Diagnosis of significant coronary artery disease (CAD) and acute coronary artery occlusion in ICU can be difficult, and an inappropriate intervention is potentially harmful. Myocardial contrast perfusion echo (MCPE) examines ultrasound contrast intensity replenishment curves in individual myocardial segments measuring peak contrast intensity and slope of return as an index of myocardial blood flow (units = intensity of ultrasound per second [dB/s]). MCPE could possibly serve as a triage tool to invasive angiography by estimating blood flow in the myocardium. We sought to assess feasibility in the critically ill and if MCPE could add incremental value to the clinical acumen in predicting significant CAD.This is a single-centre, prospective, observational study. Inclusion criteria were as follows: adult ICU patients with troponin I > 50 ng/L and cardiology referral being made for consideration of inpatient angiography. Exclusion criteria were as follows: poor echo windows (2 patients), known ischaemic heart disease, and contrast contraindications. Seven cardiologists and 6 intensivists blinded to outcome assessed medical history, ECG, troponin, and 2D echo images to estimate likelihood of significant CAD needing intervention . Clinical acumen, quantitative MCPE, and subjective  MCPE were assessed to predict significant CAD.p = 0.050). A MCPE value of 2.8 dB/s had 67% sensitivity and 88% specificity in detecting significant CAD. Clinical acumen showed no association in prediction of CAD ; however, if quantitative or visual MCPE analysis was included, a significant association occurred .Forty patients underwent MCPE analysis, 6 (15%) had significant CAD, and median 11 of 16 segments (IQR 8–13) could be imaged (68.8% [IQR 50–81]). No adverse events occurred. A significant difference was found in overall MCPE blood flow estimation between those diagnosed with significant CAD and those without (3.3 vs 2.4 dB/s, MCPE is feasible in the critically ill and shows better association with predicting significant CAD vs clinical acumen alone. MCPE adds incremental value to initial assessment of the presence of significant CAD which may help guide those who require urgent angiography. Significant coronary artery disease (CAD) and acute coronary artery occlusion can be challenging to diagnose in the critically ill . AccuratMyocardial perfusion assessment with echo contrast  is a technique used predominantly in stress echo studies for simultaneous assessment of myocardial perfusion and regional wall motion abnormality. It has been shown to improve the detection of CAD, in a safe manner and can have prognostic value over regional wall motion detection , 3. EchoEcho contrast agents have been shown to be safe in the critically ill for LV opacification . This stWe performed a prospective, observational study in the ICU at Nepean Hospital, Sydney, Australia, between May 2014 and January 2017 on non-consecutive patients . All patients or authorized representatives (next of kin) gave written consent to be involved in the study which was approved by the Nepean Blue Mountains Local Health District human research and ethics committee (study 15/17-LNR/15/NEPEAN/37). Inclusion criteria were as follows: adult (> 18 years), raised (high sensitivity) troponin I levels (greater than 50 ng/L), acute coronary artery occlusion being considered, and a request made for consideration of coronary angiography. Patients were excluded if they had urgent angiography already performed due to STEMI criteria being met, were unable to have apical echo imaging performed (2 patients), past medical history of ischaemic heart disease, contraindications to echo contrast , significant valvular abnormalities, pregnant, and study refusal.Six intensive care specialists with a high level of echo experience  as well as seven cardiologists were invited to review all relevant patient data and echo imaging to provide an estimate, based on clinical acumen, of the likelihood of the presence of significant CAD needing inpatient intervention on a Likert scale. Data included admission history, ECG, serum troponin levels, and past medical history . In addition, time of admission, imaging and troponin, APACHE III, SOFA score, and haemodynamic data were recorded. The presence of significant CAD was assessed by coronary angiography, nuclear imaging, MRI, CTCA, or normal repeat echocardiography shortly after initial imaging in patients with stress-induced cardiomyopathy diagnosis.A full comprehensive echo was performed initially by S.O. or trained sonographers with either a Vivid 9 or Vivid I echo machine . The studies and analysis were performed in accordance with the leading echo organization guidelines , 8 to obThe contrast agent Definity® was used for MCPE analysis. The microspheres have a mean bubble size of 1–10 μm enabling passage through the pulmonary vasculature . Definitt0, and signal intensity (SI) was calculated for each ROI at each end-systolic frame and plotted against time and fitted to the exponential function: y(t) = A(1 − eβ(t − t0)−) + C. y is the SI in the ROI at the end-systolic frame, A is the plateau SI corresponding to myocardial blood volume, β is the exponential decay function (decay constant) representing the rate of SI rise, and C is the intercept at the origin reflecting the background