Autoimmune rheumatic diseases (ARDs) form a heterogeneous group of disorders that include systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), idiopathic inflammatory myopathies (IIMs), and systemic vasculitis. Coronary microvascular dysfunction (CMD) is quite common in patients with ARDs and is linked to increased cardiovascular morbidity and mortality. Inflammation plays a crucial role in the pathogenesis of both accelerated atherosclerosis and CMD in ARDs, especially in patients affected by SLE and RA. In this regard, some studies have highlighted the efficacy of immunosuppressants and/or biologics in restoring CMD in these patients. By contrast, the role of inflammation in the pathogenesis of CMD-SSc appears to be much less relevant compared to endothelial dysfunction and microvascular ischemia, with calcium-channel blockers providing some benefits. Few studies have endeavored to assess the occurrence of CMD in IIMs and systemic vasculitis, thus warranting further investigations. The present review summarizes the current evidence on the occurrence of CMD in ARDs, focusing on the role of inflammation and possible therapeutic approaches. Autoimmune rheumatic diseases (ARDs) form a heterogeneous group of disorders characterized by multiple organ involvement stemming from systemic inflammation and a dysregulation of the immune system with subsequent tissue damage. ARDs include systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), inflammatory idiopathic myopathies (IIMs), and systemic vasculitis. Accelerated atherosclerosis and coronary microvascular dysfunction (CMD) are the main causes of cardiovascular (CV) involvement in these patients, leading to increased cardiovascular morbidity and mortality .In the literature pertaining to the CV implications in ARDS, much attention was initially given to the role of inflammation in inducing accelerated atherosclerosis—especially in SLE and RA—whereas the occurrence of CMD has only been more recently investigated. Endothelial dysfunction is thought to be an early event in the pathogenesis of both macro- and microvascular cardiac involvement in ARDs . DecreasThe coronary microcirculation comprises pre-arterioles (diameter 100–500 μm) and arterioles (diameter < 100 μm) and is of the utmost importance in determining myocardial perfusion as it accounts for 80% of the global blood flow resistance in the heart . ConsideKnowing the strong link between CMD and cardiovascular mortality in ARDs, it is crucial to diagnose cardiac involvement as early as possible and identify effective therapeutic strategies.CMD can be detected by both non-invasive and invasive techniques. The coronary flow reserve (CFR) is the ratio between maximal  and baseline coronary blood flow, and a CFR ≤ 2.5 indicates CMD . The assSingle-photon emission computed tomography (SPECT) is another validated imaging modality to detect microvascular impairment. SPECT is a nuclear imaging technique performed at baseline or after stress, which reveals the differences in the distribution of the radionuclide  and, therefore, the relative blood flow to the different regions of the myocardium . HoweverMicrovascular impairment can also be quantified invasively by coronary angiography with the determination of the index of myocardial resistance using an intracoronary pressure wire at baseline conditions and during hyperemia .Systemic lupus erythematosus is a heterogeneous ARD that occurs predominantly in females and causes chronic inflammation in multiple organs. Cardiac manifestations  and myocarditis) are the leading cause of morbidity and mortality. SLE is associated with an accelerated atherosclerotic process, and it has been reported that women affected by SLE carry a 7.5-fold increased risk of developing CAD versus healthy controls ,20. AlthWhile the link between symptomatic patients  and CMD is well established, the data among non-symptomatic patients are still scarce. Recent studies on SLE patients without known heart involvement or CV symptoms reported an interesting association between troponin elevation, strain rate diminution (TTE), native T1 and T2 augmentation (MRI), aortic stiffness augmentation (pulse wave velocity), and myocardial inflammation/interstitial and perivascular fibrosis on histology ,27. ThesAll these findings show that CMD is quite common in SLE and represents a major cause of persistent chest pain in the absence of obstructive CAD in these patients. CMD and accelerated atherosclerosis alike appear to stem the inflammatory burden. Thus, the efficacy of corticosteroids and immunosuppressants in CMD-SLE warrants further investigation .Systemic sclerosis is a complex autoimmune connective tissue disease (CTD) characterized by immune dysregulation, microvascular damage, and fibrosis ,29. FuncSeveral studies with CFR measurement by TTE with adenosine infusion have found that CMD is detectable in about 50–60% of clinically asymptomatic scleroderma patients ,33,34. AAs in other microvascular manifestations of SSc , the main pathogenetic mechanisms underlying primary myocardial involvement seem to be an imbalance between mediators of vasoconstriction and vasodilation, resulting in ischemic damage. In these settings, calcium channel blockers (CCBs), such as nifedipine, have been shown to improve myocardial perfusion assessed by SPECT and prevent the future onset of LV diastolic dysfunction in scleroderma ,35. MoreOn the other hand, a possible additional role of inflammation in CMD-SSc has been hypothesized recently. Conventional cardiac MRI has detected the presence of focal and diffuse myocardial fibrosis and, to a lesser extent, myocardial inflammation even in SSc with no cardiac symptoms . MavrogeMoreover, SSc patients showed significantly expanded the extracellular volume and larger areas of T1 abnormality than those identified at conventional CMR, which likely reflects a combination of low-grade inflammation and diffuse myocardial fibrosis . As a coThese data point to a continuum between disease onset with microcirculation remodeling and low-grade ischemia, to diffuse myocardial fibrosis and inflammation induced by microvascular rarefaction and immune activation. Early subclinical microvascular heart impairment seems detectable, but aggressive vasodilator and immunosuppressive regimens warrant further investigation in these asymptomatic patients.Rheumatoid arthritis is linked to an increased risk of CV events. Large epidemiological studies have suggested that while traditional CV risk factors may be crucial, they alone cannot account for the added risk in RA patients . The infAlthough the excess CV risk in RA is not fully understood, several mechanisms are believed to be responsible for endothelial dysfunction in these patients: genetic factors, immune dysregulation, inflammation, metabolic disturbances, use of steroid and anti-inflammatory drugs.Toutouzas et al. reported that RA and diabetic patients presented similar rates of ischemic alterations at dobutamine stress TTE, significantly higher vs. controls . NeverthSeveral studies have investigated CMD in patients with RA. Recently, Amigues et al. found that 30% of RA patients showing no clinical CV disease had a pathological  myocardial flow reserve (MFR) assessed by PET-CT . MoreoveAltogether, these studies suggest that CMD and accelerated atherosclerosis share similar pathogenetic mechanisms in RA. Moreover, currently available data suggest that achieving remission in RA does not necessarily ensure the reversal of microvascular endothelial dysfunction. Since the treat-to-target is a cornerstone of the management of patients with RA, these findings suggest that restoring CMD may be considered as an adjunctive potential therapeutic target in RA. The demonstrated effect of some biologic therapies on CMD-RA could represent a key point in choosing biological drugs in RA patients, considering their high CV risk ,47.Systemic vasculitis refers to a heterogeneous group of autoimmune disorders characterized by vessel inflammation. Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAVs) mainly include granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), and microscopic polyangiitis. AAVs affect small vessels, and, therefore, the cardiac impairment is intrinsically linked to a dysfunction of the coronary microcirculation. Perhaps because the microvascular origin is implicit in the classification of AAVs , there aAs it pertains to large vessels vasculitis , the involvement of small vessels is very rare, and hence, CMD is very uncommon. Behar et al. reported a case of an Asian female affected by Takayasu’s vasculitis and refractory ischemic chest pain caused by CMD .Microvascular dysfunction studied by CFR highlighted abnormalities in coronary microcirculation in Kawasaki disease. A reduced CFR was reported in medium and giant coronary aneurysms, and in stenotic lesions even of mild to intermediate severity. Therefore, abnormalities in the coronary microcirculation and epicardial lesions may occur concomitantly in these patients .Finally, myocardial perfusion defects caused by CMD have been reported in patients with Behçet’s disease ,56.Idiopathic inflammatory myopathies (IIMs) are a group of chronic, autoimmune conditions characterized by the infiltration of inflammatory cells into skeletal muscles . The mosCoronary microvascular disease is common in patients with ARDs, leading to increased CV risk. Inflammation is relevant in the pathogenesis of CMD-ARDs, especially in patients affected by SLE and RA, and, therefore, a more aggressive therapeutic approach with immunosuppressants and biologics might prove useful in these patients to prevent diastolic and systolic dysfunction. By contrast, autoimmunity and inflammation seem much less involved in CMD-SSc, whose treatment to date consists of vasodilators and low-dose aspirin. The occurrence of CMD has been less investigated in systemic vasculitis and IIMs, thus warranting further studies. The early identification of CMD and a more precise clarification of the pathogenetic mechanisms involved in CMD-ARDs is paramount in these patients to define the best therapeutic strategy and avoid major CV events.


