In the neonatal and pediatric intensive care setting, bedside cardiac ultrasound is often used to assess ventricular dimensions and function. Depending upon the underlying disease process, it is necessary to be able to evaluate the systolic and diastolic function of left and or right ventricles. The systolic function of left ventricle is mostly assessed qualitatively on visual inspection “eye-balling” and quantitatively by measuring circumferential fraction shortening or calculating the ejection fraction by Simpson’s planimetry. The assessment of left ventricular diastolic function relies essentially on the mitral valve and pulmonary venous Doppler tracings or tissue Doppler evaluation. The right ventricular particular shape and anatomical position does not permit to use the same parameters for measuring systolic function as is used for the LV. Tricuspid annular plane systolic excursion (TAPSE) and S′ velocity on tissue Doppler imaging are more often used for quantitative assessment of right ventricle systolic function. Several parameters proposed to assess right ventricle systolic function such as fractional area change, 3D echocardiography, speckle tracking, and strain rate are being researched and normal values for children are being established. Diastolic function of right ventricle is evaluated by tricuspid valve and hepatic venous Doppler tracings or on tissue Doppler evaluation. The normal values for children are pretty similar to adults while normal values for the neonates, especially preterm infants, may differ significantly from adult population. The normal values for most of the parameters used to assess cardiac function in term neonates and children have now been established. Cardiovascular instability is very common in sick neonates and children needing intensive care treatment , 2. ManyIn the last decade, there has been a great interest among the neonatologists and pediatric intensivists in using bedside cardiac ultrasound. In fact, now it is being used in most of the neonatal and pediatric intensive care units in the Western world. There is no structured training program specifically designed to train the neonatologists or intensivists in bedside point-of-care echocardiography , 7.Z scores (http://parameterz.blogspot.nl/or cardio-Z app) for precise accuracy for the individual patient.With advancement in technology, echocardiographic evaluation of cardiac function is changing rapidly and new promising techniques are being researched. This review article provides an overview of the basics for ventricular function assessment on echocardiography which can be applied by the neonatologists and pediatric intensivists in their clinical practice. A detailed description of the advanced techniques to assess cardiac function which may be difficult to use on bedside echocardiography in the intensive care setting is beyond the scope of this article. The reference range and normal values have been provided, where possible, as certain values on echocardiography depend on the age, weight and height of the child. We recommend using Measurement of cardiac dimensions is essential in the evaluation of ventricular function in newborns and children. The size of cardiac chambers and great vessels increase progressively with growth—reaching half of the adult size at birth, 75% of the adult size by 5 years, and 90% of the adult size by 12 years of age .Ventricular size can be measured by M-mode and as a standard it is measured using the leading-edge to leading-edge technique. The left ventricular M-mode tracing is obtained from the parasternal long-axis (PLAX) or parasternal short-axis (PSAX) view Figure . The curZ scores , ejection fraction (EF) and assessment of cardiac output (CO). Various methods can be utilized to get these data.Qualitative assessment on visual inspection “eyeballing” may be done by an experienced non-echocardiographer to evaluate left ventricle function . MultiplThe most commonly used parameters to assess left ventricular systolic function are FS and EF. The FS is obtained from M-mode tracings Figure  or 2D imNormal values for FS in infants and children have been established and are typically between 28 and 46% –17. LeftThe left ventricular function can also be assessed by calculation of the EF, which is a volumetric appraisal of ventricular fiber shortening. The best method to calculate EF is the biplane measurement of left ventricular volumes from the apical four-chamber and two-chamber views Figure . The lefNormal values for EF in children are between 56 and 78%. There are certain limitations to this method: especially the assumption of LV being cylindrical in shape, substantial intraobserver and interobserver variability, risk of left ventricular foreshortening, and insufficient image quality for accurate endocardial tracing , 18, 19.The image quality in children on mechanical ventilator is often sub-optimal for accurate assessment of cardiac function. In these situations, alternative echocardiographic parameters may be considered to evaluate LV function.In presence of mitral regurgitation (MR), the rate of pressure rise in early systole (dP/dt max) may be used to evaluate global left ventricular contractility. MR jet velocity depends on the pressure gradient between the LV and left atrium. As there is no significant change in left atrial pressure during isovolumetric contraction (IVCT), MR dP/dt reflects left ventricular pressure changes. Using continuous wave Doppler MR spectral is acquired to calculate dP/dt: it represents time duration between change of velocity from 1 to 3 m/s on the MR spectral. The normal value of MR dP/dt is ≥1,000–1,200 mmHg/s and a value of <500 mmHg/s is indicative of severe systolic dysfunction Figure . There aTissue Doppler imaging allows evaluation of myocardial velocities. Peak systolic annular velocity (S′ wave) measured at the level of the mitral annulus reflects left ventricular contractility Figure . S′ valuThe measurement of myocardial performance index or Tei index allows evaluation of both systolic and diastolic function simultaneously . The myowhere IVRT is isovolumetric relaxation time, IVCT is isovolumetric contraction time, and ET is the ejection time of LV.The Tei index value depends upon the age of child, especially during the first 3 years of life, with significantly greater values (0.4 ± 0.09) at birth and progressive reduction until the age of 3 years . There aIn the last decade, more emphasis has been on the assessment of diastolic function especially in the postoperative period in the intensive care unit. Evaluation of left ventricular diastolic function is complex and a combination of different echocardiographic markers may be used Table , and a dOn bedside echocardiography, diastolic function can be quickly assessed by using Doppler method and studying the changes in spectral. For example, prominent pulmonary venous A wave is a marker for flow reversal into the pulmonary veins during atrial systole, and it is a hallmark of diastolic dysfunction in a non-compliant ventricle Figure . The mitE/A ratio, velocity, and deceleration time of the E wave can be altered in patients with left ventricular diastolic dysfunction  Doppler across mitral inflow is composed of two waves: an E wave representing early passive ventricular filling (preload dependent) and an A wave representing late diastolic active filling as a result of atrial contraction. The mitral function , 12. Simfunction , 12.E/A ratio >2, deceleration time of the Doppler mitral E wave <160 ms, and diastolic flow predominance in the pulmonary venous Doppler pattern (S/D < 1) with prominent atrial wave reversal (AR ≥35 cm/s)  .The diastolic function of ventricles can also be assessed using TDI, which allows measuring peak myocardial velocities using PW Doppler. With this technique, myocardial movement velocity is measured directly rather than the Doppler velocity of blood flow across valves. Depending upon the area of interest, a pulsed Doppler cursor is placed on the myocardial wall  and peak myocardial velocities are recorded. Three waveforms are obtained: a peak systolic wave (S′), an early diastolic wave (E′), and an end-diastolic wave (A′) produced by atrial contraction Figure  22). Th. Th22). Tissue Doppler imaging signs of diastolic dysfunction are an early mitral annular or septal E′ wave velocity <8 cm/s. The E/E′ ratio  has been shown to correlate with the pulmonary capillary wedge pressure in adults . The E/EThe echocardiographic assessment of the right ventricle is more difficult because of its anterior position behind the sternum and to its complex geometrical shape . The RV Qualitative evaluation of the right ventricle  has long prevailed in the regular clinical setting. Besides being echocardiographer dependent, it is imprecise and often insufficient. An approximate assessment of the RV size can be made by comparing it to the left ventricular (LV) size, and this can be categorized into the following: normal size (RV less than 2/3 of the LV size), mildly enlarged (RV more than 2/3 of the LV), moderately enlarged (RV and LV are of same size), and greatly enlarged when RV is bigger than the LV , 30.Right ventricular function can also be evaluated qualitatively. The best view to RV function is PSAX sweep at the level of the papillary muscle to look at the RV free wall and the septal motion. With volume overload, the RV will become dilated and the septum flattened in diastole, while pressure overload results in septal flattening in systole . The difThe dimensions of the RV can be measured in the apical four-chamber view and the RV free wall thickness in best measured in the PSAX view. Like LV, the end-diastolic and end-systolic area of RV can be measured by manually tracing the endocardial border in systole and diastole. The papillary muscle and the trabeculae should be included in the cavity. The RV volume is probably best measured on 3D echocardiography. The volume estimation using 2D technique is sub-optimal because of its complex geometry and anatomical position . As the Another technique often used to assess RV function is TAPSE, which measures the excursion of the tricuspid annulus during the cardiac cycle (between early diastole and end systole). TAPSE is measured by placing an M-mode cursor through the lateral tricuspid annulus in a four-chamber view Figure . This inAs for the LV, TDI can be used to obtain a qualitative evaluation of the RV systolic function. TDI assessment is best done in the apical four-chamber view by using PW Doppler on the lateral free wall and by measuring the systolic S′ wave . An S′ wRecently fractional area change has been suggested a reliable echocardiographic marker of RV function and this is calculated using the following formula:where RVEDA is right ventricle end-diastolic area and RVESA is RV end-systolic area Figure . Normal Like for the LV, the MPI or Tei index is calculated by PW Doppler at the level of tricuspid and pulmonary valves or on TDI tracing at the lateral tricuspid annulus, with normal values of 0.24 ± 0.04 irrespective of age , 37.More advanced techniques to evaluate RV function comprise 3D echocardiography and speckle tracking, a detailed description of these techniques is beyond the scope of this review.E/A ratio <0.8 , and a ratio of tricuspid Doppler and TDI tricuspid annular annulus E/E′ >6  of the left or RV outflow tract at the level of aortic or pulmonary annulus and by measuring the velocity time integral (VTI) at the level of aortic or pulmonary valve by pulsed wave Doppler, respectively Figure . The CO where SV is the stroke volume, VTI is the velocity time integral, CSA is the cross-sectional area, and HR is the heart rate. The cardiac index can be derived by dividing the CO by the body weight in kilogram according to the equation below :Cardiacwhere BSA represents the body surface