The optimal management of chronic severe primary degenerative mitral regurgitation (MR) is to repair the valve but identification of the optimal timing of surgery remains challenging. Current guidelines suggest ‘watchful waiting’ until the onset of symptoms or left ventricular (LV) dysfunction but these have been challenged as promoting ‘rescue surgery’. Better predictors are required to inform decision-making in relation to the necessity and timing of surgery. Chronic volume overload is a stimulus for adverse adaptive LV remodelling. Subclinical reduction in LV strain before mitral repair predicts a fall in LV ejection fraction following surgery and is thought to reflect the development of myocardial fibrosis in response to chronic volume overload. Myocardial fibrosis can be detected non-invasively using cardiac magnetic resonance (CMR) imaging techniques as an expansion of the extracellular volume (ECV).This study investigates whether: 1) patients with above median ECV will have smaller reduction in end-systolic volume index (as a measure of the degree of reverse LV remodelling) on CMR following mitral valve repair, compared to those with below median ECV; and 2) higher ECV on CMR, validated through histology, adversely impacts upon post-operative complications and symptomatic improvement following surgery.This is a multi-centre, prospective, cross-sectional comparison of patients prior to and 9 months following surgery for chronic severe primary degenerative MR. To establish the natural history of ECV in MR, an additional cohort of patients with asymptomatic MR who do not wish to consider early repair will be followed. Investigations include CMR, cardiopulmonary exercise test, stress echocardiography, signal-averaged electrocardiogram, 24-h electrocardiogram monitoring, laboratory tests and patient-reported outcome measures. Patients undergoing surgery will have cardiac biopsies performed at the time of mitral valve repair for histological quantification of fibrosis.This study will advance our understanding of ventricular remodelling in MR, its impact on patient symptoms and ventricular response following surgery. Establishing the link between myocardial fibrosis , with early ventricular dysfunction, will offer physicians a novel non-invasive biomarker that can further inform the timing of surgery.NCT02355418) on 30th November 2015.This trial was registered at ClinicalTrials.gov ( Mitral regurgitation (MR) is the most common form of valvular disease in the USA, affecting 2.5% of the general population and over 10% of those aged 75 years and older .Current AHA/ACC/ESC guidelines recommend expectant management until class 1 indications for surgery are reached, namely development of NYHA II-IV symptoms; LV ejection fraction (LVEF) <60% or LV internal diameter in systole ≥40 mm . UnfortuCareful surveillance with surgery delayed until class 1 indications are met, however, may deliver outcomes that are equally as good as early MV repair. In a study of 132 consecutive patients, a programme of regular 3–12 monthly) review with referral based on Class 1 indications delivered survival rates equivalent to the general population, both in those proceeding with surgery and in those who were managed conservatively; 55 ± 6% avoided surgery altogether at 8 years without compromising their outcome . Since p monthly Whilst patients may possess the same degree of MR for a similar duration, their ventricular function and symptom status may be quite different, suggesting that differential ventricular remodelling may be a potential underlying factor that influences the onset of surgical indications. In contrast to the traditional concept that there is a transition point from ‘compensated’ to ‘decompensated’ chronic primary MR, there is strong evidence that left ventricular (LV) remodelling is progressive from the earliest stages of MR with a reduction in early myocardial velocity and global strain , 16. ThiCharacterising change in myocardial contractility in MR by fall in ejection fraction, increase in linear dimension and volume, or change in strain, whether using echocardiography or CMR, is difficult because all these techniques are volume-dependent. The evolution of CMR T1 mapping techniques offers a completely different approach that is non-invasive, quantitative but is not dependent on chamber size or volume status, since the aim is to identify interstitial myocardial fibrosis as a marker of ‘myocardial stress’ in MR . T1 mappTherefore, this study aims to assess whether left ventricular fibrosis as measured through CMR impacts upon patient outcomes including ventricular recovery following surgery, post-operative complications and symptomatic improvement. The primary endpoint of this study is the reduction in end-systolic volume index on CMR (as a measure of reverse LV remodelling) at 9 months following surgery, comparing those with ECV measured pre-operatively above and below the median. The reduction in left ventricular end-systolic volume index (LVESVi) is a commonly measured outcome parameter for the quantification of reverse left ventricular remodelling in MR . SecondaThis is a multicentre prospective, cross-sectional comparison of patients with primary degenerative MR before and after MV repair. To establish the natural history of ECV in MR, an additional cohort of patients with asymptomatic MR who are not eligible or do not wish to consider early MV repair  will be followed. Study design is illustrated in Fig. The surgical centres participating in the trial will be the University Hospital Birmingham NHS Foundation Trust, University Hospitals Coventry and Warwickshire NHS Trust, and The Royal Wolverhampton NHS Trust.2, slice thickness 7 mm with 3 mm gap, minimum 25 phases per cardiac cycle) in accordance with previously validated methodology [All patients will undergo 1.5 T multiparametric CMR at the University Hospital Birmingham site . Vertical long axis (VLA) and horizontal long axis (HLA) SSFP cine imaging  of the left and right ventricles are performed. These images will be used to pilot the LV short axis stack acquired using serial contiguous short axis cines . Measurements will be made off-line using the contiguous short axis multi-slice acquisition with delineation of atria/ventricles confirmed in matched long axis planes . For venMyocardial deformation will be assessed using 3D feature-tracking on CMR (FT-CMR) using cvi42® . 3D FT-CMR will be performed using smoothed endocardial and epicardial borders in the end-diastolic frame of all short and long axis slices before defining the superior RV insertion points within the LV. Peak systolic strain, early diastolic strain rate and late diastolic strain rate will be recorded in the circumferential, radial and longitudinal directions.For myocardial characterisation, myocardial and blood relaxation times pre- and 15 min after gadolinium contrast administration will be measured offline to calculate T1 times and ECV using cvi42® software as per European Society of Cardiology consensus statement . All T1 Haematocrit for ECV calculation is be measured contemporaneously with the CMR study.2), and carbon dioxide production (VCO2) in expired gas, from which estimates of peak oxygen consumption (peak VO2) and anaerobic threshold (AT) can be obtained using a V-slope method [Patients will undergo cardiopulmonary exercise testing (CPET) on a treadmill using an incremental RAMP protocol based on American Thoracic Society guidelines . A RAMP e method .Transthoracic echocardiography will be performed by experienced echocardiographers accredited through the British Society of Echocardiography (BSE). LV and right ventricular (RV) dimensions, atrial dimensions, systolic and diastolic function will be assessed according to the requirements for the performance of a standard transthoracic echocardiogram according to BSE guidelines . EstimatStress echocardiography will be carried out at the baseline visit according to previously described methods , but in A standard 12 lead electrocardiogram (ECG) will be performed for the assessment of baseline heart rate, rhythm, and QRS morphology, followed by signal-averaged ECG (SA-ECG) for the assessment of ventricular late potentials in those with sinus rhythm. SA-ECG will be performed by averaging 250 beats using a MAC® 5500 system  at a filter setting of 40-250 Hz and aiming for a noise level of <0.3 μV.3-channel 24-h Holter ECG recordings will be carried out using Lifecard CF monitors . Holter data will be independently analysed at University Hospital Birmingham using Pathfinder SL software . Supra-ventricular and ventricular ectopic burden, as well as the type and frequency of arrhythmic events, will be recorded. Time-domain analyses will be recorded from automated measurements of heart rate variability (HRV). Maximum, mean and minimum QT and QTc duration from automated software assisted analyses will be recorded according to previously established methodology .All patients will undergo routine blood tests for full blood count, urea and electrolytes, liver function tests, C reactive protein, N-terminal pro-B natriuretic peptide, and high-sensitivity troponin T  at the baseline and follow-up visits. Blood tests will be carried out at the Clinical Biochemical services at University Hospital Birmingham.At initial visit, serum samples will also be stored for the measurement of collagen turnover markers including the amino terminal of type I and type III procollagen, circulating levels of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 using commercially available ELISA assays.Intraoperative myocardial biopsies (Tru-Cut biopsy needle) will be taken from the LV septum, anterior and posterior LV free wall. Samples will be fixed immediately in 10% buffered formalin, embedded in paraffin, and sections will be stained with Elastic Van Gieson (EHVG) for assessment of myocardial fibrosis. The EHVG stains fibrous tissue pink, elastic tissue purple and the muscle brown. Digital images  of the whole EHVG stained slide at 4× objective magnification (12 per biopsy) will be taken and analysed using Image J software  by a specialist cardiac histopathologist, blinded to the imaging findings. The area of the tissue and the area of fibrosis will be determined by manually drawing around the outline of the tissue, and each area of pink/purple fibrosis using the surface pen on a surface book tablet. Measurements will be given in pixels and the percent fibrosis can be calculated.Subjects will be asked to provide data at entry and at 9 months post-surgery or post-first surveillance using a self-completion questionnaire (SF-36 and Minnesota Living with Heart Failure (MLWHF)) to eliminate any observer bias. The SF-36 has established validity in measurement of functional status in patients undergoing MV repair  but the Patients may withdraw consent from the study at any time. If the withdrawal is initiated by a healthcare professional, full details for the reason for withdrawal is recorded on the case report forms. In all other cases, a simple statement reflecting patient preference is noted.P value of <0.05 will be considered statistically significant without adjustment for multiple testing. Analyses will also be performed according to the following subgroups: severity of MR, degree of ventricular function as measured with above- and below-median global myocardial strain, presence or absence of subjective symptoms, and peak VO2 of ≥80% or <80% on CPET.All analyses will be carried out on an intention to treat basis. For all tests, summary statistics will be reported and 95% confidence intervals will be constructed where appropriate. A 2. A survival advantage has previously been shown with a 7 ml/m2 difference in ESVi from pre- to post-surgery in patients with asymptomatic MR [2 yield a minimum detectable difference of 7 ml/m2 at 80% power, with alpha = 0.05. We therefore plan to recruit 115 subjects allowing for a 15% drop-out rate.Applying in-house pilot data and informed by previous CMR studies , we expematic MR . This chInterventions in this study will be carried out according to the decision of the clinician responsible for the patient and are therefore independent of the study itself. Therefore, there is no formal data monitoring committee.Physicians and patients with asymptomatic severe primary degenerative MR are faced with a significant conundrum. Delaying surgery until the onset of a class I surgical indication is associated with a possible outcome penalty for the patient . Yet it The Mitral FINDER study aims to identify why patients with the same severity of MR can have such wide-range of symptoms before, and difference in ventricular response after surgery. By improving our understanding of ventricular remodelling in MR, and establishing the relationship between myocardial fibrosis and early ventricular dysfunction, this study will offer physicians a novel non-invasive biomarker that can further inform the timing of surgery. Measuring myocardial T1 relaxation offers a quantitative method of assessing ventricular fibrosis in primary MR that is not dependent on chamber volume and is not therefore subject to the limitations of ejection fraction in volume overload. This non-invasively measured imaging biomarker of fibrosis will be validated on myocardial biopsy performed at the time of MV repair. It is central to the hypothesis that patients with more myocardial fibrosis are at risk of sub-clinical myocardial dysfunction, followed by subjective exercise intolerance, that ultimately leads to overt cardiac dysfunction and irreversible myocardial damage that manifests as impaired reverse LV remodelling. We propose that in a population of patients with severe primary degenerative MR, without a class I indication for surgery, the presence of interstitial fibrosis as assessed by higher myocardial T1 / ECV values will identify patients with an increased risk of LV dysfunction after surgery. If this is shown, then there may be a role for routine use of CMR to risk stratify patients who would truly benefit from “early” surgery. It would also provide a rationale for larger clinical trials designed to examine cardiovascular morbidity and mortality end-points, as well as the use of anti-fibrotic treatments such as spironolactone to reverse or delay LV fibrosis in asymptomatic severe MR.