However, opposing results exist regarding utilization of these metabolites in LV hypertrophy or thickening. Therefore, the aim of this study was to measure metabolic alterations using 1H-CMRS in a group of patients with thickened myocardium caused by cardiac amyloidosis.Cardiac involvement of amyloidosis leads to left-ventricular (LV) wall thickening with progressive heart failure requiring rehospitalization. Cardiovascular magnetic resonance (CMR) is a valuable tool to non-invasively assess myocardial thickening as well as structural changes. Proton CMR spectroscopy  using a 5-channel receive coil in 11 patients with cardiac amyloidosis  and 11 age- and gender-matched controls . After cardiac morphology and function assessment, proton spectra from the interventricular septum (IVS) were acquired using a double-triggered PRESS sequence. Post-processing was performed using a customized reconstruction pipeline based on ReconFrame . Spectra were fitted in jMRUI/AMARES and the ratios of triglyceride-to-water (TG/W) and total creatine-to-water (CR/W) were calculated.p = 0.17). Myocardial TG/W ratios were significantly decreased compared to controls . CR/W ratios did not show a difference between both groups, but a higher standard deviation in patients with cardiac amyloidosis was observed. Pearson correlation revealed a negative association between elevated LV mass and TG/W  as well as GCS .Besides an increased LV mass and a thickened IVS concomitant to the disease characteristics, patients with cardiac amyloidosis presented with decreased global longitudinal (GLS) and circumferential (GCS) strain. LV ejection fraction was preserved relative to controls (60.0 ± 13.2 vs. 66.1 ± 4.3%, 1H-CMRS may provide an additional diagnostic tool to gauge progression of cardiac amyloidosis along with standard imaging sequences.A decrease in myocardial TG/W can be detected in patients with cardiac amyloidosis alongside impaired cardiac function with an association to the degree of myocardial thickening. Accordingly, EK 2013–0132. Amyloidosis is a multisystemic disorder which is characterized by extracellular deposition of misfolded amyloid proteins leading to consecutive organ failure . CardiacIn the healthy human heart, β-oxidation of fatty acids constitutes the major mechanism of energy production that is subject to storage of TG . In thicTherefore, the objective of the present study was to assess myocardial TG and additional CR content along with functional parameters in a group of patients with cardiac amyloidosis using CMR imaging and spectroscopy.The study was conducted in accordance to the declaration of Helsinki and its later amendments. Local ethics committee approval was obtained. All data acquired in this study were handled anonymously and written informed consent was obtained from each subject.Eleven patients with cardiac amyloidosis  were recruited from the interdisciplinary “Amyloidosis-Network” of the University Hospital Zurich. Cardiac involvement of systemic amyloidosis was confirmed by endomyocardial biopsy, biopsy of other tissue  or by imaging . Amyloid3, 50 phases, 2 slices per breathhold).CMR imaging and spectroscopy was performed on a 1.5 T system  using a 5-channel phased array coil. After scout and reference scans, anatomical and geometric data were acquired using balanced steady-state free precession (bSSFP) sequence in standard long-axis geometries  as well as in short-axis view with full LV coverage from base to apex (repetition time (TR)/echo time (TE) = 3.3 / 1.6 ms, flip angle = 60°, spatial resolution = 1.5 × 1.5 × 8 mm3, adjusted inversion delay, one breath-hold for each anatomical location) in the same anatomical location as the bSSFP scans [In cases with an estimated glomerular filtration rate (eGFR) > 35 mL/min and informed consent of the subject, a gadolinium-based contrast agent  was injected for LGE imaging to visualize fibrosis and scarring. Ethical approval constrains only allowed the administration of contrast agent in amyloidosis patients. All patients were eligible to receive gadolinium. After a period of 10 min, a 3-dimensional gradient spoiled turbo fast-field echo sequence with a non-selective 180° inversion pre-pulse was performed at end diastole  were positioned in the interventricular septum (IVS) and proton spectra were recorded using a PRESS (point-resolved spectroscopy) sequence in systole with optimized spoilers . The bSSFP imaging data were used to measure the IVS at maximum extension in end diastole, LV and right ventricular (RV) end-diastolic volume (LVEDV/RVEDV), left ventricular end-diastolic diameter (LVEDD), left and right ventricular ejection fraction (LVEF/RVEF), stroke volume (SV), and LVM indexed to body surface area (LVMi).LV strain and strain rate analysis was performed using feature tracking analysis . The bSSFP images were used to manually draw endocardial contours followed by software-driven automatic tracking. End-systolic global longitudinal (GLS) and circumferential strain (GCS) as well as peak diastolic longitudinal and circumferential strain rate were extracted.. After noise decorrelation, a singular value decomposition approach (SVD) was used for the combination of all five individual coil channels. Weights estimated from the water spectra were used for the calculation of water-unsuppressed and water-suppressed signals [Spectroscopy data were first reconstructed in MATLAB  using a customized reconstruction pipeline based on ReconFrame  as illustrated in Fig. 2 signals , 21. FolReconstructed and averaged spectra were analysed in jMRUI/AMARES (version 5.2)  Water-un1 = 970 ms and T2 = 40 ms for myocardial water, T1 = 280 ms and T2 = 80 ms for myocardial TG, and T1 = 1480 ms and T2 = 135 ms for CR [For the calculation of triglyceride- and creatine-to-water ratios (TG/W and CR/W), data were first corrected for longitudinal and transverse relaxation by using Ts for CR , 23. The.The amount of fibrosis as percentage of LVMi was calculated semi-automatically by manually applying epi- and endocardial contours to the short-axis LGE images for every slice. Then, the amount of fibrosis was calculated using a full-width-at-half-maximum (FWHM) approach as previously described .U-tests for not normally distributed data. Fisher’s exact t-test was used to examine significant differences between nominal classifications. Bivariate Pearson correlation analysis was conducted to analyze relationships between different CMR parameter including 1H-CMRS results. P-values below 0.05 were considered as statistically significant.Statistical analyses were conducted using SPSS . Continuous variables are expressed as mean ± standard deviation (SD). Categorical variables are reported as percentages. After testing for normal distribution using a Kolmogorov-Smirnov test, data between groups were compared using a 2-sided unpaired Student’s t-test for normally distributed data and a non-parametric Mann-Whitney Cardiovascular comorbidities, age- and sex were not significantly different between amyloidosis patients and the control group. Biochemical analyses revealed no differences in blood lipid levels between the groups Table . NT-proBp < 0.001 for GLS and p = 0.007 for GCS). Circumferential peak longitudinal strain rate as a surrogate for diastolic function was decreased in amyloidosis patients (p = 0.019). Fibrosis extent in the amyloidosis patients ranged from 2 to 74% (mean: 36.1 ± 27.1%) of the LV wall.Baseline CMR parameters of amyloidosis patients and controls are summarized in Table p = 0.032) and a trend towards a decrease in GLS and GCS  for the ATTR-type, there was no significant difference between both groups.Apart from an elevated LVEDV  with no statistical significance compared to the normal controls.At the time of the CMR exam, 4 amyloidosis patients had already received autologous stem cell transplantation. Those patients showed improved GCS and circumferential strain rate in comparisons to the medically treated patients   Figs. . MyocardR = − 0.46, p = 0.033; LVMi: R = − 0.59, p = 0.004).Figure R = − 0.48, p = 0.025). Fibrosis, age, NT-proBNP and blood lipid levels did not show any correlations. CR/W did not correlate to any of those parameters.Comparing myocardial functional LV parameters, there was no correlation between TG/W and LVEF, but there was for TG/W and GLS  and GCS  exhibited one of the highest TG/W ratios within the amyloidosis cohort. This indicates that these two risk factors might offset the reduction in TG/W ratios. TG/W ratios did not correlate with BMI, blood lipid levels or age in the present study, suggesting that TG/W ratios may associate with other factors, such as the accumulation of amyloid proteins. This is indicated by the negative relationship between TG content and the severity of the thickened myocardium  mapping have been used in cardiac amyloidosis to distinguish different amyloidosis types [1H-CMRS. Moreover, modulation of TG/W values may point directly to myocytotoxic effects of circulating amyloid chains which potentially contribute to ECV expansion as measured with T1/ECV mapping [Besides LGE, parametric imaging techniques including Tis types , 45. Bot mapping . These iThe present sample size was relatively small due to the technical demands of the study. Subject numbers were however comparable to previous studies assessing myocardial metabolism in heart failure , 28. AssAs cardiac amyloidosis had already been confirmed in all patients at the time of CMR, we did not perform myocardial biopsies to quantify myocardial TG content and to differentiate intramyocellular (IMCL) and extramyocellular lipids (EMCL). The differentiation of IMCL and EMCL may help to understand the mechanism of the TG/W reduction in cardiac amyloidosis and whether it is caused by expanded extracellular space or by a reduced metabolism of myocytes. Although recent work has shown feasibility to quantify IMCL and EMCL in the human heart using spectroscopy, the present method could not reliably differentiate between the different pools .Myocardial TG/W decreases in cardiac amyloidosis and is associated with the severity of myocardial thickening and systolic dysfunction, independent of age, BMI and blood lipid levels.CMR proton spectroscopy may provide additional information to gauge progression of cardiac amyloidosis.