area. The measurement of CO by this method is a simplistic method and involves various assumptions. Despite various limitations, the CO measured using echocardiography correlated well with other well-established methods such as cardiac MRI, cardiac catheter, and Fick’s dye dilution method. The published studies showed a bias under 10% .The measurement of CO on echocardiography is pretty reliable in children without shunts, and in fact, it is fairly reliable even in neonates . The norWith advances in technology, new echocardiographic techniques are being researched to assess cardiac function in neonates and children. The normal values for adults and children have been established, and initial studies have demonstrated them to be feasible in well-term neonates , 12. WhiTwo promising advanced echocardiographic techniques are on the horizons and may become available to assess cardiac function accurately in the near future.In the recent years, myocardial mechanics have emerged as a promising tool to measure myocardial function and contractility. Strain (ε) is defined as the deformation of the myocardium relative to its original length. It is a dimensionless parameter and is expressed as a percentage. SR is defined as the local rate of myocardial deformation or strain (ε) per unit of time, and it is expressed in 1/s. Both strain and SR can be obtained from tissue speckle tracking or from TDI. The strain and SR assessment does not depend upon the ventricular geometry and loading conditions of the ventricles. The evaluation of ventricular function is limited with conventional M-mode and 2D echocardiography due to the limitation of the ventricular geometry; as it is the case with the complex morphology of the right ventricle, the altered morphology of the LV in complex congenital heart disease and the changing loading conditions that occur in the critical care settings, strain and SR may be of great help for more accurate and reliable evaluation of ventricular function . The norLeft ventricular volume, mass, and function with calculation of EF can be accurately assessed using real-time 3D (RT3D) echocardiography and is independent of geometric assumption. Acquiring the entire left ventricular volume often necessitates a wide angle mode. The analysis on 3D echocardiography allows determination of global and regional wall motion when evaluated from the base to the apex with multiple slices from different orientations. Left ventricular volume assessment by RT3D is rapid, accurate, reproducible, and superior to conventional 2D methods . RT3D alAssessing cardiac function is of utmost importance in critically ill neonates and children with cardiovascular instability. Bedside echocardiography may provide anatomical and physiological information in real-time helping to make clinical decisions in patients with various pathologies including: diagnosis of underlying congenital heart defect, diagnosis and management of pulmonary hypertension, shock, hypotension, hypovolemia, and perinatal asphyxia to name a few , 5. FuncFrontiers in Pediatrics; such as echocardiographic evaluation of patent ductus arteriosus, echocardiographic evaluation of hemodynamics, and echocardiographic evaluation of pulmonary hypertension, readers are advised to refer to the relevant TINEC research articles published under the same theme in Frontiers in Pediatrics Like any other functional assessment, use of ECG tracing during imaging acquisition is recommended for the accurate assessment of ventricular function.(b)High-quality images should be obtained for the precise measurement of cardiac function. Any error in measurement is often multiplied in calculating algorithms. One should be aware of old saying—“garbage in, garbage out,” and this is very relevant for the imaging acquisition required for accurate functional assessment.(c)In emergency situations, qualitative assessment on visual inspection may be used; however, there is subjectivity in interpretation.(d)It is critical to understand the cardiac mechanics which can affect ventricular function assessment. For example, fraction shortening may not be reliably calculated in presence of paradoxical septal movements or in presence of significant right ventricle dysfunction because of ventricular interdependence.(e)The clinician performing the scan should know the limitations of the echocardiographic parameters and their interpretation. For instance, impact of the angle of insonation on Doppler assessment and influence of loading conditions on the echocardiographic parameter being analyzed.(f)Use multiple echocardiographic views while assessing ventricular function.(g)The advanced echocardiographic techniques look promising, but in today’s clinical practice, there are limitations for their application in the intensive care setting.(h)Finally but most importantly, echocardiographic assessment is only an adjunct to clinical examination and other monitoring parameters. The results from functional assessment should always be interpreted in conjunction with the clinical picture.A summary of the practical practice points for the neonatologists and pediatric intensivists in assessing ventricular functions is discussed below:Evaluation of cardiac function requires good image quality and multiples parameters in order to deliver accurate and reliable information. The evaluation of cardiac function can be easily performed by bedside cardiac ultrasound in the intensive care setting and physiological information gained may help in taking timely and accurate therapeutic decisions. Longitudinal assessment of cardiac function on serial bedside cardiac ultrasound may help in monitoring the patient condition and targeting the specific treatment.While the echocardiographic assessment of left ventricular function is well established, the complex geometry of the right ventricle and ventricular interdependence make its assessment more difficult. Recently, there has been a great interest in assessing RV function using advanced techniques such as TDI, speckle tracking echocardiography, and 3D echocardiography, and the initial results from the research studies look promising.CT is a pediatric cardiologist trained at the University Hospital of Geneva, Switzerland and in Denver, CO, USA. CT has been working as an attending pediatric cardiologist at the Children’s Hospital of Geneva (HUG) until recently and is now working in the Pediatric Center at Clinique des Grangettes, Switzerland. YS is a consultant in neonatology and pediatric cardiology at Addenbrooke’s Hospital in Cambridge, UK, and he is a course director for echocardiography in Cambridge. YS has special interest in functional echocardiography and hemodynamic assessment in children. NS is a pediatric cardiologist trained at the University Hospital of Lausanne and in Washington University, Saint-Louis, USA. NS is working as the chief of the Pediatric Cardiology unit at the Centre Hospitalier Universitaire Vaudois (CHUV). CT, NS, and YS are part of the organizing committee of the Training in Intensive Care and Neonatal Echocardiography (TINEC), a course on point-of-care echocardiography that is taking place in Lausanne, Switzerland, since January 2016.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer EM and handling Editor declared their shared affiliation.


The patient is a 73-year-old male, born in the municipality of Jacupiranga, SP, andcoming from São Paulo city, SP, complaining of 30-kg weight loss in the previous4 months and worsening of his general state of health in the previous 24 hours.He reported having coronary artery disease, with two episodes of infarction and onecoronary angioplasty with stent implantation 8 years before. He had been diagnosed withischemic cardiomyopathy and ejection fraction of 22%.He was using spironolactone, losartan, carvedilol, furosemide and propatylnitrate.His physical examination  showed emaciation, dehydration, heart rate of80 bpm, inaudible blood pressure, increased jugular venous pressure, lungs withinspiratory wheezes, regular heart rhythm and no heart murmur on cardiac auscultation,liver palpable 3 cm from the right costal margin, and mild edema of the lower limbs. Thepatient received 1500 mL of 0.9% saline solution, which increased his blood pressure to90/70 mm Hg.3; leukocytes, 7850/mm3; urea, 122 mg/dL;creatinine, 2.2 mg/dL; potassium, 6.5 mEq/L; sodium, 143 mE/L. His arterial blood gasanalysis was as follows: pH, 7.3; bicarbonate, 16 mEq/L; and base excess, (-)7mEq/L.The results of his laboratory tests  were as follows: hemoglobin, 17.2g/dL; platelets, 99000/mmHis electrocardiogram  showed sHe was admitted to the Hospital Auxiliar de Cotoxó to compensate his heart failureand acute renal failure.The patient progressed with oliguria, dyspnea, and, on the third day of admission, he hadsudden lowering of consciousness, fever and respiratory failure, requiring endotrachealintubation.3; sodium, 139 mEq/L; potassium, 3.7 mEq/L; urea, 170mg/dL; creatinine, 2.2 mg/dL; leukocyturia, 10000/mL; and hematuria, 280000/mL.His previous laboratory tests on that same day were as follows: hemoglobin, 14.5 g/dL;leukocytes, 8500/mmDuring that episode, the findings were as follows: heart rate, 75 bpm; blood pressure,100/60 mm Hg; temperature, 37.8ºC; arterial saturation, 97%; and crepitant ralesat pulmonary bases. His heart rhythm was regular, with neither murmur nor accessoryheart sound. His capillary glycemia was 166 mg/dL.The patient was referred to the emergency unit of Incor. Pulmonary aspiration and strokewere his clinical suspicions.His physical examination on admission  revealed an agitated and intubatedpatient, with heart rate of 90 bpm, blood pressure of 68/49 mm Hg, respiratory rate of36 bpm, lungs with diffuse rhonchi, no abnormality on cardiac auscultation. His liverwas palpated 3 cm from the right costal margin. There was edema (+++) of the lowerlimbs, with no signs of calf swelling.Sedation was prescribed, as were dobutamine, noradrenaline, enoxaparin, vancomycin andimipenem/cilastatin.His cranial tomography  showed a right occipital low attenuation area,widening of the cortical sulci, and no other significant change, findings compatiblewith right occipital ischemic stroke.The patient remained shocked despite the administration of vasoactive amines, hadbradycardia and asystole, and died .The patient here reported is a male elderly with ischemic cardiomyopathy, andsignificant weight loss in the previous 4 months, in addition to worsening of hisgeneral state of health and clinical instability in the 24 hours prior to admission.Some diagnostic possibilities could explain his significant weight loss.1 The physiopathology of that disorder has been firstdescribed by Pitman and Cohen2Later, new evidence showed that the cause is multifactorial, related mainly toanorexia, a change in the routine of food uptake, in absorption and in themetabolism of patients with heart failure.3 Up to 34% of the patients with CHF being followed up on anoutpatient basis are estimated to develop cardiac cachexia in the medium to longrun.4 The deleteriouseffects of that condition impair the cardiac and respiratory functions and decreaseimmunity, which leads to higher mortality. Our patient’s systemic complications thathindered the reversion of his final findings might have been aggravated by cardiaccachexia. Regarding treatment, the literature reports many simultaneous actions thatfight the most critical points in cachexia, such as nutritional therapy and the useof appetite stimulants, correction of anemia and edema, use of anabolic steroids andimmunomodulation. Parallel to drug therapy, physical activity is indicated tomaintain skeletal musculature,5respecting the limits imposed by the disease and requiring strict follow-up.Cardiac cachexia is a frequent complication in the advanced stages of congestiveheart failure (CHF) and associates with shorter survival.6has shown that the overlap between those two diseases results from the addition ofshared risk factors, such as obesity, smoking, sedentary lifestyle and diabetesmellitus. In that context, the term cancer-related ‘cardiac cachexia’ appears. Thatcomplication is part of the natural history of neoplasms, leading to a progressivemuscle mass loss (cachexia). However, many patients experience myocardial changesrelated to atrophy, remodeling and dysfunction, a set of findings known as cardiaccachexia.7Another possible explanation for cachexia would be the development of malignantneoplasia in a patient previously debilitated by heart disease. New studies haverecently shown a higher interaction between oncologic and cardiac diseases, nolonger attributed to diagnostic coincidence, but to an interaction between theirmorbidities. A recent publicationInsidious infectious diseases, such as tuberculosis and infectious endocarditis, canalso be accompanied by consumptive findings. Usually, the manifestation mostcommonly associated with those conditions is fever (70% to 90% of the cases), which,in our patient, was only reported during hospitalization, but not in the last monthsof his disease. In addition, other symptoms and signs, such as cough, productiveexpectoration, nocturnal sweating or skin lesions , lack.On admission to the emergency service, the patient had signs of dehydration, arterialhypotension and systemic congestion, such as high jugular venous pressure,hepatomegaly and edema of the lower limbs. Such findings suggest a state of lowcardiac output, which can correspond to an advanced stage of the underlying heartdisease or decompensation associated with other contributing factors. On theadmission electrocardiogram, signs of overload of the right chambers stand out,which might suggest a sudden increase in the pressures of the right atrium andventricle, as observed in cases of acute pulmonary thromboembolism. Other factorsthat might contribute to acute decompensations in patients with chronic diseases andpotentially immunosuppressed are bacterial infections, such as pneumonia and urinarytract infections.Despite the treatment instituted, the patient’s clinical status worsened with renalfailure and metabolic acidosis. On the third day of hospitalization, he had loweringof consciousness, fever, oliguria and respiratory failure, being submitted toendotracheal intubation. These findings initially suggest infectious decompensationand a possible toxic-metabolic process, but cranial tomography revealed a rightoccipital low attenuation lesion compatible with acute ischemic stroke. In patientswith structural heart disease, ischemic encephalic injuries are commonly secondaryto cerebrovascular atherosclerotic disease or episodes of cardioembolism in thepresence of atrial fibrillation or other intracardiac thrombi. Less frequently, thecardioembolic phenomenon can be related to infectious endocarditis or cardiactumors. Diagnostic hypotheses: ischemic cardiomyopathy, cardiac cachexia,acutely decompensated chronic heart failure (progression of the underlying disease?pulmonary thromboembolism? subjacent infection?), ischemic stroke (atherothrombosis?cardioembolic?). s were seen. The lungs,liver and spleen showed morphological changes of chronic passive congestionsecondary to CHF , and both ventricles were enlarged. Cross sections of the ventriclesevidenced healed transmural myocardial infarction in the left ventricular anteriorand anterolateral walls, involving at least 45% of the left ventricular myocardialmass and the anterior two-thirds of the ventricular septum, from the heart base toits tip . Signifiy to CHF . The aorhe mouth . There wAnatomopathological diagnoses: 1) systemic atherosclerosis; 2) coronaryatherosclerosis; 3) ischemic heart disease, with healed infarction in the leftventricular anterior and anterolateral walls and in the anterior two-thirds of theventricular septum; 4) left ventricular aneurysmatic dilatation in the leftventricular anterior wall with an organizing thrombus in the endocardium subjacentto the healed infarction area; 5) congestive heart failure; 6) aspiration pneumonia;7) mixed hemodynamic shock (cardiogenic/infectious). 9 Coronaryatherosclerosis is the major contributor to the occurrence of IHD, despite theglobal preventive measures and the advance in the hemodynamic and pharmacologicaltechniques to treat atherosclerotic disease. Thus, the risk factors for thedevelopment of IHD are those for coronary atherosclerosis. This case shows theprogression of coronary atherosclerosis and its complications in a male patient withrisk factors, such as age (72 years) and systemic arterial hypertension. Theatherosclerotic involvement of the coronary arteries, more marked in the AD and CXbranches, and the old recanalized thrombus in DA explain the healed transmuralinfarction in the left ventricular anterior and anterolateral walls and in theventricular septum, from the heart base to its tip. The complications of myocardialinfarction depend on the location and extension of the myocardial necrotic area,which, in our patient, are represented by left ventricular aneurysmal dilation,extensive transmural myocardial fibrosis in the left ventricular anterior wall andorganizing thrombus in the endocardium of the infarcted area. An aneurysm can occurearly or later after myocardial infarction,10 and its presence increases the risk for ventriculararrhythmias and CHF. On postmortem exams, aneurysms are found in cases of extensivemyocardial infarction and the hearts are enlarged, with hypertrophy of the remainingleft ventricular myocardium, left ventricular dilatation and significant luminalobstruction of the major branches of the epicardial coronary arteries. Congestiveheart failure is frequent, being the major cause of death.11 The mortality rate of patients of both sexes, agedat least 70 years, who develop CHF after myocardial infarction and have an abnormalleft ventricular ejection fraction, varies from 41% to 92%, respectively, from thefirst to the fifth post-infarction year.12 In the case here discussed, the complication citedcontributed to CHF, morphologically identified as anasarca, chronic passivecongestion of the lungs, liver and spleen, low cardiac output and cardiac cachexia,determining the patient’s unfavorable outcome. The cause of death was hemodynamicshock, to which CHF and aspiration pneumonia contributed. Ischemic heart disease (IHD) is the major cause of death in Brazil and worldwide,with higher incidence in men aged 40 years and older.Section editor: Alfredo José Mansur(ajmansur@incor.usp.br)Associated editors: Desidério Favarato(dclfavarato@incor.usp.br)vera.aiello@incor.usp.br)Vera Demarchi Aiello (


Compared to controls, patients showed a trend towards reduced LVMi at baseline ; this difference was lost by 1 year of GH treatment . Significantly reduced aortic area was observed in GHD . This did not change with GH treatment. There were no differences in other LV parameters including end-diastolic volume index (EDVi), end-systolic volume index, stroke volume index (SVi), cardiac index and ejection fraction. There was a trend towards reduced baseline right ventricular (RV)SVi  and increased RVEDVi over 1 year . Two patients demonstrated interstitial expansion, for example with fibrosis, and three myocardial ischaemia as assessed by late gadolinium enhancement and stress perfusion. The increased sensitivity of CMR to subtle cardiac changes demonstrates that adult-onset GHD patients have reduced aortic area and LVMi increases after 1 year of GH treatment. These early data should be studied in larger studies in the future.Growth hormone (GH) can profoundly influence cardiac function. While GH excess causes well-defined cardiac pathology, fewer data are available regarding the more subtle cardiac changes seen in GH deficiency (GHD). This preliminary study uses cardiac magnetic resonance imaging (CMR) to assess myocardial structure and function in GHD. Ten adult-onset GHD patients underwent CMR, before and after 6 and 12 months of GH replacement. They were compared to 10 age-matched healthy controls and sex-matched healthy controls. Left ventricular (LV) mass index (LVMi) increased with 1 year of GH replacement (53.8 vs. 57.0 vs. 57.3 g/m Growth hormone deficiency (GHD) causes myocardial hypokinesis, with loss of the normal response to exercise –5. EffecCardiac magnetic resonance (CMR) imaging is a reliable and reproducible technique for measuring myocardial volume, mass and function. The use of gadolinium contrast enables assessment of myocardial perfusion, scarring and focal fibrosis . CMR hasTen adult patients with GHD about to commence GH replacement were recruited from two UK endocrine centres and were studied in the main study centre. GHD was confirmed by insulin tolerance or glucagon testing (peak GH < 3.0 µg/l). Cardiac function and morphology were assessed using CMR before initiation of the chosen therapy (CMR1) and at 6 (CMR2) and 12 months (CMR3) after treatment. Patients provided quality of life (QoL) data using the Adult Growth Hormone Deficiency Assessment, a disease-specific questionnaire, weight, height and blood pressure measurements and serum IGF-1 levels at each time point. Patients with known ischaemic heart disease or hypertension before the study were excluded. Multi-centre ethical approval was given by the local Research Ethics Committee (06/Q0401/53). This was an observational study and referring physicians determined patient treatment according to the local guidelines. All patients signed a consent form following verbal and written explanation of the study..Ten patients  participated. Two patients did not attend CMR3, one due to discontinuation of GH replacement (patient 9) and one for personal reasons (patient 7). The mean age was 55 years SD ± 13.4), mean duration of GHD was 6.1 years (SD ± 5). Six patients had previously undergone treatment for pituitary tumours, one had previous hypophysitis and two had undergone radiotherapy for meningioma. All patients had at least one other pituitary hormone deficiency; these were appropriately replaced at stable doses for at least four weeks before CMR1. GH therapy was commenced at a low dose and titrated, aiming for an IGF-1 between the median and upper limit of the age- and sex-adjusted reference ranges . For pat3.4, meanTen individually age-matched controls and sex-matched controls were recruited. Controls underwent one non-contrast CMR study and provided serum for IGF-1 levels. Controls did not receive adenosine during CMR. For their characteristics see Table CMR was performed at an experienced centre using a Philips Achieva CV 1.5 Tesla magnetic resonance imaging (MRI) scanner . Standard protocols were used to generate cine images. These were analysed using dedicated software  to calculate the following cardiac parameters: LV-end diastolic volume (EDV), end systolic volume (ESV), ejection fraction (EF), stroke volume (SV), cardiac output, LV mass (M); RV-EDV, ESV, EF, SV. All except for EF were indexed  to body surface area (BSA) using the Mostellar formula and suffixed “i” . CMR imaThe GHD group underwent first pass perfusion imaging with a bolus of gadolinium contrast agent (0.05 mmol/kg), during an intravenous infusion of adenosine . Three short axis slices were acquired per cardiac cycle using a steady-state prospectively gated turbo field echo sequence. Late gadolinium images were acquired at least 10 min following the injection of a further 0.15 mmol/kg of contrast agent, using an inversion recovery sequence. Perfusion and late gadolinium images were qualitatively assessed by an experienced cardiologist blinded to the underlying diagnosis.Aortic dimensions were obtained from MRI scout images. Internal distances in lateral and anterior–posterior planes