The long-term (5-year) outcome of early  and late  combined  delivery of autologous bone marrow mononuclear cells (BM-MNCs) was evaluated in patients with ejection fractions (EF) between 30–45% post-AMI.Major adverse cardiac and cerebrovascular events (MACCE) and hospitalization were recorded. Left (LV) and right (RV) ventricular function were measured by transthoracic echocardiography. Cardiac magnetic resonance imaging (MRI) and myocardial single photon emission computed tomography was performed in a subgroup of patients. Pre-cell therapy myocardial voltage values of treated areas (assessed by NOGA mapping) were correlated with clinical outcome.Five-year MACCE incidences (7.4%. vs 24.1%) and the composite of all adverse events (11.1% vs 27.6%) were not different between the Early and Late treatment groups. The significant LV-EF increase at 1-year follow-up was preserved at the 5-year control , with no significant changes between 1- and 5-year follow-ups. Similarly, RVEF increased significantly from baseline to the 5-year follow-up . Lower baseline levels of myocardial viability of the treated cardiac area  were associated with incidence of MACCE.NCT01395212).Percutaneous combined delivery of autologous BM-MNCs is feasible and safe after 5 years, and may result in sustained improvement of cardiac function at 5 years in patients with low EF post-AMI (Clinicaltrials.gov  Recent meta-analyses of randomized clinical studies including patients with acute myocardial infarction (AMI) treated with/without intracoronary delivery of autologous bone marrow (BM) mononuclear cells (MNC) introduced debate about the efficacy of this cardiac regenerative treatment mode ,2. HowevMost cardiac regeneration studies report short-term (3–6 month) follow-up results while some mid-term (over 1-year) follow-up studies suggested a possible loss of the initial benefits of cardiac cell-based treatment . Up to nRight ventricular (RV) dysfunction develops in approximately half of patients with MI in the absence of posterior or inferior wall ischemia ,23 and iIn this prospective study, we investigated the 5-year clinical outcome, LV and RV systolic and LV diastolic function, and infarct size in patients included in the MYSTAR study. This is the only trial that used the combined delivery route and investigated the long term effect of percutaneous intramyocardial and intracoronary delivery of BM-MNCs on LV and RV function.This is a single-center, 5-year follow-up study  including patients who participated in the MYSTAR trial at the Medical University of Vienna   [5].The MYSTAR study design, inclusion and exclusion criteria, primary and secondary endpoints, and 1-year results are published elsewhere ,10. BrieThe main inclusion criteria were age >18 years, global LV EF between 30% and 45%, new persistent local wall motion disturbance, no significant coronary artery lesion of more than 50% diameter stenosis, and written informed consent.The main exclusion criteria included previous heart surgery or AMI at the same location, regional wall motion abnormality outside the index AMI area, and severe renal, lung, or liver disease. Patients presenting with severe valve disease, hemoglobin level below 9 mg%, New York Heart Association (NYHA) class IV, or ventricular thrombus were also excluded.6 and 194.8±60.4 x106 BM-MNCs intramyocardially followed by 1.3±0.68 x109 and 1.29±0.41 x109 BM-MNCs intracoronary, respectively [The detailed cell administration protocol was published previously. Briefly, after harvesting of the BM and selecting the MNCs, patients in the Early and Late groups received 200.3±68.7 x10ectively . The locectively .All patients were invited to participate in the 5-year control investigations. The 5-year follow-up study protocol was approved by the Ethik-Kommission der Medizinischen Universität Wien (EK Nr: 291/2011) and written informed consent was obtained from all study participants. The study was conducted according to the Declaration of Helsinki.The patients underwent a series of 5-year follow-up tests including interviews , physical assessment, routine clinical laboratory tests, electrocardiography, and transthoracic echocardiography. Cardiac magnetic resonance imaging (MRI) and 99m-Sestamibi single photon emission computed tomography (SPECT) stress-rest SPECT was performed in a subgroup of patients where applicable.The primary endpoint of the current follow-up study was the occurrence of major adverse cardiac and cerebrovascular events (MACCE) including all-cause death, re-AMI, target vessel revascularization (TVR), and stroke during the 5-year follow-up. Additionally, the incidence of all adverse events  or pacemaker (PM) were listed.The secondary endpoints were improvements in clinical symptoms expressed as CCS and NYHA scores, changes in global LV- and RV-EF measured by echocardiography, size of the infarction determined by stress-rest SPECT, LV and RV volumes, segmental wall motion, and infarct transmurality and cardiac output measured by cardiac MRI.Patients underwent a conventional TTE , with acquisition of the apical chamber view in accordance with the current guidelines . The lefAt the 5-year follow-up, additional tissue Doppler imaging was performed using the apical four-chamber view. The peak early diastolic (e′) velocities were measured in the lateral and septal mitral annulus by calculating the mean values. Tricuspid annular plane systolic excursions (TAPSE) of the baseline, 1-year, and 5-year follow-up images were also measured from the 4-chamber view using M-mode, with the position of the cursor on the lateral tricuspid annulus. Structural abnormalities, such as myocardial calcification, were searched .A 2-day stress/rest (500–700 MBq 99mTc-Sestamibi) SPECT protocol was performed using dipyridamole infusion over 4–6 min (0.57 mg/kg/min by infusion pump) for the pharmacological stress study. The stress tests at inclusion and at follow-ups were performed with identical tracers, exercise loads, and cumulative dipyridamole doses. Infarct size was measured by quantifying the extent of tracer defect.The MRI studies were performed on a 1.5-T, cardiac-dedicated, clinical magnetic resonance system . For the functional studies, 3 standard long-axis slices and a stack of contiguous short-axis slices  were acquired with electrocardiography-gated, steady-state, free-precession cine-images  using a breath-hold technique. The late gadolinium enhancement (LE) images covering the LV were acquired 10 min after intravenous injection of 0.2 mM/kg gadolinium-diethyltriamine-penta-acetic acid  with a segmented inversion recovery sequence and inversion time optimized to null normal myocardial signal (TI between 200 ms and 300 ms). The LE images were acquired at end-systole and in the same position as the functional studies. For quantification of LV and RV function and volumes, the endocardial and epicardial contours were traced manually in end-systole and -diastole with dedicated software. The LV mass was calculated from the total myocardial volume multiplied by the specific gravity of the myocardium (1.05 g/ml). LE was defined as myocardial areas with signal intensity above the average of apparently normal myocardium plus 2 standard deviations using a 17-segment model, and expressed as a percentage of LV. The segmental analysis was carried out using Medviso Segment software in which the AHA 17-segment model was visually aligned and registered to the segmented LV myocardium. The segmental contraction velocity of the LV myocardium at the time point of peak ejection (cm/s) and the segmental infarct transmurality (line-based approach %) was calculated.The myocardial viability expressed as unipolar voltage values (UPV), segmental wall motion  expressed as percentage, and infarct transmurality expressed as bipolar voltage values (BiP) were determined by NOGA endocardial mapping of the injected area ,26.All analyses were performed by an independent observer blinded to the randomization groups and time of the investigations. Continuous parameters are expressed as mean±standard deviation (SD); categorical variables are expressed as percentages. Descriptive statistics were used to describe the primary and secondary endpoints. The incidences of MACCE and all adverse events and continuous parameters were compared between the Early and Late groups; these were analyzed by chi-square and unpaired T-test, respectively. Baseline and follow-up data within the group were compared using ANOVA with repeated measurements supplemented by paired t-test. To analyze the effects of potential prognostic factors on the changes in the infarct size and in global EF at the 5-year follow-up (dependent variables) after excluding possible confounding factors, multivariate linear regression analysis was performed including the following independent variables: age, number of intra-myocardial and intra-coronary injected BM-MNCs, baseline values of UPV, LV EDV, and EF. Diabetes mellitus, male gender, randomization group (early or late) was correlated with MACCE using nominal logistic regression analysis.p <0.05. The statistical analysis was carried out with SPSS® software for the Mac OS 10 operating system.For all tests, two-sided analyses were used and the significance level was set at Baseline characteristics for the entire patient population have been published previously ,11. The Four patients refused the follow-up investigations ; therefore, the 5-year clinical follow-up was available for 56 (93.3%) patients. Five patients died during the 5-year follow-up; thus 51 patients completed the LV functional study.The frequency of adverse events is listed in One patient received PM due to tachycardia-bradycardia syndrome. Four of the 56 patients participating in the 5-year investigation (7.1%) received AICD; 2 with progressive heart failure and malignant arrhythmias and 2 with low EF (baseline ≤35%) and ischemic cardiomyopathy for primary prevention of sudden cardiac death.MACCE occurred in 9 of 56 patients (16.1%). Overall, 12 (21.4%) patients experienced adverse events. Some patients experienced multiple events such as implantation of AICD and TVR; in such cases, the most serious event was graded for the adverse event. The incidence of MACCE and the combined adverse events was not different between the Early and Late groups.p<0.05) while this value between 1-year and 5-year follow-up was 1.9% . The mean increase in LV-EF did not differ between the Early and Late groups, with both groups showing perceived improvement between pre-cell therapy and the 5-year follow-up , while no changes between 1- and 5-year follow-up were seen in either group. However, due to lack of placebo control group, the observed LV and RV functional improvement can not be completely attributed to the cell therapy.The increase in global LV-EF and decrease in infarct size one year after cell therapy was preserved during the 5-year follow-up. In the entire group, the mean increase in LV-EF between pre-BM-MNC therapy and the 5-year follow-up was 5.4%  between baseline and the 1-year follow-up and 6.2%  between baseline and the 5-year follow-up, with no difference between the Early and Late groups .Trends towards decrease in LA and LV end-diastolic diameter were recorded. The mean increase in RV-EF in all patients was 3.2%  was measured at the 1-year follow-up with no further change during the next follow-ups regarding all diastolic function parameters. The peak early diastolic velocity (e`) was 6.1±1.5 cm/s resulting in an E/e`ratio of 13.4±4.9. No difference between groups was detected at the 5-year follow-up.A trend towards an increase in E/A  between pre-BM-MNC therapy and the 5-year follow-up, and 3.8%  between the 1- and 5-year post-BM-MNC therapy , with noNo stress-induced myocardial ischemia was detected during the 5-year investigations.Similar to echocardiography, cardiac MRI showed a preserved improvement in LV-EF at 5 years when compared to baseline values, with a trend towards a decrease in LV end-diastolic and end-systolic volumes and increase in LV cardiac output . RV-EF iMRI with late enhancement revealed a significant decrease in infarct mass , with a Multivariate linear regression analysis did not reveal prognostic factors of improvement in infarct size (measured in a subgroup of patients) or global EF. In contrast with the 3-month