Left ventricular false tendons (LVFTs) are linear fibrous or fibromuscular bands stretching across left ventricular cavity. Although LVFTs have been associated with various heart pathologies and investigated embryologically and histologically, there is only one report in the literature connoting possible hereditary transmission of this entity. We reported a father and his daughter having similar types of LVFTs with regard to location and thickness. With this report, we will contribute in the literature in respect to potential genetic inherence of LVFTs. Left ventricular false tendons (LVFTs) are linear fibrous or fibromuscular bands that extend between ventricular septum and papillary muscle, left ventricular free wall, or apex , 2. LVFTAlthough there is no consensus on the implication of LVFTs in heart diseases, they have been associated with various clinical manifestations in otherwise structurally normal hearts such as functional murmur, preexcitation, idiopathic ventricular tachycardia, infective endocarditis, cavitary thrombi, regional myocardial hypertrophy, repolarization abnormalities, and genesis of J-waves –9.Our knowledge about LVFT continuously grows. In order to understand clinical implication of LVFT, we need to evaluate this entity in all its aspects. The questions rose regarding its clinical implication let researches to extend histologic characteristic and embryologic development of LVFT. The lacking information regarding genetic transition of LVFT is the missing link of this chain. We offered an insight into genetic aspect of this entity by reporting these cases.An 18-year-old previously healthy girl presented with complaint of palpitation. She has experienced palpitation 2 or 3 times a month for 3 years. She did not declare other triggering factors for palpitation with the exception of caffeine. She stated that her palpitation episode sometime lasts one hour, and it is rarely accompanied by dizziness. On physical examination, the followings were noted: normal S1 and S2 without added sounds (S3 or S4) and murmur on cardiac auscultation, blood pressure 118/76 mmHg, heart rate 78/min, and normal breathing sounds. A 12-lead electrocardiogram showed sinus rhythm with normal QRS morphology. Transthoracic echocardiography revealed a structurally normal heart with the exception of a broad false tendon within the left ventricle extending between apical lateral wall and basal septum The father of the girl in case 1, 52 years old, was admitted in our outpatient clinic due to a periodic examination of coronary artery disease. He had coronary bypass surgery history. At the time of admission, he was asymptomatic with regard to coronary artery disease. On physical examination, the followings were noted: normal S1 and S2 without added sounds (S3 or S4) and murmur on cardiac auscultation, blood pressure 132/82 mmHg, heart rate 72/min, normal breathing sounds, and no peripheral edema.A 12-lead electrocardiogram revealed nonspecific ST changes in precordial leads. Transthoracic echocardiography showed normal systolic contraction in all left ventricular wall segments. There was no evidence of left ventricular cavity enlargement or hypertrophy according to the measurements suggested by chamber quantification guideline . During 1(a)Although there are several reports in the literature regarding embryologic development, histologic evaluation, and its clinical association of LVFT, to date, genetic aspect of LVFT has not been scrutinized thoroughly. Many years ago, genetic transmission of LVFT became the main topic of conversation upon a presentation of resembling LVFTs in a mother and her son in Russian literature . Unlike Clinical implication of LVFTs is still not well understood although several reports have showed their association with some heart diseases . In ordeLVFTs are classified into 5 types with varying percentages based on the points of attachment. Type 1 (66%) extends between posteromedial papillary muscle and ventricular septum, type 2 (12%) between anterolateral papillary muscle and posteromedial papillary muscle, type 3 (11%) between anterolateral papillary muscle and ventricular septum, type 4 (9%) between left ventricular free wall and ventricular septum, and type 5 (1%) between one left ventricular free wall and another left ventricular free wall . Our bot1Although there is no consensus on clinical importance of LVFTs , it mighSeveral heart diseases and electrocardiographic abnormalities have been associated with LVFTs –4, 20–22By reporting these cases, we draw attention of clinicians on the potential genetic inheritance of LVFTs. Clinical studies are warranted to confirm the genetic inheritance and reveal the pattern of genetic transmission of LVFTs.


Indications for extracorporeal membrane oxygenation (ECMO) and extracorporeal cardiopulmonary resuscitation (ECPR) are expanding, and echocardiography is a tool of utmost importance to assess safety, effectiveness and readiness for circuit initiation and separation. Echocardiography is key to anticipating complications and improving outcomes. Understanding the patient's as well as the ECMO circuit's anatomy and physiology is crucial prior to any ECMO echocardiographic evaluation. It is also vital to acknowledge that the utility of echocardiography in ECMO patients is not limited to the evaluation of cardiac function, and that clinical decisions should not be made exclusively upon echocardiographic findings. Though echocardiography has specific indications and applications, it also has limitations, characterized as: prior to and during cannulation, throughout the ECMO run, upon separation and after separation from the circuit. The use of specific and consistent echocardiographic protocols for patients on ECMO is recommended. Extracorporeal membrane oxygenation (ECMO) and extracorporeal cardiopulmonary resuscitation (ECPR) provide temporary pulmonary and/or cardiac support when medical management fails , 2. NeonOverall, neonatal ECMO utilization has significantly decreased over the last 25 years , 7. NeonOver the years, the role of echocardiography in ECMO patients has transitioned from a primary means of monitoring cardiac function to a clinical tool whose findings are integrated into the overall evaluation and management of neonatal and pediatric ECMO patients. Echocardiography is a tool of utmost importance to assess indications for ECMO, choose the appropriate mode of support, and rule out mechanical complications such as anatomic defects (tamponade or aortic regurgitation) or ECMO-system complications (cannula position or thrombus). Echocardiography has also emerged as a risk stratification tool in the context of assessing ventricular function in order to determine the degree of potential ventricular recovery.Despite all of this, some challenges remain, as final outcomes for veno-venous (VV) and veno-arterial (VA) ECMO have changed little over the past 10 years. Survival following pulmonary support remains around 80% in neonates , 7 and 5This manuscript aims to provide an overview of key elements to consider in the echocardiographic evaluation of neonates and pediatric patients requiring ECMO. It highlights those areas where additional evidence is still needed and points out potential research strategies.Performing an accurate and clinically useful echocardiographic evaluation is mandatory in order to understand the ECMO circuit anatomy and physiology for each different modality (VV ECMO and VA ECMO). ECMO is a form of extracorporeal life support that evolved from cardiopulmonary by-pass. In ECMO, an artificial circulator carries venous blood from the patient to a gas exchange device (oxygenator). In the oxygenator, blood becomes enriched with oxygen and carbon dioxide is removed. This blood then re-enters the patient's circulation. Circuit flow is achieved using either a centrifugal or a roller pump Figure , but thePatients who are hypoxemic despite maximum conventional ventilator support, have significant ventilator-induced lung injury, or are in cardiogenic shock may be considered for ECMO support. In all cases, the clinical situation of the patient should be considered highly treatable and reversible in order to be a candidate for ECMO. In those conditions with respiratory failure, ECMO will allow the level of ventilator support to be reduced and time for recovery from the underlying pathology and/or ventilator-induced lung injury. The same principle applies to ECMO for cardiogenic shock, allowing time for the myocardium to rest and recover. Regardless of the indication for ECMO, neonates and children without lung/myocardial recovery may require heart/lung transplantation. ECMO remains as one of the primary options for mechanical ventilation and/or circulatory support as a bridge to heart/lung transplant , 19.There are two primary types of ECMO: Veno-Venous (VV) and Veno-Arterial (VA).2 from the blood. This allows the level of ventilator support to be decreased, which reduces ventilator-induced lung injury. The efficiency of oxygenation by the ECMO circuit depends on the pump flow relative to the patient's cardiac output. The patient's oxygenation should increase with an increasing ECMO flow rate. If this does not occur, it should raise suspicion of recirculation of blood between the inflow and outflow cannulas.VV ECMO provides pulmonary support with some degree of indirect cardiac support. VV ECMO improves the patient's oxygenation by reducing the amount of blood that passes through the lung without being oxygenated and removing CO2 from the blood than delivering oxygen. The amount of CO2 removal depends on the ECMO flow rate relative to the patient's cardiac output as well as the oxygen flow rate relative to the oxygenator. Increasing the oxygen flow rate decreases the CO2 in the blood leaving the oxygenator .VV ECMO is more efficient at removing CO2 is determined by the relationship between the ECMO pump flow and the patient's cardiac output. If the ECMO pump flow is low compared to patient's cardiac output, the arterial O2 will also be low. Increasing the ECMO pump flow will increase the O2 in the mixed venous circulation and therefore increase the arterial O2.Arterial O2 levels in VA ECMO are the result of mixing between the ECMO flow and native cardiac output.VA ECMO provides direct cardiac and pulmonary support. In VA ECMO, deoxygenated blood is drained from the patient's venous circulation into the ECMO circuit. Blood is oxygenated via the oxygenator and is returned to the arterial circulation, providing support for both heart and lung failure. It can be used at low rates to provide partial assistance or at high rates to completely replace the patient's cardiac output. Therefore, PO2, is recommended to minimize hyperoxic injury and allow time for pulmonary and cardiac recovery  in an anterograde fashion. In this clinical setting, manipulation of ECMO flow is indicated to reduce native cardiac output. Reducing ventilator support to rest settings, especially lowering the FiOrecovery –22. Of nIn both of these ECMO support modalities, it may become imperative to create an inter-atrial communication to unload the left-sided-heart, either surgically or by cardiac catheterization –25. Thisvolume