were measured at the level of the pulmonary bifurcation. Area was calculated and indexed to BSA.IGF-1 levels were measured using a chemiluminescent immunoassay , reporting IGF-1 levels between 25–1600 ng/ml. Age-adjusted reference and sex-adjusted reference ranges were used. IGF-1 standard deviation scores (SDS) were calculated using a standardised reference table from the assay manufacturer.The QoL assessment of GH deficiency in adults (AGHDA) was used for patients with GHD, in which a lower result indicates a better QoL .There were no significant adverse outcomes from this study. The only reported side effects were discomfort during venous cannulation and an uncomfortable sensation when receiving either the adenosine or the gadolinium contrast infusion. Effects from both were classed as mild.t-test was used to compare patients with controls. Repeated measures analysis of variance (ANOVA) were used to compare repeated CMR studies. Paired t-tests were used to compare IGF-1 SDS and QoL scores at the beginning and end of the study. Pearson’s correlation test was used to compare IGF-1 SDS and left ventricular mass index (LVMi). Data are reported as mean and standard deviation, except where specified. Analysis was performed using StatsDirect  and Prism . A p value of <0.05 was deemed to be statistically significant.Patients in whom new diagnoses of a non-GH related cardiac or aortic pathology were made during the study had their results excluded from the cardiac indices or aortic calculations, respectively. Details of any results excluded are given in the discussion. The Student’s p = 0.007) and had a greater body mass index  69.5 ± 2.7 vs. 74.5 ± 2.6 ml/m2, p = 0.194; ESVi 26.6 ± 1.6 vs. 26.4 ± 2.1 ml/m2, p = 0.9288; stroke volume index (SVi) 44.5 ± 1.2 vs. 46.9 ± 1.9 ml/m2, p = 0.305; cardiac index (CI) 2.96 ± 0.2 vs. 3.33 ± 0.2 ml/min/m2, p = 0.218; EF 64.6 ± 2.2 vs. 62.9 ± 0.9 %, p = 0.497. The control group had mean LVMi within the normal range [GHD patients demonstrated a strong trend towards reduced LVMi .Eight patients with GHD attended all three scans, of which one needed to be excluded . There was no change in AAi with 1 year of GH therapy  but no increase in SVi . There were no differences in other parameters.Patients with GHD showed a trend towards increased RV-EDVi with GH replacement (CMR1 vs. CMR2 vs. CMR3: 70.3 ± 3.4 vs. 74.3 ± 3.1 vs. 73.8 ± 2.7 ml/mp = 0.0032): baseline mean IGF-1 SDS − 1.60; 1 year + 0.61. Patient 3 was over-replaced (IGF-1 SDS 3.02) so the GH dose was reduced. Mean GH dose was 0.33 mg/day in males and 0.50 mg/day in females  demonstrated LGE. Patient 1 had extensive, transmural LGE, measuring 20.1 cmThree patients  with GHD had evidence of stress-induced myocardial perfusion defects. Patient 1 and 8 had mild abnormalities but were symptom-free, thus no further investigations were performed. Patient 3 demonstrated more marked perfusion abnormalities and underwent computed tomography (CT) angiography and clinical review by a cardiologist. This patient demonstrated a non-flow-limiting lesion on CT angiography.p = 0.0025).Patients with GHD demonstrated a significant improvement in AGHDA score with 1 year of GH treatment . There is, however, a significant increase in LVMi in GHD patients after 6 months of treatment , as well as 12 months of treatment when compared to their initial LVMi . The other LV parameter calculations remained similar when compared to baseline.Patients in whom a new, non-GH-related, cardiac diagnosis was made were excluded from relevant analyses: patient 9 had a bicuspid aortic valve and was excluded from AA analysis; patient 2 was discovered to have hypertension and diabetes and, therefore, was excluded from the cardiac mass and indices analysis. With patient 2 included within the calculations , validating this finding [To date, it is well established that untreated CO-GHD reduces cardiac mass but whether this occurs in AO-GHD has not been clearly demonstrated . Some ec finding . The impThe mechanism behind reduced cardiac mass in GHD is likely to be multi-factorial. Withdrawal of GH replacement in teenagers with GHD reduces skeletal muscle fibre diameter ; whereasAge may be an influential factor in the effects of GHD on LV mass. The mean age of patients in this study was 55 years range 34–76). A study of older patients with GHD demonstrated no difference in LV mass compared to controls –76. A st. It is lCMR is considered the most accurate and reproducible method for assessing RV volume parameters –37. PatiOne year of GH replacement in GHD did not result in significant changes in the RV parameters that were measured, except a trend towards increasing RV-EDVi. However, as RV measurements pose technical challenges and are more prone to error than those on the LV; larger studies may be required to ascertain if GH replacement increases RV cardiac indices .LGE utilises the gadolinium washout characteristics of collagen. Areas of fibrosis contain increased collagen and retain gadolinium-based contrast longer than non-affected areas , 40. CarCardiovascular mortality appears to be increased in hypopituitary patients taking glucocorticoids, sex-steroids and thyroxine replacement, and GH treatment may improve it to background rates –43. ThisCMR is recognised as an accurate method for assessing aortic dimensions and has been used to study the aorta in both Marfan and Turner syndromes , 47. In Patients in whom a new, non-GH-related, cardiac diagnosis was made were excluded from relevant analyses: patient 2 had LV hypertrophy thought to be due to hypertension and diabetes and therefore was excluded from the cardiac mass and indices analysis; patient 9 had a bicuspid aortic valve and was excluded from AA analysis.2, p = 0.232).There is, however, a significant increase in LVMi in GHD patients after 6 months of treatment  as well as 12 months of treatment when compared to their initial LVMi . Over the 12 months, ANOVA calculations showed a trend towards increasing LVMi in GHD patients . There remained no significant difference in all other LV parameters when compared to baseline.With patient 2 included within the calculations for this study, the trend of reduced LVMi in GHD patients is lost (53.9 ± 12.0 vs. 59.5 ± 8.0 g/mWe understand that this study was limited by small patient numbers, a few exclusions and limited length of follow-up, and future studies are needed to confirm these data.We suggest that CMR could be used to identify and track the cardiac changes that occur in patients with GHD. The accurate assessment of LV mass by CMR allowed for the demonstration of a trend towards reduced cardiac mass in patients with AO-GHD and increase in cardiac mass with GH replacement. RV-EDV was reduced in GHD and reduced AAi was demonstrated in GHD patients.Supplementary Table 1


Little is known about the time-course changes in left ventricular myocardial deformation in patients with Takotsubo cardiomyopathy (TC) using layer-specific quantification of myocardial deformation assessed by 2-dimensional speckle tracking echocardiography (2DSTE).In this retrospective 2DSTE follow-up study of 3 female patients with sepsis-induced TC, we examined changes in strain among the 3 myocardial layers, and examined the changes in left ventricular diastolic function and right ventricular systolic function. In all 3 patients, there was improvement of at least 15% in left ventricular ejection fractions, and improvement in left ventricular longitudinal and circumferential strains. The absolute differences in left ventricular global strains between the endocardium and epicardium, and between the first and the third 2DSTE studies reflect the following: a decrease in all 3 myocardial layers in patients with acute TC; and a slower improvement in mid-myocardial and epicardial function during recovery of TC. In addition, the right ventricular free wall strains were also impaired in the acute stage of TC with gradual improvement during recovery.Left ventricular strains did not fully recover even 1 month after acute TC. In addition, right ventricular free wall strains were also impaired in all 3 patients initially. In this case series, we found that layer-specific 2DSTE is a more sensitive method for myocardial function assessment than standard echocardiography. A recent cardiac magnetic resonance imaging study found that systolic function recovered faster than diastolic function in patients with TC. Unlike the right ventricle, the left ventricle is composed of 3 myocardial layers, namely endocardial, mid-myocardial, and epicardial myocardium. Little is known about the time-course changes in left ventricular myocardial deformation in patients with TC using layer-specific quantification of myocardial deformation assessed by 2-dimensional speckle tracking echocardiography (2DSTE). In this retrospective 2DSTE follow-up study of patients with sepsis-induced TC, we examined changes in strain among the 3 myocardial layers and examined the changes in left ventricular diastolic function and right ventricular systolic function.Takotsubo cardiomyopathy (TC) is a transient cardiac syndrome characterized by reversible left ventricular dysfunction, with apical ballooning and electrocardiographic changes mimicking acute coronary syndrome without obstructive coronary artery disease.2During the period July 2014 to June 2015, in all, 3 consecutive patients were admitted to our intensive care unit because of sepsis and clinically acute congestive heart failure . Since acute infectious diseases are a contraindication for coronary angiography, none of the patients underwent coronary angiography to define coronary artery disease, but instead were treated for the underlying acute urinary tract infection. Echocardiographic examinations in all patients revealed a left ventricle with a “lobster trap” appearance characteristic of TC. Therefore, the preliminary diagnosis in all 3 patients was urinary tract infection-induced TC. The patients underwent 3 serial 2DSTE studies: the first on admission, the second 7 to 14 days after admission, and the third before discharge (case 1) or 1 to 2 months after admission (cases 2 and 3). The follow-up protocols were designed to confirm the diagnosis of TC. Clinical data definitions were the same as those reported in our previous study. Analyses of layer-specific longitudinal and circumferential strains were obtained from 3 apical views and 3 parasternal short-axis views. The data on systolic longitudinal and circumferential strains from endocardial, mid-myocardial, and epicardial myocardium were obtained using off-line software  in 17 longitudinal and 6 circumferential segments. All segmental values were averaged to achieve global longitudinal and circumferential strains for each myocardial layer, respectively. The present study was approved by institutional review board of Chang Gung Memorial Hospital (No. 104–9129B). Herein, we present the results of the follow-up serial electrocardiographic and 2DSTE studies in the 3 patients with sepsis-induced TC.All echocardiographic examinations were performed using a commercially available system . Standard echocardiographic and 2DSTE techniques were performed as reported in our previous study.2.1Escherichia coli. The 12-lead electrocardiogram on the second day after admission showed ST-segment elevation in precordial leads with an initial troponin-I level of 1.622 ng/mL. The patient presented with dyspnea at rest. Transthoracic echocardiography revealed characteristics of TC and a left ventricular ejection fraction of 26%. The findings on follow-up electrocardiographic and 2DSTE studies were consistent with a diagnosis of sepsis-induced TC . Contrary to left ventricular global strains, the global longitudinal right ventricular free wall strains in the 3 patients all recovered to normal . The thinner myocardial width of the right ventricle as compared with that of the left ventricle might be partly responsible for this finding. Studies have demonstrated that right ventricular free wall strain analysis provides prognostic information in patients with cardiovascular disease.