intensity level. A × β provides an estimate of the initial rate of contrast replenishment, and this provides a surrogate of myocardial blood flow  vs 3016 [1255–8630] for those with no significant CAD vs those with significant CAD respectively). Echo was performed within median 8 h (3–22) from when troponin levels were taken. Echo data displayed predominantly a normal LV size: mean end diastolic diameter 49 mm (8); with mildly reduced LV systolic function measured by conventional ejection fraction: mean 45.7% (15); but with global longitudinal strain analysis by speckle tracking, more severe dysfunction was elucidated: mean − 9.2% (5). Substantial regional wall motion abnormalities were common .Feasibility and values for each myocardial segment analysis technique are shown in Table p = 0.091); however, if quantitative or subjective MCPE analysis was included in the model, incremental improvement and significant association was seen . The best association was seen with subjective MCPE analysis alone .Based on ROC curve analysis, the optimal MCPE cut-off value for the presence vs absence of significant CAD is 2.9 dB/s see Fig.  which haInter-rater variability was assessed by M.S. vs S.O. in random 6 patients (15%). Inter-rater variability was reasonable with mean absolute difference in estimated blood flow (± SD) of 0.31 dB/s (± 1.5) and expressed as percentage of the mean of 9% (± 36).We found performing myocardial contrast perfusion echocardiography (MCPE) to be feasible in critically ill patients, with no significant adverse reactions seen. Importantly, clinical acumen alone  did not have significant association with predicting the presence of significant CAD. However, if quantitative or subjective MCPE analysis was included in the assessment, then significant association was seen.Troponin I levels are frequently elevated in the ICU population; however, only a minority of patients have significant CAD and/or acute coronary artery occlusion (e.g. from thrombus or acute antherosclerotic plaque rupture). Ko et al. found only 30% of ICU patients with a clinical diagnosis of myocardial infarction ended up with a diagnosis of significant CAD on coronary angiography . Our stuWei et al. pioneered the method of using echo contrast to estimate myocardial blood flow, and it appeared to be correlated well with radiolabeled microsphere myocardial blood flow . This teWe found MCPE much better at assessing the apical than the basal segments, which may mean that this method may be more efficient at assessing left anterior descending coronary artery territory ischaemia than the other coronary arteries. Indeed, feasibility was much better in the LAD territory than the LCx or RCA. This is disappointing given that posterior ischaemia may be more difficult to diagnose in critically ill patients; however, other studies have reported similar results .There are several limitations to our small, single-centre, observational study. The primary issue is the lack of a recognized reference standard to exclude acute coronary artery occlusion (angiography or cardiac MRI) in a significant portion of our patients . However, often, once an acute event had settled, the risk of angiography may outweigh the benefit (e.g. likely stress-induced cardiomyopathy in a patient with subarachnoid haemorrhage). Those with an initial abnormal echo were not excluded and then normalized findings at a later date still had coronary artery disease similar to those having exercise stress tests; however, we did find a high specificity and negative predictive value in those with significant CAD found. In addition, the analysis was performed by a single operator (S.O.) who was at times the treating clinician. The blinding of the analysis was therefore, at times, not possible. Patients were not consecutive as S.O. was the sole MCPE operator in the unit and patient inclusion was based on other clinicians highlighting potential subjects, during work hours. Several patients are likely to have been missed and this suggests selection bias. However, this was primarily a feasibility study and information may be useful as pilot data to guide future studies. The analysis of our data into coronary artery territories may also be inaccurate as individual patient coronary artery blood flow does not always follow the standard anatomical boundaries.The use of MCPE in determining large defects in myocardial blood flow may be useful in the ICU environment. Further research should be done in this area to try and help improve our early recognition of significant CAD. Studies should focus on true blinded assessment, multi-operator analysis, and objective MCPE analysis being performed immediately after the study has taken place. Additional studies may assess the significant variation seen in clinicians estimating the likelihood of significant CAD being present and if MCPE analysis could help reduce some of this variation.We found MCPE estimation of myocardial blood flow to be feasible in critically ill patients and found no adverse events. Clinical correlation alone is extremely variable and unable to reliably determine the presence or absence of significant CAD, yet we know that unnecessary intervention or treatment can be harmful. MCPE may be able to improve our recognition in predicting significant CAD in the critically ill.