follow-up results, no correlation could be found between the number of injected BM-MNC and changes in infarct size in this subgroup of patients after 5 years.p<0.05)  .This is the first prospective 5-year follow-up study of cell-based cardiac therapy delivered by percutaneous intramyocardial BM-MNC delivery followed by intracoronary cell injections. Our study demonstrated preserved global LV-EF, local wall motion abnormality, infarct size, and RV-EF. Trends towards decreased LV end-diastolic and end-systolic volumes, and LV end-diastolic and LA diameter were also shown, suggesting reverse remodeling post-AMI. To the best of our knowledge, this is the first study highlighting improved RV function and the long-term prognostic importance of the NOGA-derived parameter as higher baseline UPV was associated with event-free survival during the 5-year follow-up.Table A in However, considering that the first 3-month follow-up in the Early group showed significantly better LV function when compared with the Late group, who were still on medical treatment 3 months post randomization, and the improvement in LV function and infarct size in the Late group after cell-based therapy, we could assume at least an indirect association between clinical improvement in patients treated with combined delivery of autologous BM-MNCs .The results of a very recent meta-analysis that included trials with intracoronary delivery of BM-MNCs or mixed cell types raised questions about the efficacy of this therapy in patients with recent STEMI ,2. Our pUnfortunately, not all patients could be controlled at the long-term follow-up, and five patients who initially had worse LV and RV function died; these facts might also influence the final results.As the AICD implantation frequency for primary prevention in ischemic cardiomyopathy ranges between 17–31%, and the incidence of malignant arrhythmias was low in our patient population, it is unlikely that the intramyocardial injections of BM-MNC were directly related to malignant cardiac arrhythmias . ConsideWe measured LV and RV function by transthoracic echocardiography as this functional investigation was available for all patients. Due to AICD or other implants, cardiac MRI could only be performed in a smaller group of patients (n = 26), while 31 patients underwent stress-rest SPECT. Recently, it was pointed out that the negative long-term outcome studies  used cardiac MRI to assess cardiac function ,14. In cTo our knowledge, this is the first study demonstrating the improvement of RV function in patients with AMI and treated with cardiac cell-based therapy. The underlying mechanism might be the decreased afterload as a consequence of restoration of LV function, narrowing the gap between LV and RV cardiac output. Additionally, the improvement in the infarct size and local wall motion of the septal part of the anterior (96% of patients in the MRI subgroup) or inferior infarction might influence RV function.A trend towards minor improvements in diastolic dysfunction was recorded 1-year post cell therapy; however, a clinically relevant robust change in diastolic function was not expected in patients with an initial LV-EF between 30% and 45%. However, our data are similar to those of the published diastolic dysfunction in other cell-therapy trials .The decrease in heart failure parameters such as NT-proBNP or NYHA classification is an indicator of improvement in the patients’ clinical status. This might be due to treatment with medication to treat heart failure, with a consequent decrease in WMSC and increase in LVEF. According to the study design, all patients were treated with BM-MNCs; thus, we cannot determine whether the decrease in heart failure parameters can be attributed to the cell therapy.Cardiac MRI in a subgroup of patients showed a significant reduction in the infarct mass from baseline to the 5-year follow-up, with a trend towards decreases in total LV mass, probably due to decreases in LV EDV, suggesting reverse remodeling. Parallel to decreases in infarct transmurality, the segmental contractility improved in 3/17 myocardial segments, supporting the echocardiographic data of the entire patient population. A trend towards decreased infarct size measured by myocardial scintigraphy and decreased infarct mass by cardiac MRI was observed at the 1-year follow-up. The LV EF decreased significantly at both the 1- and 5-year follow-up when measured by both echocardiography and MRI. Since the EF not only depends on the infarct size and mass, but also the geometry of the LV and adverse remodeling, the resting myocardial function expressed as EF is not necessarily directly associated with the morphological size of the infarction.Subanalysis revealed significantly lower baseline UPV values of the intramyocardially injected area in patients experiencing MACCE. Because UPV is an index of myocardial viability, this finding is in accordance with previous statements on the predictability of myocardial viability on mortality measured by SPECT ,30.8) delivered intracoronary were reported to be in association with better long-term outcomes [Higher numbers of cells  administration of autologous BM-MNCs is feasible and safe after 5 years, and may result in sustained improvement of cardiac function at 5 years in patients with low EF post-AMI. Higher initial voltage values in the cell injection area were associated with a lower long-term adverse event rate, which highlights the prognostic value of the myocardial viability factor derived from the electroanatomical mapping.S1 FileTable A in (DOCX)Click here for additional data file.


Our study aimed to demonstrate the short-term impacts of right ventricular apical pacing (RVAP) and right ventricular septal pacing (RVSP) on left ventricular (LV) regional longitudinal strain (RLS) and global longitudinal strain (GLS) in patients with preserved ejection fraction (EF). LV strain and functions may be altered by RVAP. RVSP might be a better alternative. The detrimental effect of right ventricular (RV) pacing may be mediated by regional LV impairment.Sixty-two patients indicated for permanent pacemaker implantation and preserved LV systolic function were included. Dual chamber pacemakers were implanted in all patients. Patients were divided into two groups according to RV lead position: group A  and group B . Patients were examined at baseline and after 6 months of implantation for LV systolic functions, global and regional strain by echocardiography and 2D speckle tracking echocardiography.Paced QRS duration was significantly shorter in group B compared to group A patients (P = 0.02). Regarding ventricular strain, there was no statistically significant difference between both groups at baseline measurements in comparisons of GLS, relative apical longitudinal strain (rALS) and RLS (P > 0.05). In contrast, there was statistically significant difference between both groups in results of GLS (P = 0.01) at 6 months. In addition, RLSs in septal, apical and rALS were affected after 6 months with P values of 0.02, 0.03 and 0.03, respectively.RVAP appears to worsen GLS more than RVSP, and the resultant decrease in apical strain is most correlated region to decrease in GLS. Previous studies have demonstrated that atrioventricular (AV) sequential pacing has better hemodynamic effects over single ventricular pacing. A properly timed atrial systole improves stroke volume through the Frank-Starling mechanism. Higher left ventricular (LV) end-diastolic pressures and volumes, higher systolic and mean blood pressures and lower right atrial and pulmonary capillary wedge pressures have been reported with AV synchronous pacing .The cardiac pacing at any point of the ventricle alters the natural heart activation and contraction pattern, as the stimulus conduction velocity is slower across the ventricular myocardium, when compared to that resulting from the specialized His-Purkinje system , 3. In aThe physiological rationale behind pacing the septum rather than the apex is based on initiating the ventricular depolarization in the right ventricular (RV) septal wall, across the base of the mitral septal papillary muscle, where the first activation vector normally starts , 6.Two-dimensional speckle tracking echocardiography (STE) allows detailed evaluation of left ventricular (LV) mechanics, including LV mechanical dyssynchrony, LV strain, and LV torsion , 8. MyocThe purpose of our study was to compare short-term effects of RVAP and right ventricular septal pacing (RVSP) on LV global longitudinal strain (GLS) and regional longitudinal strain (RLS) in patients with preserved ejection fraction (EF).A total of 62 patients, who were indicated for elective permanent dual chamber pacemaker implantation according to current guidelines (class I), were included from May 2103 to August 2015. Adult patients with age less than 75 years with preserved EF were enrolled in the study after 6 months of implantation if they had more than 60% pacing dependence.Patients were excluded if they had reversible causes for AV block; documented chronic heart dysrhythmias (slow AF); poor echo window; previous coronary artery disease detected by evidence of LV regional wall motion abnormalities at the echocardiogram or pathological Q waves in electrocardiogram, acute coronary syndrome and/or unstable angina; within 3 months of a myocardial infarction, coronary bypass surgery or a valve replacement, complex congenital heart disease, hypertrophic obstructive cardiomyopathy, severe mitral regurgitation, hemodynamically significant aortic stenosis, previous implanted pacemaker or ICD, post-AV junctional ablation; and terminal co-morbidities such as end-stage malignancy, end-stage renal or liver diseases.After signing the written informed consent, patients were divided into two groups according to RV lead position: group A: RVAP (n = 32) and group B: RVSP (n = 30). Appropriate positioning of the electrode was confirmed fluoroscopically at the time of the pacemaker implantation, before the baseline visit. Documentation of lead position was acquired in each patient using three standard projections: anterior-posterior, 40° left anterior oblique (LAO 40°), and 40° right anterior oblique (RAO 40°) views referring to the method described by Mond et al . The LAOPatients were subjected to full history taking with history of the medications and complete general and local examination of the heart, chest and abdomen. The 12-lead ECG was done after programming pacemaker at heart rate of 90 beat/min (at time of doing ECG only) and duration of the QRS complex included the measurement of the time interval between the emission of the pacemaker spike and the end of the QRS complex (milliseconds (ms)).Both groups were examined at baseline and after 6 months by conventional echocardiography and 2D speckle tracking. Calculations of morphometric parameters were done in accordance with the recommendations of American Society of Echocardiography . The bipTwo-dimensional speckle tracking was performed to obtain longitudinal strain (LS) using apical four-, two-chamber, and long-axis views. Three consecutive cardiac cycles of each view were acquired during a breath hold at end-expiration. All the images were obtained at a frame rate of 50 frames to 80 frames per second. Timing of aortic valve closure was assessed looking at the aortic valve motion in the long-axis apical view and guided by ECG. All studies were digitally recorded and transferred to a dedicated workstation for further analysis.Strain values from all segments were averaged to obtain a global longitudinal strain (GLS) value . Also, tRelative apical LS = Average apical LS/t-test. Comparisons within the group were performed using the paired Student’s t-test. A probability value of 0.05 was considered statistically significant. Multiple linear regression analysis was performed to provide regression analysis and analysis of variance for one dependent variable as GLS levels at 6 months to QRS width, pacing percentage and regional strain parameters at baseline.The collected data were tabulated and statistically analyzed using SPSS version 22.0 for Windows . Normal distribution of data was checked by Kolmogorov-Smirnov test. Categorical data were summarized as frequencies and percentages. Comparisons between the groups were performed using