–19 The mechanisms underlying right ventricular involvement in acute TC remain elusive. Some investigators suggest that intensive contraction of the base can introduce increased preload wall stress on the apical myocardial segments, thus causing apical akinesis. Therefore, TC and McConnell sign may share a common mechanism in the development of right ventricular apical akinesis.,21A recent investigation found that sepsis-triggered TC may be the cause of sepsis-induced myocardial depression, and that left ventricular dysfunction is reversible within 1 to 2 weeks. recently reported that diastolic recovery is slower than systolic recovery in patients with TC. They hypothesized that apical edema and calcium mishandling might contribute to the persistent diastolic dysfunction seen in patients with TC. In the present case series, we found that left ventricular diastolic function recovered as the left ventricular ejection fraction recovered as reflected by the transiently prolonged left ventricular isovolumic relaxation time.Ahtarovski et al4Left ventricular strains, one of the systolic function parameters, did not fully recover even 1 month after acute TC. In addition, right ventricular free wall strains were also impaired in all 3 patients initially. In this case series, we found that layer-specific 2DSTE is a more sensitive method for myocardial function assessment than standard echocardiography. Based on our findings, we suggest that follow-up 2DSTE studies be performed in patients with TC even after left ventricular ejection fraction has normalized.


To complement the ISO 5840 standards concerning the duration of leftventricular systole and diastole as a function of changes in heart ratesaccording to in vivo studies from the physiologic literature review.in vivostudies were compared with the durations of systole proposed by the ISO5840:2010 and ISO 5840-2:2015 for hydrodynamic performance assessment ofprosthetic heart valves.The systolic and diastolic durations from three in vivo studies analyzed, the systolicdurations proposed by the ISO 5840 standard seemed consistent for 45 and 120beats per minute (bpm), and showed diverse results for the 70 bpmcondition.Based on the Information on the realistic validation of the operation of left ventricularmodels for different heart rates were obtained. Food and Drug Administration (FDA)draft guidance-4. Therefore, the main purpose of these invitro experiments is the realistic simulation of the left human heart,under conditions of similarity. Besides geometry and flexibility , left ventricular models are expected to operate according tophysiological  characteristics, for instance, arterial impedance,dynamic viscosity of the blood analog fluid, intraventricular and systemicpressures, end-diastolic volume, stroke volume, cardiac output (CO), heart rates(HRs) and related duration of left ventricular systole and diastole. Since thesevariables are changed, different mitral and aortic pressures and flow conditions areimposed through the prostheses, in which their own type, position, dimension, anddynamic behavior are implicated.Cardiac simulators or pulse duplicator systems are required to the hydrodynamicperformance analysis of prosthetic heart valves  was assumed,instead of the electrical systole (QT). QS2 is the interval obtained from the Q wave on theelectrocardiogram (ECG) to the second heart sound (S2) on the simultaneousphonocardiogram (PCG), or theduration of both isovolumetric contraction and left ventricular ejection phases. Themechanical duration of diastole is defined as total cardiac cycle duration (RR)minus the QS2.It is important to note that, since the purpose of this study was to provide datathat can be applied to the dynamic operation of left ventricular models, thephysiological literature review was focused on electromechanical duration.Therefore, the  electromechanical systole , 25 subjects , and20 males .The data from Husmann et al.-9 and the recommendation of the ISO 5840 standard,5.,5. Since the data from Husmann et al. were explicit only for 45 and 100bpm (with black spots), white spots were placed according a previous assessment inwhich the duration of the diastole declines asymptotically as HRincreases.The testing conditions suggested by the ISO 5840-2:2015 and ISO 5840:2010 wereplotted. Systolic duration of 35% for 70 beats per minute (bpm) is the same forboth,5  in its last release  measurementinvivo studies were included in found that the length of systole shortened from 400 to 360 ms, respectively, for 45to 100 bpm. This result shows that the duration of systole lengthened from 30% to60% of the cardiac cycle. Thedata from Chung et al. andBoudoulas et al. were quitesimilar, specially as HR increases. The percentage duration of systole lengthenedfrom 35% to 54% and from 36% to 54% of the cardiac cycle, respectively, in the studyby Chung et al. and Boudoulas etal., cases with mean ageof 24 and 40 years.The data concerning systolic or diastolic duration from three invivo studies,8,9 showed diverse results if compared with the suggestion of theISO 5840 standard for the 70 bpm condition, systolic duration of 35%,5. However, specifically at 45 and 120 bpm, respectively thesystolic duration of 30% and 50%  duration according toin vivo studies,8,9. Furthermore, taking into account that the waveresponses from left ventricular models include their dynamics, they should bevalidated for the electromechanical systole and diastole intervals, as exposed in the methodology.However, in terms of general hydrodynamic performance evaluation, valid analyses arepossible for diverse experimental setups, left ventricular models, and also specificsimulated ventricular states. However, each of these variables influences the flow,and the behavior of a prosthetic valve depends on its specific simulatedconditions.Regarding the hydrodynamic characterization of prosthetic heart valves includingdifferent HRs, we consider that realistic ,4,5. Patientswith heart disease do not generally produce normal pressure and flow responses. Inthis sense, left ventricular models should be validated properly, considering the invivo pathological waveforms. For instance, patients with heart failure arecharacterized by an extended left ventricular systole and, consequently, a shorterinterval of left ventricular diastole, in which the cardiac filling could becompromised.The ISO 5840:2010 also addresses the operational environment of the prosthetic heartvalves for pathological conditions, in terms of arterial systolic and diastolicpressuresin vivo results from the literature review concerning systolicand diastolic duration based on the electromechanical intervals represent importantinformation in order to realistically validate the operation of left ventricularmodels for different HRs.The in vivo studies analyzed, the systolic durationsproposed by the ISO 5840 standard seemed consistent for 45 and 120 bpm, and showeddiverse results for the 70 bpm condition.Based on the


Over a mean follow-up period of 2.7 ± 0.8 years, there was no change in left ventricular mass, volumes, ejection fraction, native myocardial T1 times, or extracellular volume with CKD or in healthy controls. Global longitudinal strain  and mitral annular planar systolic excursion  decreased in CKD but were clinically insignificant. Midwall late gadolinium enhancement was present in 4 patients at baseline and was unchanged at follow-up. Renal function was stable in this cohort over follow-up (change in estimated glomerular filtration rate was −3 ml/min/1.73 m2) with no adverse clinical CV events. In conclusion, this study demonstrates that in a cohort of patients with stable CKD, left ventricular mass, native T1 times, and extracellular volume do not increase over a period of 2.7 years.Patients with chronic kidney disease (CKD) have a disproportionately high risk of cardiovascular (CV) morbidity and mortality from the very early stages of CKD. This excess risk is believed to be the result of myocardial disease commonly termed uremic cardiomyopathy (UC). It has been suggested that interstitial myocardial fibrosis progresses with advancing kidney disease and may be the key mediator of UC. This longitudinal study reports data on the myocardial structure and function of 30 patients with CKD with no known cardiovascular disease and healthy controls. All patients underwent cardiac magnetic resonance imaging including T1 mapping and late gadolinium enhancement (if estimated glomerular filtration rate > 30 ml/min/1.73 m The increased cardiovascular morbidity and mortality of patients with chronic kidney disease (CKD) is due to a combination of myocardial disease, arteriosclerosis, and atherosclerosis.2 with other evidence of kidney disease: proteinuria/hematuria/structural abnormality/genetic), stage 3 (eGFR 30 to 59 ml/min/1.73 m2), stage 4 (15 to 29 ml/min/1.73 m2), and stage 5  with no history or symptoms of cardiovascular (CV) disease or diabetes. Healthy controls and hypertensive subjects in the original cohort were also invited to participate. The study was approved by the National Research Ethics Service—East Midlands (15/EM/0280) and all subjects gave written informed consent. Demographic, medical co-morbidities, and blood and proteinuria data were collected prospectively. Glomerular filtration rate was assessed using the CKD-EPI equation. CV events were defined as death from CV disease, myocardial infarction, stroke, peripheral vascular disease, or hospital admission with heart failure.Patients who participated in an observational study investigating the use of CMR T1 mapping in early-stage CKD during 2012 to 2014 were invited to participate in an ongoing study examining myocardial disease and LV fibrosis in CKD (NCT03176862).2, slice thickness of 7 mm with 3 mm gap, minimum 25 phases per cardiac cycle). T1 mapping was performed before and 15 minutes after gadolinium administration on the basal and mid-SAX slices in diastole using an electrocardiography-gated Modified Look-Locker Inversion recovery (MOLLI) sequence with a 3(3)5 sampling protocol (Siemens WIP 448). Typical acquisition parameters were pixel bandwidth of 977 Hz/pixel; echo time = 1.1 milliseconds; flip angle = 35°; matrix = 144 × 256; slice thickness of 6 mm. Motion correction and a nonlinear least-square curve fitting were performed with the set of images acquired at different inversion times to generate a parametric pixel-wise color T1 map to quantitatively measure the longitudinal myocardial relaxation time. LGE imaging was acquired in the corresponding SAX stack and LAX views using a standard inversion recovery sequence 7 to 10 minutes after 0.15 mmol/kg of gadolinium contrast bolus . For the original study, ethical approval allowed administration of gadolinium to subjects with eGFR > 15 ml/min/1.73 m2. This dose was amended in the follow-up study to eGFR > 30 ml/min/1.73 m2 because of local policy change and guidance from the Medicines and Healthcare Products Regulatory Agency.All subjects underwent CMR  with a phased array 18-channel body matrix coil and spine matrix coil. Imaging sequences for LV and right ventricular structure, function, and LV mass were acquired in line with standard protocols.Offline analysis was performed by experienced operators  using CVi 42 software . Analysis of LV function, volume, and LV mass was performed with delineation of papillary muscles and trabeculations using thresholding. Tissue tracking in the 3 long-axis views was performed offline to assess 2-dimensional global longitudinal strain (GLS), strain rate, and early diastolic strain