status of the patient's venous beds, the adrenergic tone and the resistance to venous return  afterload and improves RV function due to the resolution of severe hypoxemia and hypercapnia. VA-ECMO has been associated with more physiological effects than VV-ECMO, as it short-circuits the normal hemodynamic pathway. When VA-ECMO is initiated, blood is removed from the venous bed and venous return to the right heart decreases. This causes a subsequent decrease in right atrial pressure, IVC volume and pulmonary blood flow, which will in turn affect gas exchange –34. AfteEchocardiography plays a significant role in a patient supported with ECMO. It provides information regarding patient selection, guides the insertion and placement of cannulas, monitors progress, detects complications and recognizes recovery, readiness for weaning and ECMO decannulation. However, it is important to acknowledge that management decisions should not be made exclusively based upon echocardiographic findings.The primary utility of echocardiography in this patient population relates to the evaluation of anatomy and residual lesions, cardiac function and trends, arrhythmias, and ECMO cannula position, flow and potential complications. Echocardiography has the advantages of being a non-invasive technique that is readily available at the patient's bedside and provides real-time evaluation of cardiac structure with high sensitivity and specificity –39.sine qua non condition to be efficient. Patients on ECMO support are assessed by multiple observers, which may lead to subjective interpretation of clinical status. Moreover, physiological changes induced by ECMO may alter echocardiographic findings. A systematic adherence to the echocardiographic protocol and quantification of the echocardiographic parameters may help to avoid those biases. However, the published literature on the role of echocardiography in ECMO remains scarce  (Position papers on the management of pediatric ECMO recommend that an echocardiography-trained physician should be part of the team caring for neonates and children on ECMO (delines) . Howeverdelines) .Before initiating ECMO support, it is crucial to perform an echocardiographic assessment to identify the underlying cardiac anatomy, recognize the patient's hemodynamic condition and help to choose the best ECMO modality. VV-ECMO will provide support for severe respiratory failure when no major cardiac dysfunction exists, and VA-ECMO will provide support for severe cardiac failure most commonly after cardiac surgery , 38, 42.Echocardiography is of paramount importance to provide detailed anatomical description of the heart and the great vessels. It can demonstrate inferior vena cava (IVC) and superior vena cava (SVC) to right atrium (RA) continuity, which is important for cannula placement given that the right internal jugular vein and the right common carotid artery are the most common sites for pediatric peripheral ECMO cannulation . A complThe assessment of RV function and RV dimensions is important prior to initiating ECMO support, although the complex shape of the RV chamber makes it difficult to use geometric models for volume and function quantification, and the retrosternal position of the RV creates a barrier for ultrasound waves. The finding of RV dilatation pre-ECMO initiation has been associated with increased intensive care unit mortality , 46. TheIt is well known that PAP can be estimated by measuring the TR jet maximum velocity by continuous wave (CW) spectral Doppler . HoweverRV systolic function assessment in this group of patients can be quite difficult. The fractional area change has been found to correlate with magnetic resonance-derived RV ejection fraction. A percentage of fractional area change >35% is considered normal in adults –56. MoreIncreasingly, the evaluation of strain and strain rate of the RV is being used to assist in the evaluation of RV function. Low RV strain values, especially in the apical and free wall regions, have been found to strongly correlate with mean pulmonary artery pressures, right ventricular size and function and mortality , 65. TheThe assessment of RV diastolic function should be included in the routine pre-ECMO echocardiogram, as diastolic dysfunction can precede declines in systolic function and appears to correlate with risk factors such as RV dilatation , 68. PulEchocardiography assessment of LV function, dimension together with the analysis of the left atrium (LA) is paramount. LV ejection fraction by Simpson's method and aortic VTI should be calculated. These values should be interpreted clinically, considering inotropic drug doses being administered as well as ventilator settings. If mitral regurgitation is present, dP/dt should be estimated as a good surrogate of LV function , 72. TisAttention should always be payed to the ventricular interdependence phenomenon understanding that LV contraction directly impacts RV systolic function and vice versa , 74.Valvular function should be assessed prior to ECMO initiation, because after cannula positioning, function cannot be correctly quantified due to ECMO flows. Pre-ECMO echocardiography can help to identify hemodynamic lesions that could explain the hemodynamic or respiratory compromise.Aortic valve integrity is of paramount importance in patients who are progressing toward VA-ECMO support, as the arterial cannula will eject its flow into the aortic arch. Aortic valve regurgitation may contribute to LV distension, LV dysfunction and subsequently pulmonary hypertension –77.Valvular dysfunction should be frequently re-evaluated during ECMO support, especially during weaning. For example, the detection of moderate mitral regurgitation before ECMO initiation should prompt close monitoring of fluid status, as it may be associated with increased pulmonary edema. If mitral prolapse preexists, repeated echocardiographic examinations during prolonged VV-ECMO support should be performed to exclude the development of endocarditis. Tricuspid valve anomalies should also be evaluated. The presence of tricuspid stenosis may compromise the flow of oxygenated blood from the RA to the RV. Severe tricuspid regurgitation may lead to increased RA pressure, and the consequent right to left shunt at the atrial level will manifest as severe hypoxemia. Pulmonary hypertension could be due to a preexisting condition of unknown chronic obstructive pulmonary disease or to a subacute undiagnosed pulmonary embolism.Echocardiography guidance and monitoring during ECMO cannulation in neonatal and pediatric patients is warranted , 79. TraThe size of the venous cannula is a major determinant of blood flow in the ECMO circuit. Therefore, the goal is to insert the largest possible cannula. Measuring the diameter facilitates the selection of the appropriate venous cannula size. Some authors suggest the cannula should be two thirds of the diameter of the vessel, others state that the size (in French) should be three times the diameter (in mm) or the same size as the circumference (in mm) of the vessel , 82. TheIn neonatal and pediatric patients, echocardiography has been shown to be a better imaging modality to identify the correct placement of the cannula and to reduce the rate of surgical repositioning of ECMO catheters , 84–86. In the case of single dual-lumen cannula VV-ECMO, the cannula is inserted into the SVC via the right internal jugular vein Figures , 3 80, , 80, 89.In peripheral VA-ECMO, the venous drainage is similar to that in VV-ECMO, with the drainage cannula positioned at mid-right atrium. In this case, the same precautions described for VV-ECMO should be taken. The arterial cannula is usually inserted through the right carotid, with the tip at the right brachiocephalic artery—aortic arch junction , 86. A dEchocardiography allows for real-time guidance of the cannulation process and helps to prevent procedure related complications such as vascular injury, hematoma, cardiac tamponade, ischemia, tricuspid valve damage, or atrial septum perforation , 96. IncEchocardiography assessment should be routinely performed in patients on ECMO support and not only in the presence of hemodynamic instability. The clinical targets are summarized in Table The correct positioning of the cannulas should be routinely monitored. Should the position of the cannulas are too superficial, an increased risk for incidental decannulation exists , 98. In Cardiac function in both the right and left ventricles should be carefully monitored during ECMO support. The effect of ECMO flow rates on changes in cardiac parameters has been described in the adult literature . HoweverEchocardiography can help to detect complications during the ECMO course. Patients on ECMO support are more susceptible to bleeding due to systemic anticoagulation, which may contribute to pericardial effusion and tamponade Figure . ClinicaECMO flow problems may occur both on VV and VA-ECMO. Low flow may be related to inadequate patient or cannula positioning and hypovolemia, but it is always important to rule out the presence of an intracannula thrombus –105.Echocardiography can help monitor cardiac chamber size to ensure adequate emptying of the cardiac chambers. In this assessment, aortic valve opening is paramount. As described herein, VA-ECMO may compete with the stroke volume ejected from the LV. Any condition that leads to an increased LV afterload will ultimately cause LV distention, LV subendocardial ischemia, intracavitary thrombus formation Figure  and pulmThe last step during ECMO management is to decide when to wean and separate from the circuit. The prediction of successful weaning has long been an area of active research. Successful ECMO weaning depends on several clinical, hemodynamic and echocardiographic variables. Therefore, ECMO weaning should be a decision based upon a comprehensive patient evaluation. Though echocardiography will not provide all the answers, it is a useful assessment tool.In VV-ECMO, weaning should be fundamentally based on the degree of recovery of lung function. The evaluation of oxygenation and pulmonary compliance by decreasing the gas flow through the ECMO circuit is paramount. Contrasting from VA-ECMO weaning, the role of echocardiography in weaning from VV-ECMO is not clear at present, and to date, echocardiographic data during VV-ECMO weaning are lacking. However, it is fair to state that echocardiography becomes crucial to assess optimal RV function and the absence or degree of pulmonary hypertension. Normal parameters are strongly desirable to achieve successful weaning in this group of patients. Considerations for VV-ECMO weaning may include a significant decrease in PAP, estimated by TR jet (as long as RA pressure is invasively monitored), no right-to-left shunt at the atrial and/or ductal level, normal interventricular septum motion, TAPSE>11.5 mm, PAAT>110 ms and E/e' in the left free wall <15.In VA-ECMO, echocardiography may play a more significant role. Studies have shown that patients who were successfully weaned from VA-ECMO were those with more stable hemodynamics during ECMO support reduction . TherefoAlthough recent research has started to evaluate how to assess the changes in echocardiographic