the unpaired Student’s There is no significant difference between both groups regarding baseline characteristics and medications as outlined in In our study, there was no statistically significant difference in LVEF, septal and lateral E and S waves by pulsed tissue Doppler in both groups (P > 0.05) as shown in Regarding ventricular strain, our results showed no statistically significant difference between both groups at baseline measurements in comparisons of GLS, rALS and RLS (P > 0.05). In contrast, there was statistically significant difference between both groups in results of GLS (P = 0.01) at 6 months as shown in In addition, RLSs in septal, apical and rALS were affected after 6 months with P values of 0.02, 0.03 and 0.03, respectively as shown in Two-dimensional STE is a feasible echocardiographic technique with an angle independency and high frame rate, which is capable of obtaining any directional strain. According to previous reports, the assessment of global systolic function by speckle tracking-based GLS was superior to the standard variables such as LVEF and wall motion score index for the prediction of outcome in patients undergoing echocardiography with good reproducibility , 17, 18.This study extends our understanding of how different RV pacing sites influence cardiac performance. The RV apex is the traditional site for ventricular pacing due to technical aspects such as the electrode design and the ease of the apical approach .In our results, GLS was preserved in RVS lead than RVA lead position mostly as a result of Purkinje fiber recruitment. Impulse conduction using Purkinje fibers would promote depolarization in a more physiological fashion through the rapid conduction of these specialized muscle fibers. Furthermore, it is proposed that RVS lead pacing may assist inter- and intra-ventricular conduction by recruitment of circumferentially orientated myocardial fibers . In suppMeta-analysis by Shimony et al concluded that non-RVAP generally was not inferior to RVAP and that the longer the study period, at least more than 1 year, the more likely the result would favor non-RVAP. A review of individual studies shows that other sources of variation are also important, including duration of follow-up, lead position, percentage pacing, and baseline LV function .In our study, we included only patients with preserved EF as baseline LV function is another potentially important determinant of the LV response to pacing. In a previous acute pacing study, RVAP in normal LV function produced little in the way of dyssynchrony but as baseline LV function worsened, the amount of dyssynchrony was greater. This would suggest that baseline LV function is important in the response to RV pacing .In contrast to our results, the protect-pace study showed that pacing from either RVA lead or RVS lead position results in a small but statistically significant reduction in overall LV function over a 2-year period, but RVSP does not confer any protective  effect on LV systolic function over RVAP. Thus, there is no current indication to change standard pacing practice with regard to RV lead placement, as this remains a safe and effective treatment for a high-degree AV block . But theWe found that RVAP worsens apical, relative apical and septal regional strain more than RVSP. In our study, the resultant decrease in apical strain is correlated with GLS. This was the same as Makoto et al, who found that septal apical strain was significantly lower in RVA than that in non-RVA at baseline and 2 years. Overall, change in GLS for 2 years was significantly correlated with septal apical strain at 2 years . RVAP leThis phenomenon can be explained by altered cardiac mechanics due to lead position. Myocardial fiber orientation in the LV wall is helix like and LV fibers are in two opposite directions in subepicardium and subendocardium . ContracIt is important to note that measures of regional or segmental function such as myocardial strain may actually reflect “global” systolic function better than the EF. EF can be determined by both myocardial strain and end-diastolic wall thickness . SeveralFrom the above mentioned studies, we can infer why affection of apical strain is strongly correlated to GLS, and late on to affect EF. The recognition of abnormal LV strain patterns may provide longitudinal clues to LV dysfunction in chronically paced patients and potential novel indices of effective CRT interventions to reverse these abnormalities.We could not evaluate other speckle tracking-derived parameters in a circumferential and radial direction. The present analysis focuses on the short-term impact of RVAP on LV functions and does not provide information about the long-term consequences. However, previous studies have demonstrated acute effect of RVAP on GLS , 40. We RVAP appears to worsen GLS more than RVSP, and the resultant decrease in apical strain is most correlated region to decrease in GLS.


Cardiomyopathy is a disease of the heart muscle leading to abnormal structure or function in the absence of coronary artery disease, hypertension, or valvular or congenital heart disease. Currently, cardiomyopathy is the leading diagnosis of heart transplant patients worldwide. Incorporation of next-generation sequencing strategies will likely revolutionize genetic testing in cardiomyopathy. The use of patient-specific pluripotent stem cell-derived cardiomyocytes for disease modeling and therapeutic testing has opened a new avenue for precision medicine in cardiomyopathy. Stem cell therapy, gene therapy, interfering RNA, and small molecules are actively being evaluated in clinical trials. Morphological subtypes include dilated cardiomyopathy, hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular (RV) cardiomyopathy, left ventricular (LV) non-compaction, and restrictive cardiomyopathy. The global number of deaths and disability attributed to cardiomyopathy and myocarditis has steadily increased3. Cardiomyopathy represents the leading cause of cardiac transplantation4. The hereditary nature of most cardiomyopathies creates an opportunity for early detection through family screening but also has the potential for misdiagnosis5. How we classify, detect, and treat cardiomyopathy in 2017 and what is on the horizon are the focus of our review. In addition, infiltrative myocardial disease as an important differential diagnosis will be discussed when appropriate.Cardiomyopathy is a disease of the heart muscle leading to abnormal structure or function in the absence of coronary artery disease, hypertension, or valvular or congenital heart disease6. In that document, the following morphological and functional subtypes were recognized:As stated in the “Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of Cardiomyopathies”, a classification is an attempt to “bridge the gap between ignorance and knowledge”Dilated cardiomyopathy: characterized by ventricular dilatation and impaired contractionHCM: characterized by LV and/or RV hypertrophy, which is usually asymmetric and involves the interventricular septumRestrictive cardiomyopathy: characterized by restrictive filling and reduced diastolic volume of either or both ventricles with normal or near-normal systolic function and wall thicknessArrhythmogenic RV cardiomyopathy: progressive fibro-fatty replacement of RV myocardium, initially with typical regional and later global right and some LV involvement, with relative sparing of the septumUnclassified cardiomyopathies: unclassified cardiomyopathies include a few cases that do not fit readily into any group7. Primary cardiomyopathies are subclassified into genetic, mixed (genetic and non-genetic), and acquired. In 2007, the European Society of Cardiology proposed a new classification in which each morpho-functional subtype was subclassified according to familial/genetic and non-familial/non-genetic forms. The familial/genetic forms were subdivided into unidentified gene defect and specific disease subtype, and the non-familial/non-genetic into idiopathic and specific disease subtype8. “Specific cardiomyopathies” is used to describe cardiomyopathies associated with specific cardiac or systemic disorders. For example, a recent AHA document reviews diagnostic and treatment strategies for specific cardiomyopathies such as cardiac amyloidosis, cardiotoxins, peripartum cardiomyopathy, cardiac sarcoidosis, myocarditis, autoimmune cardiomyopathy, endocrine and metabolic cardiomyopathies, and genetic cardiomyopathies9. Nevertheless, the application of morphological criteria can be misleading because diseases with similar imaging findings can have completely different pathophysiological mechanisms 10.The 2006 American Heart Association (AHA) classification divided cardiomyopathies into primary, which are solely or predominantly confined to heart muscle, and secondary cardiomyopathies, which show pathological myocardial involvement as part of generalized systemic (multi-organ) disorders1. The use of a web-based application facilitates the implementation of this classification system (http://moges.biomeris.com/moges.html) (The MOGE(S) classification of cardiomyopathies proposes a descriptive phenotype and genotype nosology system that incorporates the following five attributes: morpho-functional phenotype, organ(s) involvement, genetic inheritance pattern, etiological annotation including genetic defect or underlying disease/substrate, and functional status of the patient and disease process using both the American College of Cardiology/AHA stage and New York Heart Association functional class. The MOGE(S) nosology system is the most recently proposeds.html) .12. Quartaet al. recently proposed a framework to navigate this uncertainty13. Their major criteria to diagnose cardiomyopathy include “1- Marked morphological abnormalities, clearly outside the limits of physiological remodeling, 2- Clear evidence of global or regional LV (and/or RV) systolic or diastolic dysfunction, or dynamic LV outflow obstruction at rest or on effort, 3- Frequent  and repetitive ventricular ectopic beats, which do not subside or tend to increase with exercise and/or are polymorphic, or runs of sustained or nonsustained ventricular tachycardia, 4- Symptoms such as dyspnea, angina, pre-syncopal or syncopal episodes of non-vasovagal nature , or reduced performance as assessed by cardiorespiratory testing, 5- A positive genetic test — when available and robust — or specific family history of cardiomyopathy and/or juvenile heart failure or sudden death; if unknown or not investigated, judgment should be suspended until relatives have been screened”.Because the presence of a morphological abnormality is not synonymous with cardiomyopathy , and the risk of developing genotype-positive and phenotype-negative cardiomyopathy is unknown, the clinician faces major challenges when evaluating an individual patientEchocardiography is often the first diagnostic modality used when cardiomyopathy is suspected. Although morphological two-dimensional echocardiography and ejection fraction are key elements for phenotype characterization, advanced echocardiographic modalities such as tissue Doppler and strain have made possible the detection of early stages of myocardial dysfunction.15. Machine learning models that incorporate longitudinal strain, among other volumetric and mechanical function variables, may help in the distinction between physiologic and pathologic hypertrophy16. In patients with sarcoidosis but without evidence or history of cardiac involvement, impairment of global LV longitudinal strain was associated with increased risk of cardiac events17. In patients exposed to anthracyclines, a relative percentage reduction in global longitudinal strain of at least 15% early during the course of therapy predicts the development of cardiotoxicity18. Abnormal regional patterns of strain are useful for the identification of specific cardiomyopathies such as apical sparring usually seen in patients with preserved ejection fraction heart failure due to cardiac amyloidosis or apical compromise in patients with apical HCM20. In patients with obstructive HCM refractory to medical therapy who underwent septal myectomy, basal septal (myocardium removed during myectomy) mean systolic strain and diastolic strain rate correlated within vitro measured