rate. Native and postcontrast myocardial T1 values were measured from parametric T1 maps. Endocardial and epicardial borders were manually drawn in the basal and mid short-axis slices with meticulous care to avoid partial voluming and blood pool contamination. Anterior and inferior septal borders were defined with semiautomated segmentalization of the LV in accordance with the AHA model.All T1 map studies were analyzed twice by a single blinded observer (MKH) for intraoperator reproducibility and a second blinded observer (AP) for interoperator reproducibility. Analysis was performed on studies anonymized to time and date by a third observer who assigned a unique number to all scans before analysis.t test or the Wilcoxon signed-rank test for parametric and nonparametric data, respectively. Paired nominal data were compared using the McNemar test. Statistical tests were 2-tailed, and a p value <0.05 was considered to indicate statistical significance.Continuous variables are expressed as mean ± SD if normally distributed or median (25th to 75th percentile) if non-normally distributed. Paired group comparisons for continuous data were made using the paired samples 2/year over the study period [median and interquartile range for change in eGFR −2 (−10.5 to 1.75)] but 7 patients did change their CKD category during the follow-up period.In total, 30 subjects with CKD from the original cohort (43 subjects) were followed up for a mean period of 2.7 ± 0.8 years. Baseline and follow-up demographic, biochemical, and treatment data for the patients with CKD are presented in 2 (22 of 30 subjects) at follow-up. Midwall LGE was observed in 4 patients. None had subendocardial LGE. There were no new cases of myocardial LGE in either CKD or control groups over follow-up, but 4 patients with CKD did develop new focal right ventricular insertion point LGE . In those patients from the original study with native myocardial T1 values greater than the upper limit observed in controls , there was no change in myocardial T1, ECV, LV function, or LV mass. There was no systemic bias detected by Bland-Altman analysis between intra- and interoperator agreement for native myocardial T1 times. The mean intra- and interobserver differences [mean ± SD (95% limits of agreement)] were −1 ± 6 (−12 to 10) and −1 ± 7 (−13 to 11), respectively.This study demonstrates that in a cohort of patients with predominantly stable CKD, with controlled blood pressure and without known CV disease or diabetes, myocardial T1 times and ECV do not change over 2.7 years. There is also stability of LV ejection fraction and LV mass. These data are encouraging in that they demonstrate stability in the CMR measurement of T1 relativity in the context of CKD. The data are also reassuring for patients with stable early CKD and provide further support for remote community follow-up of such patients provided that blood pressure and renal function are monitored.This is the first longitudinal study evaluating T1 and ECV in early CKD. No progression of T1 times or ECV was found in subjects over 2.7 years. We cannot exclude progression of these parameters over longer time periods and we are not able to comment on the influence of declining renal function. In keeping with these findings, a recent small longitudinal study of 22 hemodialysis (HD) patients studied twice over 6 months did not show a change either in septal T1 times or in BNP.The unexpected stability of CKD in the study prevents us from addressing our original hypothesis that deteriorating renal function promotes myocardial fibrosis, a key intermediary in the progression of UC. It should be noted that this is not a new concept, as the earliest reports of histology dating back to the late 1980s from postmortem and cardiac biopsies confirmed that extensive fibrosis is detected in HD patients.GLS provides a potential functional biomarker for CKD cardiomyopathy. It provides a quantitative evaluation of ventricular global and regional function that has been linked to the extent of myocardial fibrosis and is a better predictor of mortality and adverse CV events in a range of conditions particularly when EF is within normal range.There are several limitations to acknowledge; the effects of progressive renal dysfunction on myocardial disease cannot be addressed from this study because of the stability of our patient's CKD. Our patients with mainly low levels of proteinuria, no diabetes, and well-controlled blood pressure were a relatively low-risk cohort and we note that other studies have reported considerable variability in rates of renal progression over such a time period.In conclusion, in patients with early-stage CKD, noninvasive imaging biomarkers of myocardial fibrosis do not progress if renal function remains stable. These findings are paralleled by stability of LV mass and systolic function.


The main etiology of constrictive pericarditis (CP) has changed from tuberculosis to therapeutic mediastinal radiation and cardiac surgery. Occult constrictive pericardial disease (OCPD) is a covert disease in which CP is manifested in a condition of volume overload.A 60-year-old patient with a history of thoracic radiation therapy for non-Hodgkin’s lymphoma (40 years earlier) was transferred to our hospital for treatment of repeated congestive heart failure. For a preoperative hemodynamic study, pre-hydration with intravenous normal saline (50 mL/hour) was used to manifest the pericardial disease and prevent contrast-induced nephropathy. The hemodynamic study showed a right ventricular dip-plateau pattern and discordance of right and left ventricular systolic pressures during inspiration, which was not seen in the volume-controlled state. These responses were concordant with OCPD. A pericardiectomy, aortic valve replacement, and mitral and tricuspid valve repair were performed. Postoperatively, the heart failure was controlled with standard medication.This case revealed a volume-induced change in hemodynamics in OCPD with severe combined valvular heart disease, which suggests the importance of considering OCPD in patients who had undergone radiation therapy 40 years before. Occult constrictive pericardial disease (OCPD) is a rare disease characterized by a change in hemodynamics to a typical constrictive pericarditis (CP) pattern after volume loading . The maiA 60-year-old woman presented to another hospital with shortness of breath on exertion. Her family history was unremarkable. She had undergone chemo-radiation for non-Hodgkin’s lymphoma 40 years earlier and achieved complete remission. CHOP  chemotherapy did not induce cardiac toxicity. Twenty years earlier, she had an anterior myocardial infarction and underwent percutaneous coronary intervention. Moderate combined valvular diseases  were also followed. She had received standard treatment for chronic heart failure. However, she had suffered from acute exacerbation of congestive heart failure several times beginning 2 years before and was referred to our hospital because of refractory repeated congestive heart failure.2 97% on room air, with a body mass index of 15.8 kg/m2. The conjunctiva showed no signs of anemia or jaundice. The first and second heart sounds were normal, but the third one was increased. There was a pan-systolic murmur at the cardiac apex (Levine III/VI). There were no rales in the lungs. The abdomen was flat and soft and the liver was palpated two finger widths below the ribs. There was no edema, ascites or coldness of the limbs. She had hepatomegaly and jugular vein distention remarkable at inspiration, also known as “Kussmaul’s sign”.Her vital signs were blood pressure 106/43 mmHg, heart rate 72/min, and SPO5 and V6.Laboratory tests revealed mild renal and liver dysfunction, and the brain natriuretic peptide (BNP) level was 492 pg/mL. There were no signs of an inflammatory response, anemia, or thyroid dysfunction. Chest X-ray showed a cardiothoracic ratio of 47% and no evidence of pleural effusion, pulmonary congestion, or pericardial calcification. The electrocardiogram showed a pulmonary P wave, high left-side voltages, poor R progression, and ST changes in VEchocardiography showed decreased motion of the left anterior septum and the left ventricular ejection fraction (LVEF) was 42%. There was bilateral atrial enlargement, but no left ventricular dilatation. No pericardial effusion was seen. Although moderate mitral regurgitation, and tricuspid insufficiency were seen at the end of a previous hospitalization Fig. , severe Computed tomography revealed a mild pericardial thickening of 4 mm in front of the right ventricle Fig. . ConsidePrior to the cardiac catheter examination, normal saline was infused at a rate of 50 mL/h for 12 h to manifest the pericardial disease and to protect renal function from the contrast medium. Coronary angiography showed that the coronary arteries were intact and there was a stent in the left anterior descending artery. The right atrial, end diastolic right ventricular, diastolic pulmonary artery, and pulmonary capillary wedge pressures were 15 mmHg. This finding was not seen in a right heart pressure study performed previously in hospital about 6 months ago Fig. . In the Pericardiectomy, aortic valve replacement, and mitral and tricuspid valvuloplasty were performed. At surgery, there was a hard, thickened pericardium, and very mild pericardial adhesion. Histological examination of the resected pericardium revealed hyaline-like fibrous hypertrophy.Twelve months postoperatively, there was no acute exacerbation of the congestive heart failure. The New York Heart Association functional class had also improved from III to II. On echocardiography, although mild tricuspid and mitral regurgitation remained, the size of both the left and right atria decreased. The percent difference in E-velocity between expiration and inspiration was improved to 12% after pericardiectomy, compared to 27% before.To the best of our knowledge, this is the first report of OCPD emerging in a patient who had undergone radiation therapy 40 years ago. The patient was considered to be suffering from radiation-induced pericardial disease as well as valvular heart disease. Veinot et al. reported that the frequency of pericardial disease was as high as 70% when thoracic surgery was performed in patients with radiotherapy . This imA previous report demonstrated that valvular disease is seen in about 15% of patients within 40 years after radiation therapy for Hodgkin’s lymphoma. Valvular disease is more frequent with radiation doses ≥30 Gy, and the frequency of valvular disease increases with time and radiation dose . AlthougRight ventricular pressure waveform is important to determine the accurate diagnosis for heart failure. However, in some cases of heart failure, the right ventricular waveform often shows a dip-plateau pattern on the right heart catheterization. Both right and left ventricular pressures should be measured simultaneously to distinguish between heart failure and CP. Hurrell et al. demonstrated that the right and left ventricular pressures in heart failure decrease concordantly during inspiration, while the left ventricular pressure decreases and the right ventricular pressure increases during inspiration in CP . TherefoIn decompensated heart failure, chronic mitral regurgitation generally deteriorates in response to prominent left ventricular enlargement . In our Although there are no recommended therapies to date for OCPD, the treatment generally follows the guidelines for CP . In our We experienced a rare case of OCPD with severe combined valvular heart disease 40 years after thoracic radiation therapy for non-Hodgkin’s lymphoma. In this case, OCPD emerged due to volume overload. Therefore, we should consider OCPD in patients who have undergone mediastinal radiation therapy, even decades later.