indices during ECMO, there is still a lack of evidence and validation of the previous named parameters in the clinical setting of pediatric VA-ECMO.Echocardiography is undeniably a critical tool for the evaluation of patients on ECMO or progressing toward mechanical assistance. Its utility is apparent when evaluating potential ECMO candidates, preparing for cannulation, assessing readiness for separation from the circuit, and following-up after decannulation. Notwithstanding this well-recognized fact, therapeutic and weaning decisions should not depend exclusively on echocardiographic findings, but rather on the patient's functional capacities and the markers of tissue perfusion and end-organ performance. Reliable and efficient interpretation of the echocardiographic findings in patients requiring, undergoing or recently separated from the ECMO device requires an in-depth understanding of both the patient's as well as the ECMO circuit's anatomy and physiology. The use of protocols for the sake of consistency, low variability in practice and effectiveness is highly recommended, as it fosters better outcomes and data tracking for quality and safety purposes.CB-R, JS-d-T, and ED conceived of the presented idea, developed the theory and performed the research, verified the results, and supervised this work. All authors discussed the results and contributed to the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Recently introduced fast strain-encoded (SENC) cardiac magnetic resonance (CMR) imaging (fast-SENC) provides real-time acquisition of myocardial performance in a single heartbeat. We aimed to test the ability and accuracy of real-time strain-encoded CMR imaging to estimate left ventricular volumes, ejection fraction and mass.Thirty-five subjects  were investigated. All study participants were imaged at 1.5 Tesla MRI scanner  using an advanced CMR study protocol which included conventional cine and fast-SENC imaging. A newly developed real-time free-breathing SENC imaging technique based on the acquisition of two images with different frequency modulation was employed.All parameters were successfully derived from fast-SENC images with total study time of 105 s (a 15 s scan time and a 90 s post-processing time). There was no significant difference between fast-SENC and cine imaging in the estimation of LV volumes and EF, whereas fast-SENC underestimated LV end-diastolic mass by 7%.The single heartbeat fast-SENC technique can be used as a good alternative to cine imaging for the precise calculation of LV volumes and ejection fraction while the technique significantly underestimates LV end-diastolic mass. Currently, cine cardiac magnetic resonance (CMR) is the accepted standard of reference for quantification of ventricular volumes, mass and function . AccordiThe aim of this pilot study was to assess the ability and accuracy of recently proposed fast-SENC technique to estimate LV volumes, ejection fraction and end-diastolic mass.We prospectively invited 35 subjects  to participate in this single center study. The coronary artery disease (CAD) was confirmed by previous quantitative coronary angiography. The study complies with the Declaration of Helsinki and was approved by the Ethics Committee of the Charité–Universitätsmedizin Berlin. All individuals were able to give written informed consent before entering the study.Study protocol and design details have been previously published . All CMR3, and 30 phases per cardiac cycle.The study protocol included an initial survey to define imaging planes. Cine images were derived using balanced steady state free precession (bSSFP) sequence with short periods of breath-holding in three LV long-axis planes. Short-axis cine images were acquired and used to calculate LV volumes, mass and ejection fraction. The following parameters were used: repetition time (TR) = 3.3 ms, echo time (TE) = 1.6 ms, flip angle = 60°, acquisition voxel size = 1.8 × 1.7 × 8.0 mm2, slice thickness = 10 mm, voxel size = 4.0 × 4.0 × 10 mm3, single-shot spiral readout (3 interleaves) with acquisition time (TA) = 10 ms, flip angle = 30°, effective echo time (TE) = 0.7 ms, repetition time (TR) = 12 ms, temporal resolution = 36 ms, typical number of acquired phases = 22, spectrally selective fat suppression (SPIR), total acquisition time per slice < 1 s.A newly developed real-time free-breathing SENC imaging technique  was employed to acquire fast-SENC images. Data were derived in three LV long-axis  views  or Virtue software  in accordance to a recent consensus document for quantification of LV function and mass using CMR , while ap value < 0.05.Data analysis was performed using IBM SPSS Statistics version 21.0 software  for Windows. Continuous variables were expressed as mean ± standard deviation. Differences in continuous variables were established using an unpaired Student t test or Wilcoxon signed rank test depending on their distribution. Pearson’s correlation coefficient was calculated to express the relation between the continuous variables. Bland-Altman analysis was performed to test if there was any bias in either CMR technique. Intraobserver and interobserver reproducibility for LVEF and LVEDM was quantified using intraclass correlation coefficient (ICC) and Bland-Altman analysis. Agreement was considered excellent for ICC > 0.74, good for ICC 0.60–0.74, fair for ICC 0.40–0.59, and poor for ICC < 0.40. Statistical significance was defined by a p < 0.001). In the CAD group there were more male subjects (p < 0.001). Healthy volunteers had significantly lower body surface area (p = 0.026) and body mass index (p < 0.001). LVEDV and LVESV were similar in both groups, whereas LVSV and LVEF were significantly lower in CAD patients . Subjects with CAD had significantly higher LVEDM than healthy volunteers . Table All study participants were able to complete the entire study protocol. Study participants with suspected or confirmed CAD were significantly older than the healthy volunteers   and three short-axis fast-SENC images (for GLS). LV GLS and GCS were significantly lower in CAD patients than in healthy volunteers   , LVESV , LVEF  and LVEDM   and LVEDM: ICC 0.983 0.949–0.994) derived using fast-SENC technique. The analysis of interobserver reproducibility also demonstrated excellent agreement, with slightly larger limits of agreement: ICC 0.895 (0.654–0.966) for LVEF and ICC 0.846 (0.157–0.958) for LVEDM. Figure 9–0.994 dThe total scan time spent to acquire CMR images using fast-SENC was 15 s as only six heart beats without any breath-hold are necessary to derive 3 long-axis and 3 short-axis slices. In contrast, conventional cine imaging using bSSFP sequence in a patient with heart rate of 75 beats per minute lasted approximately 45–60 s per slice (30 phases per cardiac cycle including breathing commands and recovery period before the next breath-hold and following slice acquisition could be started). To acquire 3 long-axis and 3 short-axis images the same process was repeated 6 times (for every slice) with a total scan duration of 270–360 s.The time spent for data post-processing using automated contour detection algorithm or machine learning software for fast-SENC (90 s) or bSSFP (120 s) was comparable. However, total time required for data acquisition and analysis was shorter for fast-SENC technique.p < 0.001) [SENC is an advanced CMR technique for measuring regional myocardial function  as an al< 0.001) . A furth< 0.001) . These a< 0.001) . In our < 0.001) . In thisThe single heartbeat fast-SENC technique can be used as a good alternative to cine imaging for the precise calculation of LV volumes and ejection fraction in the interest of time-spent, especially in patients who are unable to perform breath-holds or with cardiac arrhythmias. However, LV mass is significantly underestimated with current fast-SENC technique. LVEF and LVEDM measurements derived using fast-SENC technique are highly reproducible.


Autonomic dysfunction is a very common, early and distressing aspect of hereditary transthyretin (ATTR) amyloidosis leading to significant loss of quality of life and morbidity for patients. Although the clinical variability of ATTR has been well characterized as neuropathic, cardiac or mixed phenotype, the extent of autonomic involvement remains poorly understood. Despite the fact that the autonomic nervous system has not been specifically evaluated in any of the clinical trials of tafamidis, and that, for some primary and secondary endpoints used in these trials, the behavior cannot be separated from non-autonomic items, an attempt was made to use published material to indirectly access the efficacy of tafamidis in treating dysautonomia.Literature review summarizing the results of primary and secondary endpoints related to the autonomic features used in the original tafamidis trials, the post hoc publications, and real-world data, on the effect of tafamidis on autonomic dysfunction in patients with ATTR amyloidosis.There is some evidence that indirectly demonstrates that tafamidis is safe and could slow or arrest the progression of autonomic neuropathy in patients with ATTR amyloidosis, in addition to its well-described effects to ameliorate sensory-motor peripheral neuropathy.Although the current evidence is scarce, tafamidis might be effective in arresting the progression of autonomic neuropathy in patients with ATTR amyloidosis. Tafamidis might be more effective at the early stage of the disease; however, individual responses must be monitored. Hereditary transthyretin amyloidosis (ATTR) is a rare disease caused by the deposit of misfolded transthyretin (TTR) monomers as amyloid in several tissues, resulting in a length-dependent axonal degeneration of the peripheral nerves, involving initially and preferentially unmyelinated and small myelinated nerve fibers .Autonomic dysfunction is a very common, early and distressing aspect of TTR amyloidosis affecting the gastrointestinal, urogenital and cardiovascular systems, leading to significant loss of quality of life for the patients, consequentially resulting in a reduction of work capacity and social life. It is also life-risking when considering severe orthostatic hypotension, diarrhea, vomiting and eventually cachexia due to malabsorption as leading causes of death if untreated. Early sexual dysfunction in men is another important psychological aspect to be considered .Although the clinical variability of ATTR has been well characterized as neuropathic, cardiac or mixed phenotype, the extent of autonomic involvement remains poorly understood. Using data from THAOS , Barroso and colleagues investigated the prevalence of autonomic symptoms, relationship with different genotypes and phenotypes, and clinical burden for the patients . As of JTafamidis selectively binds to TTR with negative co-operativity and kinetically stabilizes wild-type native TTR and mutant TTR; tafamidis, therefore, has the potential to halt the amyloidogenic cascade initiated by TTR tetramer dissociation, monomer misfolding, and aggregation , 4.The aim of this manuscript is to discuss relevant autonomic endpoints in relation to the use of tafamidis in clinical trials, and use post hoc analysis as well as in real life