myocardial contractile performance21. Longitudinal strain and early diastolic strain pre-transplant showed significant correlations with mRNA expression of titin isoforms, sarcoplasmic reticulum Ca2+ ATPase, and phosphorylated phospholamban in dilated cardiomyopathy22.Abnormal tissue Doppler signals may help to identify the presence of HCM in the pre-hypertrophic stage and to differentiate athlete’s heart from HCM23. Also, vortex formation has been correlated with functional capacity in a pilot study24.Vector flow mapping, a novel method of Doppler signal analysis, has shown that the cause of systolic anterior motion of the mitral valve and obstruction in HCM is early systolic ejection flow or isovolumetric vortical flow impacting the posterior aspect of the mitral valve and not Venturi forces related to high flows in the LV outflow tract26. Fractal dimension, a parameter used to quantify myocardial muscle trabecular complexity, is increased in HCM mutation carriers without LV hypertrophy27. LV structural abnormalities in patients with arrhythmogenic RV dysplasia have also been described with increased frequency29.Cardiac magnetic resonance imaging has become an integral part of cardiomyopathy evaluation and risk stratification. Apical–basal bundles and mitral valve abnormalities  have emerged as new phenotypic markers of HCM that are observed also in the pre-hypertrophic stage30. In HCM, for every 10% increase in LGE, there was a 40% increase in SCD events. Of particular importance is that, in patients who were considered to be at low risk of SCD by traditional risk stratification systems, the presence of LGE of at least 15% of the myocardial mass had a five-year risk of SCD of 6%31. In patients with Duchenne muscular dystrophy, the presence of LGE is associated with a progressive decline in LV ejection fraction (LVEF), and the magnitude of this decline is proportional to the number of myocardial segments with LGE32. In patients with cardiac amyloidosis, cardiac magnetic resonance imaging shows a characteristic pattern of global subendocardial LGE; in addition, patients with systemic AL amyloidosis show markedly increased non-contrast T1 relaxation times in the myocardium when compared with healthy controls and patients with aortic stenosis34.The presence, distribution, and burden of macroscopic myocardial scar tissue as measured by late gadolinium enhancement (LGE) are of particular importance. In a meta-analysis of 2,390 patients with various types of dilated cardiomyopathies, LGE was independently associated with higher risk of sudden cardiac death (SCD) and ventricular arrhythmias35. Increased interstitial fibrosis is a marker of subclinical cardiac involvement in patients who are carriers of lamin A/C gene mutation36.Extracellular volume fraction, which includes both diffuse and macroscopic patchy fibrosis using the modified look–locker inversion (MOLLI) recovery method, has been shown to correlate better with regional LV myocardial velocities than ejection fraction in patients with non-ischemic cardiomyopathyin vivo diffusion tensor cardiac magnetic resonance has been shown to characterize the microstructural dynamics by analyzing sheetlet (laminar microstructures 5–10 cardiomyocyte thick) mobility and orientation during the cardiac cycle. Reduced mobility is seen in both dilated cardiomyopathy and HCM. Nevertheless, in HCM, abnormal diastolic conformation is present, whereas abnormal systolic conformation characterizes dilated cardiomyopathy37.Recently,38.The use of four-dimensional (4D) flow (3D + time = 4D) allows the generation of 3D streamlines that permit the analysis of different flow patterns. The application of this technique in patients with HCM, with and without obstruction, revealed abnormal flow patterns in the ascending aorta in both groups. The significance of these findings is unknown39.99mTechnetium phosphate derivatives can bind to transthyretin in the myocardium and can be used to identify wild-type and mutant transthyretin-related amyloidosis. If amyloidosis is suspected and a scan is negative, this favors the diagnosis of light-chain amyloidosis40.Cardiac positron emission tomography evaluates the presence of perfusion and metabolic abnormalities. In cardiac sarcoidosis, the coexistence of myocardial perfusion defects and increased focal metabolic activity, which reflects active disease, is associated with increased risk of death and ventricular tachycardia41.Invasive hemodynamic evaluation is particularly useful to differentiate restriction from constriction. In this case, simultaneous pressure measurements of the right and left ventricles are performed ideally with high-fidelity conductance catheters to evaluate for the presence of enhanced ventricular interaction and systolic area index in the case of constrictive pericarditis. Careful evaluation is necessary to avoid missing the diagnosis of a potentially reversible condition42. The importance of tissue-based diagnosis for accurate prognostication in patients with unexplained cardiomyopathy has been known for a long time43. The procedure is usually performed by using fluoroscopic guidance, with increasing interest in the use of 3D echocardiography to decrease the chances of RV free wall biopsy44. The endomyocardial biopsy sensitivity can reach almost 100% in amyloidosis or approximately 30% in focal diseases such as sarcoidosis46. Usually, RV biopsy is performed, but the biventricular approach has been reported to increase diagnostic yield with a similar major complication rate in very experienced operators47. The performance of voltage mapping to guide endomyocardial biopsy has been described to increase diagnostic yield in patients with focal myocardial diseases such as sarcoidosis or lymphocytic myocarditis48.Transvenous endomyocardial biopsy is an invasive procedure with a reported major complication rate  of less than 1%50. Interestingly, the presence of focal derangement or diffuse lysis of myofilaments observed by electron microscopy in the endomyocardial samples obtained from the posterolateral LV wall of patients with dilated cardiomyopathy admitted with acutely decompensated heart failure was a strong predictor of death or heart failure re-hospitalization during a follow-up period of 4.9 ± 3.9 years51.In myocarditis, the use of immunohistochemistry to characterize inflammatory mechanisms, molecular techniques such as polymerase chain reaction to detect viral genomes, and—more recently—the analysis of non-coding transcripts such as microRNA hold the promise to continue to improve prognostication and treatment in this potentially lethal condition53. In cardiac sarcoidosis, the use of programmed electrical stimulation may assist in SCD risk stratification54. Approximately 30% of patients will fail to respond to cardiac resynchronization therapy, and many causes or associated factors have been identified 55. A novel mechanism to potentially improve cardiac resynchronization response is pacemaker-induced transient asynchrony. Six hours of daily RV pacing halted LV dilatation and myocyte dysfunction in a tachycardia-induced cardiomyopathy model in dogs56. The recognition of a significant premature ventricular contraction burden (>24%) should increase the suspicion of premature ventricular contraction-induced cardiomyopathy; this is important because ablation of the ectopic foci may lead to improvement of cardiac function57.Implantable cardioverter defibrillators are indicated for the prevention of SCD in selected patients with heart failure and reduced ejection fraction and HCM at high risk of sudden death58. The use of electro-anatomical mapping to guide endomyocardial biopsy has been previously described48.Electro-anatomic scar patterns differentiate RV outflow tachycardia from arrhythmogenic RV/dysplasia (ARVD) or cardiomyopathy. In ARVD, dominant sub-tricuspid scars with extensions toward the apex and RV outflow tract (RVOT) are seen where, in RVOT, isolated RVOT scar may be seen59.Most cardiomyopathies are monogenic disorders. Unexplained cardiomyopathy, family history of SCD or cardiomyopathy, and electrocardiogram suggesting an inherited arrhythmia should trigger genetic evaluationhttps://familyhistory.hhs.gov/FHH/html/index.html) if possible. Early consultation with genetics professionals is encouraged. It is important to convey the reason for consultation and potential implications to the patient. In cardiomyopathy, the main roles of genetic testing are to aid in the identification of family members at risk for the condition and to inform screening strategies.The first fundamental step is a family history using a standardized template  and controls (n = 249), respectivelyet al. have reported that patients with HCM who have a mutation affecting the thin filament are at increased risk of developing LV dysfunction, heart failure, and severe diastolic dysfunction when compared with patients with thick filament mutations61. Nevertheless, it is important to recognize that HCM is a disease where gene-phenotype correlations are more notable for their absence than presence.Coppini62. In addition, in a large cohort of patients with ARVD/C who had pathogenic mutations, desmoplakin mutations were overrepresented in patients with SCD/ventricular fibrillation as a presenting symptom63. In the same study, the negative prognostic implications of having more than one pathogenic mutation and male sex were also reported.Studies showing the impact of genotype in prognosis in ARVD/C have been reported. Patients with ARVD/C and carriers of a desmosomal gene mutation have worse outcomes when compared with those with titin mutations64. Pan-cardiomyopathy panels have not been shown to increase the diagnostic sensitivity in HCM65. The decrease in cost and turn-over time of next-generation sequencing strategies, including exome (sequences the genes involved in protein synthesis) and whole genome (sequences both coding and non-coding), has led some institutions to adopt this strategy. From a clinical standpoint, one of the main challenges of non-directed second-generation sequencing is the increase in the identification of variants of unknown significance; this is non-actionable genetic information66. Nevertheless, recent reports combining these techniques with functional studies show encouraging results in detecting new pathogenic mutations67. The creation of large repositories of genetic and phenotypic information, along with powerful analytic techniques, will shape the implementation of next-generation sequencing68.Future applications may include the development of genotype-specific therapies, and pilot studies of pharmacologic therapies in the pre-phenotype phase have been completed (see below). If concomitant congenital malformations are present and a chromosomal disorder is suspected, a chromosomal microarray analysis should be considered. When cardiomyopathy is the main feature and genetic abnormalities at the nucleotide level are suspected, several options are available. Gene panels directed to specific morpho-functional phenotypes that screen for pathogenic mutations are available. Results of genetic testing have five categories: pathogenic, likely pathogenic, variables of unknown significance, likely benign, and benign. The diagnostic yield of these panels is variable and ranges from 50 to 60% in ARVD and from 20 to 30% in dilated cardiomyopathy69.The incorporation of genetic information in epidemiologic studies with long-term follow-up has opened a new chapter in understanding the natural history of disease. Amyloidosis is a systemic disease due to the deposition of misfolded proteins that may affect the heart. There are two main forms of cardiac amyloid disease: AL amyloidosis due to immunoglobulin light chains and transthyretin amyloidosis. Patients with transthyretin may have wild-type  or genetic variants. The V122I variant, where isoleucine is substituted for valine, has a prevalence of approximately 3% in African-Americans and is the most common point mutation associated with hereditary transthyretin amyloidosis. Carriers of this mutation were believed to have an increased risk of death. In a study that included 3,856 African-Americans, 124 carriers were detected, and over a follow-up period of 21.5 years, those patients were at increased risk of heart failure development, but