Sepsis, trauma, and burn injury acutely depress systolic anddiastolic cardiac function; data on long-term cardiac sequelae of pediatriccritical illness are sparse. This study evaluated long-term systolic anddiastolic function, myocardial fibrosis, and exercise tolerance in survivorsof severe pediatric burn injury.2) and heart rate at rest andpeak exercise. Demographic information, clinical data, and biomarkerexpression were used to predict long-term cardiac dysfunction andfibrosis.Subjects at least 5 years after severe burn (post-burn:PB) andage-matched healthy controls (HC) underwent echocardiography to quantifysystolic function (ejection fraction[EF%]),diastolic function (E/e′), and myocardial fibrosis  of the left ventricle. Exercise tolerance wasquantified by oxygen consumption , and peak heart rate. The PB group hadmoderate (28%) or severe (15%) systolic dysfunction,moderate (50%) or severe diastolic dysfunction (21%), andmyocardial fibrosis (18%). Biomarkers and clinical parameterspredicted myocardial fibrosis, systolic dysfunction, and diastolicdysfunction.Sixty-five subjects  were evaluated. At study date, PBsubjects were 19±5 years, were at 12±4 years postburn, andhad burns over 59±19% of total body surface area, sustainedat 8±5 years of age. The PB group had lower EF%,E/e′ ,VOSevere pediatric burn injury may have lasting impact on cardiacfunction into young adulthood and is associated with myocardial fibrosis andreduced exercise tolerance. Given the strong predictive value of systolicand diastolic dysfunction, these patients might be at increased risk forearly heart failure, associated morbidity, and mortality.Conflicts of Interest and Sources of Funding: The authors do not haveany conflicts of interest to declare. This work was supported by NIH , NIDILRR , Shriners Hospitals forChildren , FAER(MRTG CON14876), and the Department of Defense (W81XWH-14-2-0162 andW81XWH1420162). It was also made possible with the support of UTMB’sInstitute for Translational Sciences, supported in part by a Clinical andTranslational Science Award (UL1TR000071) from the National Center forAdvancing Translational Sciences (NIH). There is evidence, that pediatric critical illnessdue to trauma, sepsis, or burn injury induces considerable systemic perturbationsand stress through severe inflammation, hypermetabolism, and a protracted surge ofserum catecholamines, that can persist for years with little knownaftereffects.6 A major challenge in conductingprospective long-term studies of cardiac outcomes in pediatric sepsis and trauma isthe significant loss to follow-up that occurs once the underlying condition isresolved and patients are discharged.6 The treatment of severe pediatric burn injury, which inducessystemic effects comparable to those of severe trauma and sepsis,2 is unique at our institution and otherspecialized pediatric burn centers in that patients continuously return forreconstructive and rehabilitative procedures long after discharge from criticalcare. Thus, this particular patient population may provide insights into long-termcardiac function after pediatric critical illness.While ample evidence suggests that cardiac dysfunction can occur incritically ill patients, there are limited and inconclusive data regarding long-termcardiac function in survivors of pediatric critical illness, with this data beingderived mainly from studies of small and diverse study populations.7 Two recent population-based longitudinalstudies were conducted in adults who sustained burn injuries as children or youngadults to assess long-term morbidity and mortality due to a variety ofcardiovascular diagnoses.9 Although the spectrum of cardiovasculardiagnoses included in these analyses was broad, the authors reported significantincreases in incidence and length of hospitalization as well as mortality related tocardiovascular disease among middle-aged survivors of pediatric burn injury. Theimportance of this clinical problem may be considerable given that systolic anddiastolic dysfunction are powerful predictors of poor cardiovascular prognosis,morbidity, and mortality in young adults.10Basic science studies show that acute systolic and diastolic dysfunctionafter burn injury result from circulating depressants such as pro-inflammatorycytokines , gut-derived factors from plasmaand mesenteric lymphatics, and other neurohumoral mediators.The purpose of this study was to determine long-term cardiac function andexercise capacity in pediatric burn survivors. Clinical and pathophysiologicalfactors contributing to systolic and diastolic dysfunction as well as myocardialfibrosis were also evaluated. The collection of pilot data from this trial couldserve as a template for the evaluation of long-term cardiac sequelae in other typesof pediatric critical illness.The institutional review board of the University of Texas MedicalBranch, Galveston, TX, approved this study and informed consent was obtainedprior to enrollment of each subject. Between 2016 and mid-2017, we prospectivelystudied 40 consecutive subjects returning to our institution for long-termfollow-up or reconstructive procedures, who had a history of severe pediatricburn injury affecting at least 30% of the total body surface area(TBSA), sustained the injury at least 5 years prior to enrollment, and weretreated acutely at Shriners Hospitals for Children – Galveston. The control group consisted of a convenience sample of 25healthy volunteers who underwent echocardiographic evaluation for systolic anddiastolic function as well as exercise testing during the same time period.2(m)]. The study subjects’ personal and relevant family medicalhistory were recorded; all subjects were screened for congenital heart disease,which was an exclusion criterion for this study.Collected data included demographics , informationconcerning acute hospitalization , concomitant injuries , Baux –score and receipt of research medication .Body mass index (BMI) at the time of echocardiographic and exercise assessmentswas calculated for the study groups as ), which indexed reference fibrosis. For quantificationof myocardial tissue reflectance, the sampling cursor was placed in themid-myocardium of the anterior septum (sepIB) and posterior wall (postIB) ofthe LV and the measures recorded. The position of the sample volume wasmonitored and adjusted per frame to maintain the sample volume within thesame region during the whole cardiac cycle. Next, cIB was calculated bysubtracting refractive intensities, eg, [cIBpost= postIB – perIB] and[cIBsept= sepIB – perIB], andaveraged per patient to obtain avcIB as a global indicator of myocardialfibrosis. Given the mathematic relationship to sepIB, values of avcIB closerto zero indicate a greater degree of fibrosis. Patients were classified asnormal (avcIB < −15 dB) or presenting with myocardialfibrosis (avcIB > −15 dB).13Calibrated integrated backscatter (cIB) is a reproducible,noninvasive measure of ultrasonic tissue reflectivity and a validated markerof myocardial fibrosis.16Symptoms of heart failure during everyday activities were assessedaccording to the New York Heart Association (NYHA) classification, based onspecific questions pertaining to breathlessness during everyday activitiesand difficulties climbing stairs.17 Peak oxygen consumption(VO2peak) was measured using the modified Bruce treadmillprotocol. After 15 minutes of rest and measurement of baseline heart rateand oxygen consumption, breath-by-breath flow and volume of inspired andexpired gases were continuously monitored using a Medgraphics CardiO2combinedVO2/ECG exercise system  duringprogressively increasing treadmill speed and elevation angle. Subjects wereconstantly encouraged to complete 3-minute stages, and the test wasterminated once peak volitional effort and peak heart rate were recorded.VO2peak was normalized to body weight (ml/min/kg) forinterindividual comparison.Exercise testing was performed as described previously.18IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13,IL-17, TNFα, interferon γ, granulocyte-monocyte-colonystimulating factor (GM-CSF), monocyte chemoattractant protein-1, andmacrophage inflammatory protein-1β. Concentrations of catecholamines in urine, and cortisol in serum andurine per 24 hours were measured and recorded similarly. For statisticalmodelling, the maximum and mean levels of cytokines, catecholamines, andcortisol were calculated for the period of acute hospitalization and for theperiod between discharge and study date.Abundance of the following cytokines were determined as describedelsewhere:Prior to enrollment, a power analysis was carried out to determine thenumber of subjects needed to demonstrate differences in systolic function fromhealthy controls. Based on a normal EF% of 60±20%, ahypothesized effect size of 15%, a type-I error rate (α) of0.05, and power (1-β) of 0.8, it was determined that 39 burn subjectswould need to be enrolled to detect a statistically significant differences inEF%. All analyses were carried out with R 3.3 for Windows  or Graphpad Prism 7.00 for Windows . Student’st-test and one-way ANOVA were used to compare continuous outcomes. Standardunivariate and multivariate least-squares regression models were fit tocontinuous responses. As necessary, predictors and responses were transformed toallow for better fitting of the model assumptions. For categorical outcomes,logistic regression models were fit; inference was based on comparisons ofdeviances among hierarchically fit models. Multi-variable logistic regressionmodels were fit and assessed using standard generalized linear model functionsin R. All data are reported as mean ± SD unless otherwise noted. For allanalyses, statistical significance was reported with p < 0.05.http://dx.doi.org/10.17632/xrh3pd9by7.1R code and data of univariate and multivariate analyses can be accessedonline through the Medeley network: None of the study sponsors had any role in the study design; in thecollection, analysis, or interpretation of data; in the writing of the report;or in the decision to submit the paper for publication. The