Symptoms of right ventricular failure include dyspnea, a reduction in exercise capacity, and fluid retention. Right ventricular (dys)function strongly influences functional state and survival. The right ventricle is directly involved in a variety of diseases. A thorough analysis of right ventricular size and function, as well as estimation of pulmonary artery pressures is an important part of every echocardiographic examination. This review analyses the most commonly used parameters for quantification of right ventricular function. It gives a practical approach for estimation of right ventricular size and function, as well as pulmonary artery pressure. The right ventricle is directly involved in a variety of diseases. Right ventricular size and function play a crucial role in patients with pulmonary hypertension, cardiomyopathies, pulmonary embolism, right ventricular infarction, pulmonary and tricuspid valvular heart disease and intracardiac shunts. In recent years, right ventricular function in left heart disease has received more and more attention , 16, 20.The shape of the right ventricle (RV) has been compared to that of a bagpipe and consists of an inflow and an outflow compartment. The RV and the left ventricle (LV) are closely linked together. The interventricular septum connects the two ventricles. They share the same pericardial space and have mutual epicardial fibers. The RV generates the same stroke volume as the LV but due to low resistance in the pulmonary vasculature it requires only one quarter of the stroke work. This explains the thin right ventricular wall as compared to the left ventricular myocardium . When puThe gold standard for quantification of size, ejection fraction, and stroke volume of the RV is cardiac magnetic resonance imaging (MRI). The gold standard for the measurement of pulmonary pressures is right heart catheterization; however, echocardiography is usually used as the first diagnostic tool to assess size and function of the right heart. As an echocardiographer, it is important to always keep in mind the power but also the pitfalls of echocardiographic assessment of pulmonary pressures and right ventricular size and function. Lang et al. published the most recent recommendations for cardiac chamber quantification by echocardiography in adults in 2015 , amendinAssessment of the size of the RV in 2D echocardiography is challenging. Common diseases that lead to right ventricular dilatation, such as left-to-right shunts, pulmonary valve disease, tricuspid regurgitation, pulmonary hypertension, right ventricular infarct and cardiomyopathies, e.g. arrhythmogenic right ventricular dysplasia (ARVD) have to be excluded. In patients with chronic pressure and/or volume overload, follow-up examinations have to clarify if the patients are stable or if there is deterioration in size and/or function. Precautious analysis of the size of the RV has to be performed and the examiner must ensure that measurements are made in a comparable way to the previous studies. The right heart has to be imaged from multiple acoustic windows, and the report should be based on a comprehensive interpretation of all findings.Echocardiography allows reliable detection of a severely or moderately dilated RV. While the ratio between the size of the LV and the RV is more than 1.3 under physiological circumstances, the RV often exceeds the size of the LV in patients with moderate or severe right ventricular dilatation (ratio <1). It is more difficult to differentiate “normal” from “abnormal” when the RV is only mildly dilated. In such situations, quantitative parameters become very important.The normal RV has a triangular shape in the 4‑chamber view. Transverse measurements differ significantly the closer one gets from the base (tricuspid annulus) to the apex. In the RV focused 4‑chamber view three measurements can be performed. The RV at its base, at mid-level and in the longitudinal dimension. The second imaging window is the RV outflow tract. First the proximal diameter should be measured in the parasternal short axis view and/or in the parasternal long axis view. Finally, the distal diameter of the RV outflow tract should be measured at the level of the pulmonary valve insertion . Normal In contrast to the LV, no exact geometric model exists for the RV, which would allow for volumetric assumptions by 2D echocardiography. The size of the RV is underestimated in 2D echocardiography as opposed to cardiac MRI. This especially applies to patients with congenital heart disease and to patients with RV volume overload . The useThe main role of the RV is to sustain an effective cardiac output. Stroke volume of the RV is predominantly generated by longitudinal shortening rather than by reduction of the cavity diameter  as is the case in the LV . Due to Visual examination is the most commonly used method to quantify right ventricular function (RVF). There are many pitfalls that can lead to overestimation or underestimation of function. If used as a single parameter, visual examination proved to be an inaccurate method for evaluation of RVF , 19; theTAPSE is the most commonly used parameter for RVF quantification. In an apical 4‑chamber view the