there were no statistically significant differences in mortality70.Other genetic variants include Val30Met  and Thr60Ala (Irish), both of which commonly affect the nerves and the heart. Nevertheless, early cardiac involvement is not as frequent in Val30Met71. In this regard, the development of transcription factor-mediated reprogramming techniques, which allowed the production of human-induced pluripotent stem cells (hiPSCs), represents a major step forward72. Protocols for the production of patient-specific pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are available73. Applications of hiPSC-CMs include disease modeling, regenerative medicine, drug discovery, and toxicity screening74. For hiPSC-CMs that carry a mutation in cardiac transcription, factor TBX20 develops phenotypic characteristics of LV non-compaction cardiomyopathy. In this experiment, abnormal transforming growth factor-beta (TGF-β) signaling was detected. Inhibition of TGF-β signaling and genomic correction of the TBX20 mutation were sufficient to reverse the phenotype75. Using patient-derived hiPSC-CMs, the mechanisms by which titin mutations cause sarcomere insufficiency in dilated cardiomyopathy were explored76. In another exciting experiment, hiPSC-CMs from patients who experience doxorubicin cardiac toxicity were more sensitive toin vitro doxorubicin toxicity than hiPSC-CMs of patients who did not experience doxorubicin toxicity. Several mechanisms were identified, including decreased cell viability, impaired mitochondrial function, metabolic derangements, and increased production of reactive oxygen species77. This finding suggests that hiPSC-CMs could be a potential tool to predict chemotherapy-induced cardiotoxicity.Precision medicine is an emerging approach for disease treatment and prevention that takes into account individual variability  and is of particular relevance for cardiomyopathy78. One of the advantages of detecting genotype-positive phenotype-negative patients is the potential to intervene and alter the trajectory of disease. In a pilot and first-of-its-kind study, 38 patient carriers of pathogenic sarcomere mutations associated with HCM, but without LV hypertrophy, were randomly assigned to diltiazem or placebo. Patients who received diltiazem showed stable LV diameter and mean thickness-to-dimension ratio compared with control patients who showed a decrease and an increase in LV diameter and mean thickness-to-dimension ratio, respectively79.Mutation silencing therapy in a murine model of HCM has shown that irreversible triggers to phenotypic expression occur early in development (<6 weeks of life)81.There has been pre-clinical evidence of the potential benefit of renin-angiotensin axis inhibition in modifying the course of HCM in a randomized controlled trial that included 133 patients with obstructive and non-obstructive cardiomyopathy, but the administration of losartan, though well tolerated, did not show significant difference when compared with placebo with regard to the primary endpoint (change in LV mass as measured by computed tomography or cardiac magnetic resonance imaging)83.The presence of LGE has been used to identify patients with Duchenne and Becker muscular dystrophies who have normal LVEF but who are at higher risk of developing cardiac dysfunction. In this particular patient population, treatment with eplerenone (Duchenne) and angiotensin-converting enzyme inhibitor (Duchenne and Becker) delayed and attenuated adverse cardiac remodeling84. In non-ischemic dilated cardiomyopathy, myocardial blood flow at rest and after cold pressor test improved after 12 weeks of cardiac rehabilitation85.The value of moderate exercise training in selected patients with HCM has been recently evaluated in a pilot randomized trial. After 16 weeks, patients randomly assigned to the unsupervised exercise protocol had a small but significant increase in exercise capacity as measured by cardiopulmonary exercise testing with no significant adverse events86. The intravenous administration of MYK-461 decreased contractility and eliminated systolic anterior motion of the mitral valve, relieving outflow obstruction in a feline model of HCM87. Initial experience in humans shows encouraging results with a dose-dependent reduction of contractility and abolition of LV outflow gradients in two patients. Of note, one patient experienced asystole after receiving the highest dose studied, but it resolved without intervention88.MYK-461, a small molecule which binds to myosin decreasing its ATPase activity in a dose-dependent manner and consequently sarcomere contractility, has been shown to prevent the development of the HCM phenotype in a murine model of HCM if administered early (8–15 weeks of age) in the pre-hypertrophic stage, and it partially reversed structural abnormalities if administered once the hypertrophic phenotype became manifestet al. described that, in a murine model of Noonan syndrome and Noonan syndrome with lentigines, the administration of low-dose dasatinib (tyrosine kinase inhibitor) improves cardiomyocyte contractility, reduces fibrosis, and—if administeredin utero—rescues HCM phenotype89.Noonan syndrome and Noonan syndrome with multiple lentigines (formerly LEOPARD syndrome) as other RASopathies are autosomal dominant disorders caused by germline missense mutations of the Ras/mitogen-activated protein kinase (Ras/MAPK) signaling pathway; one of the phenotypic abnormalities is the development of HCM. A hyper-tyrosil phosphorylated form of protein-zero related (PZR) is present in the hearts of mice with those conditions. YiLMNA gene encodes lamins C and A that are the major constituents of nuclear lamina, a proteinaceous meshwork that gives structural support to the nucleus and enables correct gene expression and DNA repair. Lamins A and C are generated through alternative splicing90. Laminopathies are a diverse group of disorders caused byLMNA gene mutations and the most common one is dilated cardiomyopathy91. Current pathophysiological mechanisms ofLMNA mutations include increased susceptibility to mechanical stress, altered gene expression, and accumulation of pre-lamin A93. The feasibility of alternative splicing modulation with antisense oligonucleotides to increase lamin C and decrease pre-lamin A accumulation has been successfully tested in fibroblasts of patients with Hutchinson-Gilford progeria syndrome and a mouse model94. The recognition of abnormal activation of the MAPK and Akt/mTOR  pathways has led to promising experimental data using protein kinase inhibitors and mTOR inhibitors, respectively, to block the development of cardiac dysfunction in mouse models of laminopathies96.The97.Constitutive activation of mammalian target of rapamycin complex 1 (MTOR-1) by tuberous sclerosis mutations is a recognized mechanism of tumor formation in this syndrome. In a patient with tuberous sclerosis and cardiomyopathy in which phosphorylation of ribosomal protein S6 (marker of MTOR-1 activation) was detected in endomyocardial biopsy, the administration of everolimus (MTOR inhibitor) led to improvement in systolic function and LV dimensions98. Increasing cardiac contractility by targeting molecules related to calcium cycling  or increasing beta-adrenergic system function  and enhancing stem cell tissue repair by increasing the expression of stem cell-derived factor 1 (SDF-1) have undergone clinical trial evaluation99. Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2) that included 250 patients with NYHA (New York Heart Association) functional class II–IV and LVEF of not more than 35% who were randomly assigned to intracoronary infusion of adeno-associated virus loaded with SERCA gene versus placebo failed to achieve the primary endpoint of recurrent events  with a median follow-up of 17.5 months. Nevertheless, the absence of significant adverse events is promising and has helped to enhance the interest in this therapeutic strategy100. A recent phase II trial has shown a significant increase in LVEF in patients who received intracoronary delivery of adenovirus hAC6 when compared with placebo101.Increased understanding of the molecular mechanisms of heart failure have led to the recognition of potential targets for gene therapy102. In a previous article, trans-endocardial injection of allogenic mesenchymal stem cells was superior to auto-mesenchymal stem cells in terms of efficacy  and safety with an extremely low risk of allosensitization103. A phase I clinical trial of transplantation of scaffold-free cell sheets derived from autologous muscle to the epicardial surface through left thoracotomy in patients with severe LV dysfunction due to ischemic (n = 15) or dilated cardiomyopathy (n = 12) has shown promising results regarding safety with no major procedural adverse events and efficacy with improvement in symptoms, 6-minute walk test, and LVEF104.Intravenous allogenic mesenchymal stem cells were shown to be safe and effective in improving the 6-minute walk test and quality-of-life measures in patients with non-ischemic cardiomyopathy with a mean LVEF of 31%. There was no evidence of myocardial scar as measured by LGE in patients on maximal medical therapy70. In light-chain amyloidosis, the use of an amyloid fibril-reactive chimeric monoclonal antibody is undergoing clinical trial evaluation. This approach was shown to be safe in a phase I clinical trial that included six patients with refractory amyloidosis. Those three patients showed organ response: two cardiac and one gastrointestinal105.Novel therapies that block abnormal protein synthesis such as small interfering RNA and antisense oligonucleotides are undergoing phase III clinical trial evaluation in transthyretin amyloidosis, the most common form of cardiac amyloidosis106. Anti- tumor necrosis factor therapy has been shown to be ineffective and even potentially harmful in this patient population in large randomized clinical trials107. Non-specific immunomodulation was also unsuccessful in reducing death from any cause and hospitalization from cardiovascular causes108. There is increasing interest in the manipulation of the innate immune system109. Toll-like receptors, which are the primary receptors of the innate immune system and related molecules , constitute attractive targets that are the subject of intense research111. In addition, the recognition that embryonic-derived macrophages that have anti-inflammatory properties and promote tissue regeneration are replaced in heart failure with monocyte-derived macrophages that have pro-inflammatory properties may open a new pathway to cardiac recovery112.Inflammation is a key player in the development and progression of heart failure113. A novel operative technique that consists of trans-aortic cutting of thickened secondary mitral valve chordae seems to be effective in relieving outflow tract obstruction in patients with HCM and mild septal thickness with the advantage of avoiding additional mitral valve procedures114. This technique is based on the pathophysiological hypothesis that fibrotic and retracted secondary chordae may cause abnormal tethering of the anterior mitral valve and favor the displacement of the “slack portions of the leaflet (and attached primary chordae) into the LV outflow tract”114.In HCM, surgical septal myectomy often resolves mitral regurgitation related to systolic anterior motion of the mitral valve; nevertheless, some patients need additional mitral valve procedures such as mitral valve repair or replacementThe number of patients affected by cardiomyopathies is increasing. Given the strong genetic basis of many cardiomyopathies, a complete family history is mandatory. Judicious use of cardiac imaging is extremely useful in defining the morpho-functional phenotype, informing prognosis, and detecting subclinical disease. Genetic testing is being increasingly incorporated into clinical practice. MOGES classification provides a good framework to facilitate communication and patient classification. The use of patient-specific pluripotent stem cell-derived cardiomyocytes for disease modeling and therapeutic testing is exciting and hopefully will be incorporated into clinical practice in the near future. Gene therapy, small molecules, small interfering RNA, and antisense oligonucleotides are being tested in clinical trials.


