysfunction will also influence the signs and symptoms presented by the patient with pediatric HF. Right ventricular HF will generate jugular venous distention, hepatomegaly, and occasionally peripheral edema and ascites; on the other hand, left ventricular HF presents more frequently as dyspnea reflecting elevated left atrial pressure, with effort and feeding intolerance, pallor, abdominal pain, or syncope .The presence of ADHF at initial presentation remains an important risk factor for eventual death or cardiac transplantation in children, despite improved outcomes in the contemporary era , 16. TheThe immediate treatment of ADHF is simultaneously a process of reversing hemodynamic instability, and of discovering potential reversible causes as diverse as inherited tachyarrhythmia, acquired myocarditis or congenital anomalous origin of the left coronary artery from the pulmonary artery in infants. Treatment is directed at remedying any reversible cause, and addressing the primary symptomatic profile of the patient . The medHaving re-established adequate perfusion and diuresis, the chronic use of vasoactive drugs is only indicated as a bridge to a mechanical support device or to heart transplantation . In pativia the opening of the potassium channels on the sarcolemma of vascular smooth muscle; additionally, a cardioprotective effect has been postulated, due to the opening of mitochondrial potassium channels in cardiomyocytes by levosimendan . The net effect is an increase in intracytoplasmic calcium in systole, and an increase in sarcoplasmic reticulum calcium uptake in diastole. Pharmacologic behavior suggests more inotropic effect and less proarrhythmic effect than digoxin. Originally conceived of as an intravenous drug for acute heart failure syndrome, the HORIZON-HF trial demonstrated a reduction in pulmonary capillary wedge pressure, and improved diastolic function following a 6 h infusion in hospitalized HF patients  in sinoatrial tissue, and slows the rate of phase-4 depolarization, reducing heart rate. Following initial approval of this drug for the management of refractory angina in adults in the European Union in 2005, the drug was studied in adult HF populations, in the SHIFT and BEAUTIFUL studies. Although the results were somewhat discrepant, a pooled analysis suggested a decreased risk in HF hospitalization and mortality in patients with HFrEF . The hemodynamic effects of this increase in BNP include vasodilation and diuresis. Neprilysin inhibition also activates the RAAS pathway, and thus the combination of neprilysin with a classical RAAS antagonist is a logical choice of a combination-agent. Initial attempts to develop such a drug combined an ACE inhibitor with sacubitril: this combination drug, omapatrilat, resulted in an excessive amount of angioedema, and was abandoned . Howeverpost-hoc analyses of the PARADIGM-HF trial have shown that sacubitril/valsartan is superior to enalapril in reducing sudden cardiac death in adults, and has comparable efficacy and safety profiles across all doses of drug, with similar effects in black adults compared with other races , the FDA approved the use of sacubritil/valsartan for pediatric patients with symptomatic heart failure with systemic left ventricular systolic dysfunction, 1 year of age and older. This was based upon the analysis of 110 subjects in the PANORAMA-HF trial, where they analyzed NT-proBNP levels at baseline and 12 weeks into the study. Based on this data, the FDA was able to show comparable reductions in NT-proBNP between enalapril and sacubitril/valsartan. These changes paralleled what was seen in the PARADIGM-HF trial and therefore was felt to be adequate data to infer that sacubritil/valsartan could be approved for use in children ≥1 year. At the time of writing, the PANORAMA-HF trial has completed enrollment and is now waiting for all subjects to complete the 52 weeks of therapy before performing data analysis. Dosing recommendations in younger children are currently pending.The discovery of the first small molecule activator of cardiac myosin, omecamtiv mecarbil, was reported by Morgan et al. in 2010 and has since progressed through to phase III clinical trials in adults with HFrEF , 71. ThiEvidence of the clinical efficacy of omecamtiv mecarbil is pending, with data already reported from phase I and II studies, and with two phase III studies . In GALACTIC HF, 8,256 adult inpatients and outpatients with symptomatic chronic HF and an EF of 35% or less were recruited to receive omecamtiv mecarbil or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event  or death from cardiovascular causes. This outcome