maximum systolic excursion of the lateral tricuspid annulus is measured by M‑mode. The tracing can be acquired quickly and its interpretation is straightforward. A low TAPSE value is associated with lower cardiac index and worse survival , 11. TAPThe Tissue Doppler of the free lateral wall (S’) measures the longitudinal velocity (base to apex) of the tricuspid annular plane by tissue Doppler imaging. The sample volume is placed in the basal segment of the free lateral wall of the right ventricle or into the tricuspid annulus. Since the method is angle-dependent, the Doppler beam has to be aligned parallel to the motion of the free lateral wall towards the apex. The measurement is reproducible and easily obtained. A comparison with MRI-derived RV ejection fraction (RVEF) showed a significant correlation with S’ . An S’ vThe fractional area change (FAC) is a 2D surrogate for RVEF. It is performed by tracing the endocardial RV borders during diastole and systole and is calculated by the following formula: 100 × (RV-Area end-diastolic [ED] − RV-Area end-systolic [ES]) / RV-Area ED. A RV focused 4‑chamber-view is essential to ensure that the entire endocardial border is visible in end-systole and end-diastole. Trabeculations and the tricuspid valve leaflets are included when tracing the area. The FAC showed good correlation with MRI-derived RVEF  and in pThe longitudinal strain is the percentage of systolic shortening of the myocardium. One can assess both regional and global contractile function. Global longitudinal strain is a well-established tool to detect early LV dysfunction but it can also be used for quantification of RVF. Global strain of the free lateral wall of the RV is calculated by averaging peak systolic strain of the three segments of the free lateral wall in an RV focused 4‑chamber-view. Higher negative strain values represent better systolic function. Numerous studies showed that RV strain is a powerful method to assess RVF. It is a predictor of survival in patients with pulmonary hypertension  and corrThe prognostic value of RVEF was shown in several studies. Radionuclide angiography derived RVEF ≥35% vs. 25–35% vs <25% predicted survival as 93% vs 77% vs 59%, respectively, in patients with left heart failure . Loss ofSo far, the problem for echocardiographers was the unreliable estimation of RVEF via 2D echocardiography since it is not able to calculate true volumes. This limitation is overcome with 3D echocardiography, which does not rely on geometric assumptions but calculates true 3D volumes. The RVEF derived by 3D echocardiography proved to be an independent predictor of adverse cardiovascular outcomes in patients with various cardiovascular diseases ; howeverMany conditions have been described where TAPSE and S’ do not reflect true RVF. These include patients after cardiac surgery, tetralogy of Fallot, and tricuspid regurgitation , 27, 29.Other parameters such as RV myocardial performance index (RIMP) and the rate of RV pressure rise during early systole (dP/dt) proved to correlate with pulmonary vascular resistance  and to p2 and for men 25 ± 7 ml/m2 [2 as an echo-sign for elevated RA pressures [The right atrium (RA) assists filling of the right ventricle . When th 7 ml/m2 . The guiressures .Fig. 3RiEstimating pulmonary artery pressures is an important part of every echocardiographic evaluation of the right heart. Echocardiography plays a crucial role in the diagnosis of pulmonary hypertension. Underestimation of pulmonary pressures can lead to delayed or false diagnosis. Overestimation can result in unnecessary right heart catheterization and possible complications.The guidelines for the diagnosis and treatment of pulmonary hypertension (PH) suggest the following approach for echocardiographic assessment of patients with suspected PH: maximum tricuspid regurgitation (TR) velocity and other echo signs of PH should be evaluated  is not exact and the value should not be used to grade severity of PH. Instead, maximum tricuspid regurgitant jet velocity is used as a surrogate of RV systolic pressure. Due to the angle dependency of the Doppler method, it has to be imaged from different views.If tricuspid regurgitation velocity is ≤2.8 m/s and in the absence of other echo signs of PH, the probability for PH is low. If TR velocity is ≤2.8 m/s or there is no sufficient signal but there are echo signs of PH or if TR velocity is 2.9–3.4 m/s and there are no echo signs for PH, then the PH probability is intermediate. In the presence of a TR velocity 2.9–3.4 m/s together with other echo signs or if TR velocity is above 3.4 m/s regardless of the presence of other echo signs, the probability for PH is high [A comprehensive assessment of the RV is an integral part of every echocardiographic examination. Dilatation of the RV must be ruled out using multiple views, visual examination, and measurements of RV size. Ideally, multiple parameters should be used to determine right ventricular systolic function. Validated and commonly used parameters are: visual examination, TAPSE, S’, FAC, longitudinal strain, and 3D echocardiography. The standardized approach suggested by the PH guidelines should be followed when evaluating pulmonary pressures.