Hemodynamic instability and inadequate cardiac performance are common in critically ill children. The clinical assessment of hemodynamic status is reliant upon physical examination supported by the clinical signs such as heart rate, blood pressure, capillary refill time, and measurement of the urine output and serum lactate. Unfortunately, all of these parameters are surrogate markers of cardiovascular well-being and they provide limited direct information regarding the adequacy of blood flow and tissue perfusion. A bedside point-of-care echocardiography can provide real-time hemodynamic information by assessing cardiac function, loading conditions (preload and afterload) and cardiac output. The echocardiography has the ability to provide longitudinal functional assessment in real time, which makes it an ideal tool for monitoring hemodynamic assessment in neonates and children. It is indispensable in the management of patients with shock, pulmonary hypertension, and patent ductus arteriosus. The echocardiography is the gold standard diagnostic tool to assess hemodynamic stability in patients with pericardial effusion, cardiac tamponade, and cardiac abnormalities such as congenital heart defects or valvar disorders. The information from echocardiography can be used to provide targeted treatment in intensive care settings such as need of fluid resuscitation versus inotropic support, choosing appropriate inotrope or vasopressor, and in providing specific interventions such as selective pulmonary vasodilators in pulmonary hypertension. The physiological information gathered from echocardiography may help in making timely, accurate, and appropriate diagnosis and providing specific treatment in sick patients. There is no surprise that use of bedside point-of-care echocardiography is rapidly gaining interest among neonatologists and intensivists, and it is now being used in clinical decision making for patients with hemodynamic instability. Like any other investigation, it has certain limitations and the most important limitation is its intermittent nature. Sometimes acquiring high quality images for precise functional assessment in a ventilated child can be challenging. Therefore, it should be used in conjunction with the existing tools  for hemodynamic assessment while making clinical decisions. The goal of hemodynamic monitoring is to assess the adequacy of perfusion and tissue oxygenation, which primarily depends upon preload, cardiac function, afterload, and adequate perfusion pressure. The physiological information from hemodynamic monitoring allows the clinicians in making early diagnosis and providing specific treatment. The clinical assessment of hemodynamic status is reliant upon monitoring heart rate (HR), capillary refill time, serum lactate, urine output, and often continuous monitoring of blood pressure (BP). These parameters are only surrogate markers of the adequacy of tissue oxygenation and perfusion, and are poorly validated for cardiovascular assessment in children with hemodynamic instability . MoreoveThe echocardiography is increasingly being used for hemodynamic assessment and monitoring in the intensive care units (ICUs), and with the use of bedside echocardiography, it is possible to assess cardiac function, preload, afterload, fluid responsiveness and estimate pulmonary artery pressure (PAP) and cardiac output. Echocardiography is easily available on beside, it is non-invasive and portable, and it can be used to acquire information of physiological changes in real time. This physiological information, in conjunction with clinical assessment, can help in guiding targeted specific therapy –9.The role of functional echocardiography is evolving at a rapid pace, and currently, it is considered a key tool for hemodynamic assessment in the intensive care setting. Recently, published studies have demonstrated significance of the use of echocardiography in management of critically ill patients. The studies have reported that clinical management was changed in 30–60% cases after point-of-care echocardiography, and now it is considered as an indispensable tool in management of shock , 11. TheHence, it is no surprise that there has been a significant increase in the use of bedside echocardiography in the neonatal and pediatric ICUs. Different terms have been used to describe the use of bedside echocardiography in various settings such as neonatologist-performed echocardiography, targeted neonatal echocardiography, functional echocardiography, or point-of-care-ultrasound –9. HowevIn this article, we will review the role of echocardiography in hemodynamic evaluation in neonates and children, and re-visit various echocardiographic parameters which could be helpful specifically in ICU setting. At this point, it is worth emphasizing on using ECG during performing echocardiography, especially while functional assessment.The accurate estimation of preload on echocardiography is one of the most challenging areas. This becomes even more difficult in neonates and young children needing mechanical ventilation, which has a varying effect on loading conditions (filling) and cardiac function. Moreover, changing lung compliance complicates the pressure–volume relationship even further . The assThe left ventricular end-diastolic area and volume are probably best measured by using the Simpson’s biplane method . The latGenerally, right ventricular dimensions are normally smaller than those of the LV in children. The dilatation of right ventricle (RV) may indicate volume overloading of right side of the heart or pulmonary hypertension, and to complicate the matter even further, neonates may have slightly dominant RV soon after birth . Similarly, an enlarged right atrium (RA) with bowing of intra-atrial septum toward the left atrium may indicate elevated right atrial pressure.The triad of a “kissing” small LV cavity, RV size, and a normal or small RA is strongly suggestive of hypovolemia. However, this is relevant only in spontaneously breathing patients and not applicable to children needing mechanical ventilation or abdominal distension.One of the major challenges in the intensive care setting is to recognize how a particular child is going to respond to fluid therapy—who will improve, who would have no response, and who can even deteriorate with a fluid bolus? Apart from “eyeballing” for under-filled heart , the following quantitative methods have been described to assess the fluid responsiveness in children.The variation in VTI at left ventricular outflow tract level or just proximal to aortic valve (AV) level during inspiration and expiration has been reported to predict volume responsiveness. A variation of >15% has been reported to have a high predictive value with a sensitivity and specificity exceeding 90% , 22. ThiThe IVC collapsibility index is calculated by measuring the maximum (Dmax) and minimum IVC diameter (Dmin) from the subcostal view on echocardiography, and a collapsibility of >55% is reported to be predictive of fluid responsiveness , 33:IVCInferior vena cava distensibility index is calculated by measuring the Dmax and Dmin of IVC from the subcostal view Figure , and IVCHowever, one should be mindful that these methods are validated in self-breathing adults. They are difficult to assess in children on mechanical ventilation and their role in assessing fluid responsiveness in children needing mechanical ventilation remain uncertain. In author’s experience, these methods can help in guiding the fluid therapy in emergency situations, especially in the intensive care settings. Clinicians performing echocardiography should know their limitations and results should be interpreted in conjunction with other clinical parameters.The assessment of cardiac function and hemodynamic evaluation in sick children by performing physical examination is unreliable, even when it is performed by an experienced clinician . The stuA comprehensive review of the cardiac function is out of the scope of this article. We will review the common echocardiographic parameters used in assessing cardiac function in children, especially in the intensive care setting.It has been suggested that echocardiographic analysis of LV function should be part of hemodynamic assessment in children with shock, and it should be used in conjunction with clinical parameters and physical examination . Ranjit The qualitative assessment of LV contractility may be quickly performed by “eyeballing” by an experienced clinician from the apical four-chamber view, parasternal long axis view (PLAX), parasternal short axis view (PSAX), or subcostal view , 15. ThiThe common echocardiographic parameters used for quantitative assessment of LV function in children are as follows: fraction shortening (FS), ejection fraction (EF), Doppler pattern of LV filling , and tissue Doppler imaging (TDI). Some of the newer techniques such as speckle tracking, strain rate, and 3-D imaging have been reported to be more accurate in assessing cardiac function. However, these parameters may need longer time and special equipment making them less useful for the clinical practice in the intensive care setting.Fraction shortening and EF can be calculated using M-mode in PLAX or PSAX views Figure  or usingFraction shortening has been shown to correlate well with alterations in ventricular function related to preloading conditions following arterial switch operation .Ejection fraction reflects stroke volume assessed on echocardiography. It can be calculated by using any echo mode, such as 2D, M-mode, and 3-D mode, which can delineate LV endomyocardial lining at end-systole and end-diastole. The recommended method for EF calculation is the Simpson’s or modified Simpson’s method  using apEjection fraction has been studied to assess LV function immediately following cardiopulmonary bypass, and it has correlated well with invasive measures of LV function longitudinally. The clinical utility of EF in pediatrics has been established in multiple studies , 40. TheThe image acquisition for assessment of FS and EF is rapid and easy, and the calculations are simple and easily reproducible making them good bedside echocardiographic parameters for use in emergency situations and in the routine clinical practice . The cliTissue Doppler imaging allows quantitative assessment of regional and global myocardial function by detecting changes in myocardial deformation based on the tissue velocities , 45. DurPulse-wave Doppler interrogation of the myocardium, rather than on blood flow, is performed, and hence, this Doppler study reflects low velocity signals on TDI. A Doppler trace of a small segment of myocardium or atrioventricular valve annulus is obtained. Using PW Doppler, a velocity waveform is generated—spectral above the baseline (s′) shows