to gather experience of different stages of the disease and mutations.We performed a literature review to summarize the impact of tafamidis on autonomic dysfunction in patients with ATTR amyloidosis. Autonomic markers were not specifically evaluated in any of the tafamidis trials. Moreover, the change of primary and secondary endpoints used in these trials, although related to autonomic dysfunction, cannot be separated from other non-autonomic systems. Thus, an attempt was made to include published material to indirectly access the impact of tafamidis in autonomic dysfunction.Among the primary and secondary outcomes related to autonomic dysfunction used in the tafamidis trials, we focused on nerve function accessed by quantitative sensory test and heart rate variability to deep breathing as measures of small nerve fiber function; The Norfok Quality of Life Questionnaire encompasses several questions related to sphincter control, gastrointestinal and other dysautonomia aspects and their burden, as well as other non-autonomic functions, and, finally, the modified body mass index (mBMI), a well-known prognostic index of disease severity.FX-005 was the first tafamidis double-blind, placebo-controlled, multicenter trial. The objective was to evaluate the effect of 18 months of treatment (20 mg daily) on disease progression and its safety. Patients with definite diagnosis of hereditary ATTR, presenting V30M mutations and an autonomic or sensory-motor neuropathy at stage 1  of disease, were included. The corresponding primary efficacy endpoint of interest analyzed in the intent-to-treat  population was that least-square (LS) mean change from baseline in Norfolk QOL-DN score in the two groups. Another analysis was performed in the population that completed the study (EE). The efficacy evaluable (EE) population was pre-specified assuming a dropout of patients for liver transplantation (LT). A total of 128 patients were randomized, with 69% on the waiting list for LT. From this population, 21% in each treatment arm, active drug, or placebo discontinued to undergo LT. As secondary autonomic endpoints of interest, change from baseline at months 6, 12, and 18 in Norfolk QOL-DN, the summated three nerve tests (Σ3 NTSF), and mBMI were used. The summated three nerve tests small-fiber normal deviate score (Σ3 NTSF nds), a composite of cooling detection threshold, heat/pain detection threshold and heart rate response to deep breathing, ranges from − 11.2  to 11.2 . They can be obtained by quantitative sensory test examination with dedicated equipment . In the tafamidis group, BMI significantly increased from baseline at 18 months (LS mean + 39.3) compared to a worsening in patients under placebo (− 33.8). There was an 84% preservation of small-nerve fiber function in the tafamidis-treated group of patients. Adverse events were equally distributed in both treatment groups and were mostly related to the disease itself. The excellent tolerability profile of tafamidis is essential when considering dysautonomia in patients who are very sensitive to gastrointestinal disturbances, cardiovascular and kidney possible adverse events [In the ITT population, change from baseline in Norfolk QOL-DN score in the two groups was not significant at month 18. However, in the EE population, significantly less LS mean change from baseline in Norfolk QOL-DN in the tafamidis group was observed  were enrolled in Fx-006.P < 0.01) and there was a positive rate of change of mBMI as opposed to a decline observed in Fx-005  [In the tafamidis–tafamidis group, there were no statistically significant differences in the monthly rate of change in measures including Norfolk QOL-DN and Σ3 NTs nds scores comparing the first 18 months of the previous study with the 12 months of the extension study. The monthly rate of change of mBMI dropped in the tafamidis–tafamidis group after entry into Fx-006, but remained higher than at baseline of the previous study. In the placebo–tafamidis group, the rate of progression measured by Σ3 NTs nds score (0.09 for Fx005 and 0.04 for Fx006) was decreased during the extension phase of the study. The deterioration attested by the Norfolk QOL-DN score during Fx-005 was arrested in Fx-006 in this group  to assess effects of tafamidis on TTR stabilization and clinical outcomes. This was a 12-month study open-label design . As secoAn open-label extension of these trials is ongoing. The aim is to assess long-term safety and efficacy of tafamidis in ATTRV30M and non-ATTRV30M patients. Ninety-three patients from previous studies were enrolled. Barroso and colleagues performed an interim analysis after up to 6 years of treatment for ATTR-FAP. At the time of the data cut-off, 17 of the 93 were ongoing. The remainder were the ones from countries where tafamidis was still not available by prescription . Norfolk2 . The placebo–tafamidis group of patients showed steady worsening on mBMI relative to baseline during placebo treatment and an improvement (increase) after switching to the active drug, persisting at month 66. . This long-term analysis expands the favorable safety and efficacy profile of tafamidis in several aspects of autonomic and QOL aspects of ATTR and confirms the growing body of evidence that early initiation of tafamidis is of upmost importance for the clinical outcome [LSMean changes from baseline in TQOL for ATTRV30M patients showed variability, but increased over time. By month 66, LSMean increases from baseline were similar in the tafamidis–tafamidis and placebo–tafamidis groups. By month 48, LSMean increases from baseline for non-ATTRV30M was 24.8. In the same study, a post hoc slope analysis used extrapolated projection of TQOL in patients who were originally under placebo if they would have continued to be under placebo, thus mimicking natural evolution of the disease, and a significant difference was observed, indicating that, although increasing, the change in TQOL compared to no treatment at all is much lower in both groups of patients (treated or not treated previously by tafamidis in FX005). Regarding mBMI at month 66, tafamidis–tafamidis group LSMean change was − 2.7 g/L × Kg/m outcome .In addition to clinical trials, two different post-hoc analysis have been performed to assess the efficacy of tafamidis. Keohane and colleagues described additional post hoc analysis of the data from the pivotal, Fx-005, double-blind trial, employing alternative methods of analyzing change from baseline is NIS-LL (neuropathy impairment score of lower limbs) by itself and in combination with other measures as Σ3 (NIS-LL +  Σ3), a pre-specified efficacy measure of small-nerve fiber function.The NIS-LL has been described extensively . BrieflyP = 0.0001). The LS mean increase from baseline at month 18 was 3 points in the tafamidis group versus 7.5 points in the placebo group . The combination of NIS that is basically a neurological examination, with neurophysiological parameters provided a stronger measure for the heterogeneous aspects of this neuropathy  [Repeated-measures analysis of change from baseline of the parameters described before was repeated with the addition of baseline as covariate and multiple imputation analysis for missing data by treatment group. It was conducted to account for a numeric difference in baseline NIS-LL between groups . Significant treatment group differences in the LS mean change from baseline in NIS-LL +  Σ3 were observed from month 12 to month 18. At baseline the mean NIS-LL + Σ3 in the tafamidis group was 13.9 points and in the placebo group was 17.1 points. The LS mean increase from baseline at month 12 was 1.6 points in the tafamidis patients versus 6.1 points in the placebo-treated ones . Mean changes from baseline in NIS-LL and mBMI were 5.3 points and − 7.8 Kg/ml status .After the approval of tafamidis in Europe in 2011, several centers reported their experience with tafamidis in a real-world context of use. Lozeron and colleagues studied the effect of tafamidis on the disability and safety in late-onset patients with ATTRV30M. Late-onset V30M patients differ from early onset in presentation of disease after 50 years of age, but also in the greater severity of the neuropathy, and as presentation with a cardiomyopathy or mixed phenotype . The stuCortese and colleagues reported the monitoring of efficacy and safety of tafamidis in ATTR in Italy. It was a longitudinal multicenter survey in a non-endemic area. Patients from non-endemic areas differ from most of the patients of the pivotal trial in terms of the possibility of mixed (cardiac and neuropathic) presentation, late-onset, later disease stage and non-V30MTTR mutations. Sixty-one patients were followed according to a protocol including general medical, cardiac and neurological assessments at baseline and every 6 months for up to 3 years . Only 28% had V30M TTR mutation. Mean age of onset was 59 years and 18% had advanced stage at the start of treatment. Patients were assessed by NIS, Kumamoto Scale, FAP stage, Charcot Marie Tooth Scale, PND, different cardiac and echocardiographic parameters and mBMI  . Thirty-® [Planté-Bordeneuve and colleagues reported the effect of tafamidis in 43 TTR-FAP-treated patients with a variety of mutations (53% non-V30M TTR) at different stages of neuropathy followed long term. Clinical assessments, including BMI and neurological assessment, including neurophysiological variables of small-nerve fiber function, were performed every 6–12 months. The mean duration of follow-up was 2.1 years. Autonomic and small-nerve fiber function measures included in the neurophysiological score of small-fiber (SFNS) were: sympathetic skin response (SSR), heart rate variability with deep breathing (HRDB), laser-evoked potentials (LEP), warm detection threshold during quantitative sensory testing (WDT) and electrochemical skin conductance (ESC) (Sudoscan®  (Table 1Autonomic abnormalities are frequent among a majority of the clinical presentations of ATTR, and can be the initial presentation of the disease, being very prevalent in patients with the early-onset Val30Met phenotype. Autonomic dysfunction represents a critical part of the burden of the disease, and is generally challenging to treat.Trials, post hoc analysis, and real-world experience publications presented different results of the efficacy of tafamidis to treat dysautonomia in different groups of patients, from different parts of the world, using many different measures, mostly as indirect secondary endpoints.There is a consistent beneficial effect of tafamidis to preserve nutritional status, an important prognostic factor in ATTR. The initiation of tafamidis should be considered early in the stage of the disease, when it seems to be more useful. Treatment of ATTR should be individualized, requires experienced practitioners, a multidisciplinary approach and frequent follow-up visits.Taking into consideration the published data about tafamidis and autonomic dysfunction, there is some evidence indirectly demonstrating that tafamidis is safe and could slow the progression of autonomic neuropathy in some cases, in addition to its well-demonstrated beneficial effects to slow the progression of sensory-motor peripheral neuropathy.