following authorshad access to the raw data: GH, RPC, VNC, PW, AMQ, KJ, LKB, NRM, CCF, OES, DNH,MPK. The corresponding author had full access to all data in the study and hadfinal responsibility for the decision to submit for publication.As shown in Echocardiographic findings concerning systolic and diastolic function,as well as myocardial fibrosis are summarized in The avcIB of the septal and posterior wall was -22 ± 6 dB, and18% of burn subjects were classified as presenting with myocardialfibrosis (avcIB > −15 dB). Significant correlations weredetected between diastolic dysfunction and fibrosis  and systolic dysfunction and fibrosis. Nosignificant correlation was found between systolic and diastolic dysfunction.2 or heart rate were detected between thegroups  and weight-adjustedVO2 peak . They also had a lower absolute heartrate increase , relative heart rate increase , andpeak heart rate .Twenty-six burn subjects (65%) were classified as NYHA I, 13(33%) as NYHA II, 1 (3%) as NYHA III and none as NYHA IV. Nodifferences in resting VOegroups . ExercisClinical variables: Length of hospitalization , ventilation days , TBSA burned , and Baux score had significant least squares effectson long-term myocardial fibrosis; Baux score had a significant logisticeffect on the categorical outcome of fibrosis  . AdminisCytokine concentrations: Linear regression of cytokineconcentrations measured during intensive care hospitalization showedsignificant association between maximal levels of IL-1β , TNFα , and G-CSF  and EF% as well as mean levels of TNFα  and EF% . There wLogistic regression of acute cytokine concentrations showed thatmaximum IL-5  and mean IL-5  were significant predictions of EF%< 40%. Maximum IL-8 and mean IL-8  during acutehospitalization predicted an abnormal E/e′ > 8. Logisticregression yielded no other significant results for any of the otheranalyzed parameters, time points, and outcomes.Multivariate modelling: Multi-variable logistic regressionmodels  showedsThis study provides evidence for fibrosis and long-term cardiac dysfunctionin young adults who survive severe thermal trauma as a child. Here we haveestablished long-term associations between injury severity and systemic inflammatorystress on one hand and specific indicators of myocardial fibrosis and systolic anddiastolic dysfunction on the other.19 may not be fully reversible, as suggested in reportsemphasizing temporary dysfunction instead of structural impairment.20 Systolic dysfunction in youngadults has important implications, as large prospective trials identified it as apowerful predictor of heart failure.10Almost half (43%) of the long-term burn survivors examined in thisstudy showed signs of systolic dysfunction with an EF% below 50%,and the average EF% was substantially lower than that in healthy controls.Our data suggest that acute depression of contractility, as described in variousreports on pediatric and adult burn injury and other critical illness, may persistlonger than originally anticipated.11 A considerableproportion of burn subjects displayed signs of moderate (50%) or severe(21%) LV diastolic dysfunction, and average diastolic function wassignificantly worse than in healthy controls. Secondary findings of decreased E/Aratio and increased pulmonary capillary wedge pressure support the presence ofincreased LV filling pressure. LV diastolic dysfunction develops early in mostcardiac diseases, has a high prognostic value, and is an important indicator for LVheart failure in the absence of systolic abnormalities.21 In young adults it has been identified as anindependent predictor for the early development of heart failure, reduced exercisecapacity, and increased mortality.23LV diastolic dysfunction characteristically results in increased LV fillingpressure.25 Increased LV filling pressure, systolic and diastolicdysfunction and myocardial fibrosis interact with and promote one another:Deregulated interstitial collagen I synthesis and deposition occur as a result ofincreased ventricular pressure, induce subsequent diastolic dysfunction throughventricular stiffening, which also worsens LV systolic function.27The significant correlations between avcIB, EF% and E/e′, underscorethis interdependence. The presence of diastolic dysfunction and myocardial fibrosisis associated with poor prognosis, a greater risk of death and a further decline incardiac function.28We found that 20% of the study population showed evidence ofmyocardial fibrosis, when using a conservative cut-off for average LV and septalintegrated backscatter of -15dB.29 At rest, few burn survivors showedany of symptoms of heart failure while peak oxygen consumption during exercise wassignificantly reduced. Resting diastolic function has been established as thestrongest echocardiographic correlate of exercise tolerance, while systolic functionplays a minor role.29 Peak heartrate, as well as the absolute and relative increase in heart rate were reduced inburn patients. While the exact mechanism remains unclear, chronotropic failure(defined as the inability to reach target heart rates during strenuous exercise) hasbeen shown to reliably predict mortality and incident cardiac disease in adults withclinically asymptomatic heart failure.30 We have previously proven prolonged elevation of resting heartrates and systemic catecholamines in pediatric burn survivors for more than twoyears postburn; a chronic down-regulation of beta-adrenergic receptors maycontribute to the inability to increase heart rates and meet oxygen demand duringexercise3.Echocardiographic findings in our study population were associated withimpaired exercise tolerance – a hallmark of diastolic dysfunction.19 In line with studies, that suggest systemicstress and inflammation as inductors of cardiovascular sequelae31, we found significant associations betweenacutely elevated pro-inflammatory cytokines and measures of systolic and diastolicdysfunction. Systemic inflammation has been linked to LV hypertrophy, collagen Ideposition, and ventricular stiffening.31 In line with our multivariate models, a number of reportshave identified TNFα, IL-1β, and IL-6 as main drivers of acutecardiac depression and long-term structural remodeling.7Whether our long-term findings are associated with critical illness ingeneral or burn trauma in particular is unclear. Echocardiographic markers offibrosis were associated with general clinical measures of critical illnessseverity, such as length of hospitalization, ventilation days, and TBSA burned. Theadministration of inotrope medication in general and dobutamine in particularsignificantly increased the probability of long-term severe systolic and milddiastolic dysfunction, suggesting that the severity of initially sustained cardiacstrain may play an important role in long term dysfunction.9 However, noprospective studies have followed a cohort of survivors to assess the progression ofmorphologic and functional changes. Based on data showing systolic and diastolicdysfunction as well as myocardial fibrosis to be independent risk factors for poorcardiovascular and overall health, it is reasonable to assume that, in childrensurviving burn injury, cardiovascular disease burden may increase disproportionallylater in life.The implications of our findings are difficult to gauge at present. Data byDuke et al. suggest that adult and pediatric burn survivors are more prone tosequelae of cardiovascular disease later in life.32 or quality of life post burn were not evaluated as possiblecontributors to cardiac dysfunction. Data on specific sports activity was notcollected. Future studies will need to include this variable, as exercise may havepositive effects on the progression of cardiac dysfunction. Also, due to the noveltyof the observed data, our univariate analyses are broad and bound to the type andtiming of measurements made in the past. This study was underpowered to confirm theestablished linear relationship between diastolic dysfunction, fibrosis and exerciseintolerance.This study has limitations that bear consideration. The observational andcross-sectional nature of this study prevents conclusions of a prospective,longitudinal trial. This is emphasized by the fact, that no consistentechocardiographic baseline data of cardiac function during acute hospitalization wasavailable for analysis. Therefore, no inferences can be made regarding the exacttrajectory and possible persistence of cardiac dysfunction. As a consequence of thisstudy, structured and prospective assessments of the presented and additionalendpoints, spanning time points from the acute phase to long term recovery have beenimplemented at our institution to elucidate the trajectory of cardiac dysfunctionand remodeling more comprehensively over the next decades. While the repeatedhospitalization for reconstructive procedures of our study subjects enabled thisstudy in the first place, the implicated systemic strain itself may have contributednegatively to the observed results. Systolic and diastolic function measurementscould not be obtained in two subjects due to hypertrophic scarring of the chest. Thegroup of healthy volunteers was ethnically more diverse than the group of burnpatients; except BMI, no objective measures of cardiac risk factors independent ofburn injury were assessed; mental statusClearly, well-powered prospective trials with systematic assessments fromthe acute phase through long-term time points are needed to elucidate all complexmechanisms at play. Such research, also in other fields of pediatric and adultcritical care, will ultimately assess the generalizability of our findings.Long-term survivors of severe pediatric burn injury show signs of systolicand diastolic dysfunction as well as evidence of structural cardiac remodeling, andresultant exercise intolerance. Surrogate parameters of inflammation and severity ofcritical illness are associated with extent of cardiac dysfunction in young adults.The implications of these findings for future cardiovascular disease burden in thesepatients are unclear at present.supplement