measure was met, with a small reduction in relative risk of 2% (hazard ratio 0.92), and a 10% reduction in NT proBNP levels in the treatment group. The major impact appeared to be in a reduction of HF events rather than in mortality . The effThe cyclic GMP (cGMP) pathway has been implicated as an important regulator of endothelial function in both primary and secondary pulmonary hypertension, and is relevant to myocardial and vascular smooth muscle dysfunction in HF states as well. Vericiguat is a new oral soluble guanylate cyclase stimulator, now approved for the treatment of patients with HFrEF. Its mechanism of action involves the enhancement of the cGMP pathway stimulation and directly increasing endogenous nitric oxide by stabilizing the nitric oxide binding to its site. In the recently reported VICTORIA trial, adult patients with chronic symptomatic HFrEF and an EF of <45% were monitored for a composite endpoint of cardiovascular death or first HF hospitalization . The trivia sarcolemmal sodium-hydrogen co-transporter blockade  in the proximal tubule of the kidney. Recent trials in adults have demonstrated a beneficial effect of SGLT-2 inhibition on survival in adult patients with HFrEF with or without type II diabetes mellitus. In DAPA-HF, outpatients with EF <40% and NYHA Class II-IV symptoms showed a 30% reduction in the occurrence of first HF admission and an 18% reduction in cardiovascular death on a 10 mg daily dose of dapagliflozin . This reblockade . Howeverblockade . No clinGiven a wider variety of current or potential therapies for both acute and chronic HF, pediatric cardiologists and intensive care specialists find themselves in a period of transition, with limited guidance as to the applicability of specific drug therapies for children, and with more drugs introduced, or likely to be introduced soon. As we have suggested, the optimal approach to acute decompensated heart failure is to recruit systolic function and adequate blood pressure to achieve decongestion (diuresis) and reduce lactate production at first. Thereafter we recommend graduated withdrawal of pure inotropic support (epinephrine or dopamine) first, followed by reduction in dosage of inotropic vasodilators (such as milrinone) over 48–72 h, coupled with the introduction of sacubitril/valsartan or an ACE inhibitor as maintenance therapy. As a general guide, the authors still endorse a phased approach of introducing a combination of oral maintenance therapy drugs following de-escalation of vasoactive drugs in patients with ADHF. The logical approach remains to initiate RAAS pathway inhibition first, as well as an MRA drug. There is now evidence that direct introduction of sacubitril/valsartan is tolerated well in this setting, and so this may become the preferred option . This caSerum biomarkers have acquired an important role in heart failure management. From initially being purely a diagnostic tool, they have since been used to monitor treatment response, and have also become an acknowledged surrogate endpoint in Pediatric and Adult HF clinical trials. BNP is the best studied of these, and yet for adults with HFrEF the data is conflicting. Biomarker-directed care, while demonstrated to be helpful in smaller trials has however not been validated in a large-scale randomized trial in adults, or in any meta-analysis of smaller studies , 84. In The most recent published guidelines from the United States and Canada give recommendations for the management of HF in children provide recommendations for the management of acute HF including diuretics for fluid overload, judicious use of inotropes for hemodynamic instability, and ACE inhibitors, (ARBs if intolerant to ACE inhibitors), β-blockers, and MRAs for chronic HF. However, new guidance is required for the indications and timing of ivabradine and sacubritil/valsartan, and potentially for the future adoption of the other drugs indicated here, into the management of pediatric HF.Until very recently, medications made available for the treatment of HF have traditionally been developed and tested in adults with HFrEF, and gone on to be used in children, with or without clear experimental evidence of efficacy. The American Academy of Pediatrics has stated that “It is morally imperative to formally study drugs in children so that they can enjoy appropriate access to new and existing therapeutic agents” . AlthougAll authors contributed to the conceptual design, data review, writing, and review of this manuscript.RES is a consultant for Novartis, Bayer, and Bristol Myers Squibb. PFK is a consultant for Novartis. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.