Fibroblast growth factor−23 (FGF23) is a mainly osteocytic hormone which increases renal phosphate excretion and reduces calcitriol synthesis. These renal actions are mediated via alpha-klotho as the obligate co-receptor. Beyond these canonical “mineral metabolism” actions, FGF23 has been identified as an independent marker for cardiovascular risk in various patient populations. Previous research has linked elevated FGF23 predominantly to left-ventricular dysfunction and consecutive morbidity and mortality. Moreover, some experimental data suggest FGF23 as a direct and causal stimulator for cardiac hypertrophy via specific myocardial FGF23-receptor activation, independent from alpha-klotho. This hypothesis offers fascinating prospects in terms of therapeutic interventions, specifically in patients with chronic kidney disease (CKD) in whom the FGF23 system is strongly stimulated and in whom left-ventricular dysfunction is a major disease burden. However, novel data challenges the previous stand-alone hypothesis about a one-way road which guides unidirectionally skeletal FGF23 toward cardiotoxic effects. In fact, recent data point toward local myocardial production and release of FGF23 in cases where (acute) myocardial damage occurs. The effects of this local production and the physiological meaning are under current examination. Moreover, epidemiologic studies suggest that high FGF-23 may follow, rather than induce, myocardial disease in certain conditions. In summary, while FGF23 is an interesting link between mineral metabolism and cardiac function underlining the meaning of the bone-heart axis, more research is needed before therapeutic interventions may be considered. Despite relevant progress in diagnosis and therapy, mortality in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) remains high, with an overall 65% 5-year mortality . MortaliThe cardiovascular disease spectrum of CKD and ESRD patients is specific in various aspects. In addition to accelerated cardiovascular calcification the central characteristic feature of CKD-associated CVD is the development of left-ventricular hypertrophy (LVH). The pathophysiology of CKD-associated LVH is complex and multifactorial and LVH occurs even in the absence of severe and long-standing uncontrolled arterial hypertension or aortic valvular disease in CKD patients . InsteadAn important milestone in our understanding of the bone-heart axis was the discovery of the profound metabolic, specifically mineral effects of FGF23 . FGF23 iThe next evolutionary step in our FGF23 understanding was the transfer from association toward causality: Recent experimental data established a causal pathway and linked extra-cardiac FGF-23 directly to the development of cardiovascular pathologies, specifically cardiomyopathy . Howeverin vitro, FGF23 treatment of bovine parathyroid cells inhibits PTH secretion  depend upon its interaction with FGF23 receptors and its obligate renal co-receptor alpha-klotho . In renaecretion  (summariecretion .There is a striking association between decreasing glomerular filtration rate (GFR) and raising FGF23 levels in humans. In fact, the magnitude of FGF23 increase with the decline in kidney function is unique among the various biomarkers of the CKD-MBD syndrome. While a PTH increase by a factor of 20–30 may already represent severe, uncontrolled hyperparathyroidism, FGF23 levels over 1,000-fold higher than in healthy controls have been described in CKD .2D3] which appear to be main stimulators of FGF-23 synthesis  ynthesis , 30, whiynthesis .in vitro experiments have to date yielded conflicting results. In mice, feeding a high phosphate diet has been shown to increase circulating FGF23  2D and PTH  and  effects. FGF-Receptor 1 (FGF-R1) is thought to be the major renal effector of FGF23, mediating primarily phosphaturic and calcitriol-regulatory effects of FGF23 . Klotho As already mentioned, over the last years many studies have shown significant and independent associations between increased FGF23 and dismal outcomes in humans. Remarkably, this association is not limited to CKD patients  . SCD in Indeed, LVH is a very common finding in patients with CKD and ESRD with up to 74% of patients showing some form of this pathological cardiac remodeling –53. The Recent research has attributed a substantial role in LVH pathogenesis to FGF23: As early as 1997 Nehme et al. hinted at it by showing that children with X-linked hypophospataemic rickets (XLH), an X-linked dominant disease with FGF23 overexpression and consecutive hypophosphataemia, to have signs of LVH .In much less selected patients, evidence for an association between FGF23 and LVH was first published by Mirza et al. who showed that in the PIVUS cohort, a Swedish cohort with around 800 patients aged 70 or more, intact FGF23 correlated with the presence of LVH, as determined by echocardiography . NoteworIn vitro, the treatment of neonatal rat ventricular myocytes for 48 h with different concentrations of FGF23 induced morphometric hypertrophy similar in extent to treatment with FGF2, a known strong inducer of LVH. These histological changes accompanied a change in the gene expression profile reflecting pathological hypertrophy. The effect was dose dependent, with no further increase seen after 15 ng/ml FGF23 . Hence, this challenged the mono-directional hypothesis that external factors stimulate bone FGF23 release which in turn induces myocardial damage.These experimental data are supported by some clinical data fueling the hypothesis that FGF23 release and myocardial damage is not a one-way route from the skeleton to the myocardium: Cross-sectional data derived from a cohort study and tabolism , 71: thetabolism . ConsideRecent data by Anderson et al. underlines how much this topic is currently still up for debate. The authors found that, in a group of patients with acute heart failure, FGF23 is sharply elevated in the circulation . In contSince many data and researchers suggest that FGF23 excess negatively impacts the cardiovascular system, it appears a potential treatment modality to reduce the circulating amount or to block the FGF23-target organ interaction. However, there are at least two relevant arguments that pharmacological FGF23 blockade is not as straightforward as one could assume. First, as mentioned above, some (early) rise in FGF23  might have stabilizing effects in the setting of acute myocardial damage. Second, the optimal level and the most appropriate tool of intervention to lower (systemic) FGF23 are unclear.in vivo experiments by Shalhoub et al. The authors showed that pharmacological blockade of FGF23 using a pan-blocking antibody failed to prevent the development of LVH in uraemic rats  blockade emerge from mic rats . Not onlmic rats  but worrmic rats . The autmic rats . These dmic rats . Furthermic rats . AgainstIn summary, the jury is still out on the exact role of FGF23 in the development of cardiovascular abnormalities. The FGF23-klotho axis and pathophysiological cardiac effects are a constantly evolving field. Each players' role  needs to be exactly determined. Facing the massive threat induced by left-ventricular dysfunction to patients with CKD and ESRD and the potential direct and indirect involvement of low klotho, high FGF23 levels, together with other features of CKD-MBD in this setting an urgent roadmap for further research emerges.Prior to any therapeutic intervention with the aimtominimize potentially negative FGF23 effects upon cardiac structure and function, research needs to focus on and clarify relevant unsolved issues. Just to name a few, the community needs to prove how cardiac disease induces (rather than follows) FGF-23 secretion, to what degree cardiomyocytes may themselves produce FGF-23 in health and disease, whether such locally produced FGF-23 has a physiological role in (acute) myocardial damage; and whether or not (systemic) FGF23 excess itself directly drives the development of myocardial damage. Only when these questions have been answered, can we try to discuss whether and how to intervene on serum FGF-23 level.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Living arrangements are critical to intra-family exchanges that affect older persons’ health and well-being. The conventional conceptualization of living arrangements has emphasized coresidence with children, while overlooking proximate residence from children. Additionally, existing research often relied on cross-sectional data which confound intrapersonal differences with interpersonal variations. This study examined the dynamics of living arrangements in old age by depicting their trajectories as a function of social stratification . Data came from the Health and Retirement Study and included a national sample of 7,822 older Americans with at least one living child from 1998 to 2014. Multi-level mixed effects models were employed to analyze the trajectories of living arrangements and their key determinants for the young-old and the old-old separately. Among the young-old , the probability of coresidence increased slightly over time, whereas the probabilities of proximate residence and distant residence decreased slightly and remained stable respectively, and the risk for institutionalization increased moderately. Similar but more accelerated trajectories were observed among the old-old . Age, gender, race/ethnicity, education, income, and asset were significantly associated with not only the levels of the probabilities of various living arrangements but also their slopes. For instance, among the old-old, Hispanics had a lower level of nursing home residence as well as a slower rate of increase in the risk of institutionalization than Whites. These findings may inform public policies to strengthen family-based support and long-term care for older people.