movement of myocardium during systole while e′ and a′ waves (below the baseline) show diastolic movement of myocardium Figure .Assessing myocardial function using TDI has several benefits in children. This is relatively independent of ventricular geometry and loading conditions. The image acquisition is easy and fast. The results are easily obtained on bedside without using any special software, which makes it an attractive echocardiographic parameter in the ICU setting. However, like all other Doppler techniques, TDI is highly dependent on the angle of insonation and emphasis should be on keeping it minimal by aligning ultrasound beam parallel to the myocardium while imaging acquisition.vice versa  is a common condition affecting infants in the neonatal ICU. The echocardiographic assessment of pulmonary hypertension is one of the most immediate uses of bedside functional echocardiography in the intensive care setting, and it helps in providing targeted specific therapy and monitoring response to such intervention. Due to the ventricular interdependence, impaired RV function may lead to LV dysfunction Figure  and vicece versa , 49. Thece versa , 51. Thece versa .The shape of the RV makes RV function assessment more challenging, even in the expert hands. Recently, there has been a great interest in assessing RV function in sick children. Similar to LV function assessment, RV function can be quickly assessed from its size, wall thickness, and contractility by “eyeballing” . Apical four-chamber view provides good overview of RV contractility, assessment of RV and RA size, and presence of tricuspid regurgitation (TR). However, it should be examined in multiple views PLAX, PSAX, and sub-costal views to further assess interventricular septal movements, RV wall thickness, and RV dimensions. Direct measurement of RV size is not recommended due to its complex geometry and the presence of trabeculations within the RV cavity. Traditionally RV systolic function was assessed qualitatively only. However, newer techniques such as TDI and tricuspid annular plane systolic excursion (TAPSE) can be used to assess RV function reliably in children, even in the intensive care setting , 42, 53.Comprehensive guidelines for the echocardiographic assessment of the right heart are given in a recent report of the American Society of Echocardiography . SimilarThe pulmonary artery systolic pressure (PASP) can be reliably estimated using echocardiography in the presence of TR. Using the continuous-wave (CW) Doppler, the pressure gradient between RV and RA is calculated by using modified Bernoulli’s principle , 55–58. The mean PAP can be estimated by measuring the pulmonary regurgitant velocity at the start of pulmonary regurgitation when present.The presence of ductal and/or atrial shunt can provide a quick guide whether PA pressure is higher than systemic pressure, equal, or lower. The visual inspection on color flow Doppler or PW/CW Doppler can help in assessing the direction of blood flow. The right to left ductal shunt suggests a supra-systemic PAP, while bi-directional shunt suggests that PAP is equal to systemic artery pressure. A left to right shunt is reflective of PAP lower than systemic pressure. In PPHN, atrial shunt [across persistent foramen ovale (PFO)/atrial septal defect (ASD)] is often bi-directional. In presence of a pure right to left shunt, total anomalous pulmonary venous drainage should be excluded until proven otherwise.This is best assessed by using PSAX sweep views. Normally, LV is seen as a circular structure in PSAX view because LV pressure is much higher than the RV pressure. In presence of pulmonary hypertension, there may be flattening of IVS, making LV a D-shaped structure. The severity of flattening or reversal of IVS reflects severity of pulmonary hypertension as shown in Figure Normally, LV size is bigger than RV in children and adults. RV/LV ratio of more than 1 suggests pulmonary hypertension, and it is best calculated in the PSAX view on 2D mode , 42.Tricuspid annular plane systolic excursion reflects systolic displacement of the tricuspid annulus toward the RV apex along the longitudinal axis, and it closely correlates with RV EF. TAPSE is usually acquired by placing the M-mode cursor through the lateral tricuspid annulus and measuring the amount of longitudinal motion of the annulus in peak systole Figure . There iA quick visual inspection of pulmonary artery Doppler spectral showing “dicrotic notch” may suggest presence of pulmonary hypertension. However, this is a qualitative test with low sensitivity and specificity, and it may not be seen even in severe pulmonary hypertension. The PAAT can be easily calculated from PW spectral of pulmonary artery Figure  and PAATThe echocardiographic assessment of blood flow across any “vessel or outflow tract” can be performed by multiplying the cross-sectional area (CSA) of the vessel by the VTI of blood flow across specific point where CSA and HR are calculated, and applying these values in the equation below , 64:BloThis principle can be applied to calculate the blood flow across any blood vessel or outflow tract. It is being applied in the clinical practice to estimate left ventricular output (LVO), right ventricular output (RVO), and superior vena flow in children. Blood flow and cardiac output are not interchangeable.The systemic blood flow equals LVO in the absence of cardiac shunts. The CSA is calculated by measuring the diameter at the hinge point of AV annulus at end-systole in the PLAX, and VTI is measured just proximal to the AV valve by using PW Doppler in the apical five-chamber view Figure . HR is cDespite various assumptions and limitations (discussed below), the assessment of LVO on echocardiography correlate strongly with the measurements acquired by other well-established techniques such as pressure measurement by cardiac catheter and Fick’s dye dilution method. The published studies showed a bias under 10%. In a recently published study, left ventricular cardiac output estimate on echocardiography correlated strongly with the results from phase contrast MRI, which is very reassuring , 65.The RV output equals to systemic venous return in the absence of cardiac shunts. RV output can be easily assessed on echocardiography. The CSA is calculated by measuring diameter at the hinge point of pulmonary valve (PV) annulus at end-systole in the parasternal long axis sweep view (PLAX) or PSAX, and VTI is measured just proximal to the PV by using PW Doppler in the same views Figure . HR is c(1)LVO and RVO assessment is contaminated by presence of shunts , which are quite common in neonates and in children with congenital heart defects. In the presence of patent ductus arteriosus (PDA), left ventricular output reflects systemic blood flow plus the amount of ductal shunt. Similarly, in the presence of PFO or ASD, RVO reflects the systemic blood flow plus atrial shunt volume. The presence of other septal defects such as ventricular septal defect or ASD will result in further over-estimation of LVO or RVO;(2)Measurement of CSA is prone to mistakes, especially in neonates and young children. As CSA is calculated by squaring the diameter, any error in measurement is multiplied;(3)Measurement of VTI/stroke distance is also prone to errors. The angle of insonation, angle between the Doppler cursor and the blood flow, should be minimal. If the angle of insonation is >5–10%, it would under-estimate the cardiac output. Moreover, calculation of VTI needs manual tracing of PW Doppler spectral which also carries the risk of error in measurement; and(4)Intra-observer variability on the echocardiographic assessment of blood flow is quite high. The published studies have reported an intra-observer variability of 12 and 22% for RVO and LVO assessments, respectively , 67. TheThe measurement of LVO and RVO using echocardiography has the following limitations:The echocardiographer should be aware of these limitations and precautions should be taken to minimize such errors.Despite the limitations discussed above, assessment of left and RVO is reliable in children without shunts, and even in neonates, it is fairly reliable in expert hands. The authors find the trend on serial echocardiography more useful than the absolute value in clinical practice—CSA for any patient does not change and HR can be calculated precisely at any time. Hence, serial assessment of VTI may help in studying the impact of any intervention on cardiac output in real time.Superior vena cava flow can be assessed on echocardiography using an approach similar to RVO and LVO measurements. SVC flow has been proposed as a surrogate measure of cerebral blood flow, and it has been associated with short-term and long-term outcomes in neonates , 69. No For the measurement of SVC flow, CSA is calculated by measuring SVC diameter in modified PSAX view at the level of right pulmonary artery, and VTI is measured just proximal to its connection to RA by using PW Doppler in the sub-costal or right suprasternal view Figure . The SVCThe reference values for SVC flow in term and preterm infants have been published with considerable variations –26. GiveEchocardiography remains the investigation of choice for diagnosing congenital heart effects in children. Traditionally used clinical parameters  are surrogate markers of cardiovascular well-being. Functional echocardiography has the ability to provide direct evaluation of hemodynamic status in children. Bedside echocardiography is easily available. It is safe and non-invasive, which makes it an attractive tool for hemodynamic assessment in the intensive care setting.The point-of-care echocardiography is now increasingly being used to assess cardiac function, fluid responsiveness, estimate PAP in pulmonary hypertension, provide specific intervention and monitor response to treatment, and choose inotropes or vasopressors based upon echocardiographic findings. Bedside echocardiography should be considered as an extension of physical examination, and it should be used in conjunction with the existing clinical parameters in making clinical decisions. The physiological information acquired by echocardiography may help the intensivists in making a timely, accurate, and appropriate diagnosis. However, clinicians should know the limitations of these parameters needing high-quality images for accurate measurement, which can be a challenge in the intensive care setting even in the expert hands. There is an urgent need of a structured training program for the intensivists to learn echocardiography skills, which can be used safely and effectively in the intensive care setting.The author confirms being the sole contributor of this work and approved it for publication.The 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.