LV LS values were significantly reduced in CM vs CTRL (p < 0.001) and in DCM vs HCM (p < 0.01), with no other differences between the remaining groups. LA peak systolic strain and strain rate values showed a steady and significant decrease with worsening of DD. Receiver Operating Characteristics (ROC) curves showed area under the curve of 0.976 (p < 0.001) for LA strain and 0.946 (p < 0.001) for LA strain rate, to distinguish CTRL from CMs. Conclusions: LA strain and strain rate could be a promising tool to better understand and classify DD in children with cardiomyopathies, opening the way to its clinical use.Background: Left ventricular (LV) diastolic dysfunction (DD) carries worse prognosis in childhood. 2-dimensional (2-D) left atrial (LA) strain accurately categorizes DD in adults but its role in children is unknown. Thus, the aim of this study is to investigate whether LA strain and strain rate could diagnose and classify DD in children with dilated (CMD), hypertrophic (HCM) and restrictive (RCM) cardiomyopathies (CM). Methods and Results: The study includes 136 children (aged 8.8 ± 6 years): 44 with DCM, 40 with HCM, 7 with RCM and 45 healthy controls (CTRL). They underwent standard echocardiographic examination and 2-D speckle-tracking analyses , LA peak systolic strain and strain rate). No significant differences in mitral E/A and pulmonary S/D ratios were observed among the four groups. Although E/E’ and indexed left atrial volumes were found to be significantly higher in HCM, DCM and RCM compared to CTRL ( It is well known that left ventricular (LV) systolic function is associated with reduced outcomes in childhood cardiomyopathy (CM) ,2. Less The evaluation of the LV diastolic function is still a challenge in paediatric patients. Although invasive atrial pressures and LV end-diastolic pressures are commonly employed as indices of ventricular stiffness and compliance, they are both influenced by other confounding factors ,8. FurthEchocardiography still represents the cornerstone for the assessment and follow-up of diastolic dysfunction in children and young patients with CM. However, a recent study  demonstrThe left atrium (LA), via its reservoir, conduit, and booster functions, has a key role in modulating LV filling . Many stRecently, 2-D LA strain has been proposed to accurately categorize diastolic function in adults .Unfortunately, there are very few data about LA strain in young patients with cardiomyopathies  and no dThus, the aim of our study is to investigate the utility of LA myocardial deformation properties to diagnose and classify diastolic dysfunction in children with hypertrophic (HCM), dilated (DCM) and restrictive (RCM) cardiomyopathies, in addition to standard echo Doppler criteria.The study population comprised 136 children  if they had increased wall thickness in any myocardial segment (z score > 2.5) with normal/increased LV ejection fraction (EF) [Children were diagnosed with HCM (ion (EF) ,19. Measn = 44) was diagnosed in patients with LV EF < 50% and LV end-diastolic dimension z score > 2 [DCM  were recruited from the Royal Brompton Hospital Outpatient Clinic. CTRL group encompasses subjects referred for atypical chest pain, otherwise healthy, not on any medication, and with normal cardiac evaluation, EKG, echocardiogram and performed stress echocardiogram .Transthoracic echocardiographic studies were performed by using a commercially available ultrasound system  equipped with adult, paediatric and neonatal transducers , according to the standardized protocol of the Royal Brompton Paediatric Echolab. All data were transferred to a commercially available workstation  and analysed offline. Chamber size and function were assessed according to the latest guidelines . Values All the patients underwent a comprehensive diastolic assessment. Diastolic standard parameters were measured by one expert paediatric cardiologist, according to the latest guidelines in adult patients : mitral Two-dimensional speckle-tracking echocardiographic analyses were performed by a different experienced paediatric cardiologist , using TomTec 2-D .For speckle tracking analysis, we acquired apical four-chamber views images using conventional two-dimensional gray scale echocardiography, during breath hold and with a stable ECG recording. To guarantee optimal tracking, three consecutive heart cycles were obtained at a frame rate of 50–80 frames/second, sinus rhythm and ≤10% variability in heart rate.The LA endocardial border was traced in the apical 4-chamber view, excluding the appendage and pulmonary veins from the LA cavity. Then, LA longitudinal strain and strain rate curves were generated throughout the cardiac cycle. Accuracy of the automated border tracking was verified and manually adjusted if needed. The LA wall longitudinal lengthening, during the LV systole, was measured and used for the analysis (LA peak systolic strain and strain rate) . Longitudinal strain (LS) of the LV was assessed using apical four-chamber view. The peak longitudinal strain values were calculated for each patient as previously described . Diagnostic cardiac catheterization was performed in 8 pts according to clinical indications. Of these, 2 had DCM, 1 HCM, 5 RCM. In only 1 child from the RCM group, cardiac catheterization was requested to be repeated a second time after four months. Cardiac catheterization was performed within 24 h after the echocardiographic study in 8 patients with clinical indication. LV pressure was obtained using a catheter-tipped micromanometer and recorded on a polygraph system, then the LV end-diastolic pressure was calculated.Interobserver variability for myocardial deformation properties was assessed in 15 randomly selected studies and was calculated as the ratio (expressed as a percentage) of the difference between the values obtained by each observer  divided by the mean of the two values and as intraclass correlation coefficients. Intraobserver variability was calculated by a similar approach. Statistical analyses were performed using SPSS version 22.0 statistical package . Distribution of variables was evaluated by visual inspection of frequency histograms and normality was tested using the Shapiro Wilk Test. Continuous variables were presented as mean (standard deviation). Comparisons among groups were performed using analysis of variance (ANOVA). The post hoc Bonferroni correction was used to account for multiple testing. The correlation of variables was calculated by linear regression analyses with determination of the Pearson’s correlation coefficient. p value < 0.01.The ability of atrial strain and strain rate values to discriminate diastolic dysfunction in children with CM was assessed using ROC Curve (Receiver Operating Characteristics Curve) with 95% confidence interval. We used the value of Area Under the Curve (AUC) = 1.0 to characterize the perfect discrimination . In ordeStudy population characteristics are described in 2 versus controls 17 mL/m2). The HCM group had thicker ventricular septum and posterior walls, slightly smaller LV diameters and higher EF. The DCM group presented younger age than the other three groups, higher heart rate and lower LV EF. The RCM group was characterized by normal LVEF and significantly dilated atria , angiotensin-converting enzyme inhibitors , diuretics , and digoxin . Twenty-one HCM (52%) patients were on β-blockers.Thirty-two DCM and five RCM patients were on medication for heart failure, including β-blockers . DT was also significantly higher in the HCM group when compared to the DCM group (p = 0.006). No other significant differences in DT values were observed among the study groups (MV DT significantly decreased in the RCM group (87 msec) compared to the CTRL . A significant impairment in LV LS was observed in the DCM group compared to the HCM group. No other significant differences in LV LS values were noted between the studied groups . Significant and moderate correlations were found between peak systolic LA strain or strain rate and the average E/E’ . Also, a moderate correlation was found between LA strain and peak tricuspid regurgitation gradient , and between LA strain and LAVI .No significant correlations were found between peak systolic LA strain and the E/A ratio  and 0.946 (p < 0.001) for LA peak systolic strain and LA peak systolic strain rate to differentiate normal young individuals from the three groups of juvenile cardiomyopathies  (Receiver-operating characteristic curves showed area under the curve (AUC) values of 0.976  . p < 0.001; LA strain rate AUC = 0.934, p < 0.001)  . We were able to collect a total of nine invasive LV end-diastolic pressures from eight children (mean age 9 ± 7 years). p < 0.001) (p = 0.721), E/E’ avg , MV DT  and LAVi .Univariate regression analysis demonstrated that peak LA strain had a strong significant inverse correlation with invasive LV end-diastolic pressure  . On the Intra- and inter-observer variability expressed as the mean percentage error (absolute difference/mean) and the intraclass correlation coefficients were optimal for LV longitudinal strain  and for LA peak systolic strain , good for LA peak systolic strain rate .The results of this study demonstrate, for the first time, that the assessment of LA strain and strain rate, using 2-D speckle tracking analysis, may be an accurate diagnostic tool for functional evaluation of different cardiomyopathies in children and young patients, with a strong significant correlation with invasive LV end-diastolic pressure. These findings represent a positive change in evidence, because standard echo-Doppler criteria can classify diastolic dysfunction only in a small proportion of CM young patients, even when their disease is severe . Our findings are particularly relevant because of the lack of the availability of reference values for diastolic dysfunction in childhood. Indeed, the sole existing guidelines and recommendations are currently derived from adult studies . In this study, although we analysed a number of traditional echocardiographic and Doppler parameters , we obseDragulescu et al. suggested that E’, DT and LAVi appeared to be the most helpful, among the other conventional echo parameters, in the evaluation of diastolic function in pediatric CM (175 patients age range 0–18) [Moreover, the mean DT, compared to the one observed in healthy children, significantly decreased in RCM, but lost significance between the more severe grades of diastolic dysfunction, i.e., DCM and RCM. In our study, E/E’ was only able to differentiate normal young subjects from those with CM, without the ability to further discriminate through the various CMs in young patients.Of interest, in the subgroup of patients who underwent cardiac catheterization no significant correlation was found between LAVi, E/E’ avg, E’ avg, MV DT and LV end-diastolic pressure.By comparison, LA strain and strain values were able to identify diastolic dysfunction with high accuracy . In addition, atrial strain myocardial deformation properties were significantly different among all the CM groups, differentiating RCM from all the other cardiomyopathy groups. These findings suggest that LA myocardial deformation properties may be a key indicator of LA dysfunction that occurs with the gradual progression of diastolic dysfunction. Our findings are in agreement with Singh A et al. who elegantly demonstrated that the LA strain can categorize the LV diastolic dysfunction in adult patients, because unlike the traditional parameters, it changes progressively and significantly through all the grades and the severity of the diastolic dysfunction . p < 0.001). However, although we found that peak systolic tricuspid regurgitation gradient was significantly higher in HCM and RCM compared to CTRL, there were no significant differences among all the study groups. In this study we observed a significant and moderate correlation between LA strain and peak tricuspid regurgitation gradient (r = −0.571, These findings are in agreement with previous papers suggesting that elevated levels of pulmonary arterial systolic pressure are closely related to elevated LV filling pressures and/or enlargement of LA volumes in adult patients ,28. It is well known that the LA behavior consists of modulating the LV filling through its function of reservoir, conduit and booster pump. The reciprocal relationship existing between the distributions of LA functions is a sort of compensatory mechanism that facilitates the LV filling in patients with myocardial disease . Atrial reservoir phase is fundamental for LV filling, by storing energy during ventricular systole that is released after the mitral valve opening. It has been demonstrated in adults that peak systolic LA strain has a strong inverse correlation with invasively assessed LV filling pressures ,31. In lThis is a single-centre study. The DCM study group encompasses a relatively younger population compared to the other two groups of CM; it is also difficult to determine whether patients of the same group were at the same time point in the disease process. However, this reflects the variety encountered in the real clinical practice. Similarly, since the duration of different heart failure therapies may have an impact on the assessment of diastolic function, we used in our study the first echocardiogram performed at our Institution. It was considered not ethical to stop cardiac medication for the assessment of diastolic function.We could not correlate atrial strain values with invasive LV filling pressures in the whole population, since these were not available, retrospectively, and cardiac catheterization is not routinely performed in these patients. However, we were the first to study the relation between LA strain and LV end-diastolic pressure in children. In addition, we demonstrated that atrial strain and strain rate can accurately stratify diastolic dysfunction as opposed to standard echo Doppler parameters. Finally, the diagnostic accuracy of the cut-off values of LA strain and strain rate proposed in our study should be confirmed in larger prospective studies.Our findings suggest that LA myocardial deformation analysis, by 2-D speckle tracking, is feasible and could be a promising tool to better understand and classify diastolic dysfunction in children and adolescent patients, while conventional echo-Doppler parameters have only a limited ability. Our findings, if confirmed by other studies, may open the way to a novel diagnostic approach for the assessment of diastolic function in the paediatric age range.