The aim of this review is to explore the possible role of ST2 derived-protein as an early marker of cardiovascular diseases, above all in heart failure and ischemic heart diseases.Cardiovascular diseases (CVD) are the major cause of death worldwide. The identification of markers able to detect the early stages of such diseases and/or their progression is fundamental in order to adopt the best actions in order to reduce the worsening of clinical condition. Brain natriuretic peptide (BNP) and NT-proBNP are the best known markers of heart failure (HF), while troponins ameliorated the diagnosis of acute and chronic coronary artery diseases. Nevertheless, many limitations reduce their accuracy. Physicians have tried to develop further detectable molecules in order to improve the detection of the early moments of CVD and prevent their development. Soluble ST2 (suppression of tumorigenicity 2) is a blood protein confirmed to act as a decoy receptor for interleukin-33. It seems to be markedly induced in mechanically overloaded cardiac myocytes. Thus, HF onset or worsening of a previous chronic HF status, myocardial infarct able to induce scars that make the myocardium unable to stretch well,  Cardiovascular diseases (CVD) are the main leading cause of death worldwide . Their iet al.  in a risk model adopted within their population by considering all the clinical variable of the sample [ et al. [i.e., >35 μg/L) in NSTE-ACS patients predicted a >3-fold higher risk of cardiovascular death and heart failure at 30 days and 1 year, even after adjustment for major clinical risk factors and biomarkers (cTnI and BNP) [Non-ST segment elevation acute coronary syndrome (NSTE-ACS) patients did not differ from their STE-ACS counterpart . sST2 ple sample . These r[ et al.  who demoand BNP) . Neverthand BNP) .et al. [Furthermore, the value of sST2 as predictor of functional recovery and remodeling of LV in the post-infarct phase was also evaluated. Weir et al.  effectivet al. .p = 0.02); and if both ST2 and B-type natriuretic peptide levels were elevated, the risk resulted even higher (p = 0.01) [sST2 role in predicting mortality was recently demonstrated in 588 outpatients referred for echocardiograms. The optimal cut-point of sST2 for predicting 1-year mortality was 28.25 ng/mL. Patients with high ST2 levels had an increased risk of death ( = 0.01) .p = 0.006), antihypertensive medication use (p = 0.03), and diabetes (p = 0.001) [p < 0.0001) and old age (p = 0.004) were related to higher sST2 concentrations [In the Framingham Heart Study, sST2 concentrations were related to systolic blood pressure (= 0.001) . By adjutrations .Nevertheless, the measurement of sST2 in 348 patients presenting to the emergency department with chest pain sST2 was found to be increased in those suffering from pulmonary disease , systemic infection or inflammation, and alcohol abuse .The ST2/IL-33 pathway is involved in pathophysiology of myocardial dysfunction by potentially attenuating the cardioprotective effects of IL-33. It seems to reduce the extent of cardiac damage after myocardial infarct, cardiomyocyte apoptosis, inflammatory cardiac activation, fibrosis, adverse myocardial remodeling. sST2, by acting as a decoy receptor, could prevent the beneficial effects of IL-33/ST2L interaction. sST2 measurements in blood samples could be a clinical prognostic biomarker useful in risk stratification of patients suffering from myocardial infarction, HF and dyspnea. Further studies are needed in order to better point out the evidence for a routine use of sST2 evaluation in the clinical evaluation of a patient suffering from myocardial infarction and HF.


FXN) gene. The number of GAA repeats have been shown to relate to disease severity in FRDA, this thought to be via an inverse relationship of GAA repeat number and cellular frataxin levels. We investigated the effects of FRDA on regional long axis function of the left and right ventricles, and also the relationship of long axis systolic (s`) and early diastolic (e`) peak velocities with GAA repeat number on the shorter (GAA1) and longer FXN alleles (GAA2).Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative condition which also has effects on the heart. In 96% of affected individuals FRDA is due to homozygosity of a GAA repeat expansion in intron 1 of the frataxin (The study group of 78 adult subjects (age 32±9 years) with FRDA and normal left ventricular (LV) ejection fraction were compared to 54 healthy control subjects of similar age, sex and body size. Tissue Doppler imaging (TDI) signals were recorded at the mitral annulus for measurement of s`and e`of the septal, lateral, anterior and inferior walls and at the tricuspid annulus for measurement of right ventricular (RV) s`and e`.All the regional LV s`and e`, and both RV s`and RV e`, were lower in individuals with FRDA compared to controls . On multivariate analysis, which included LV septal wall thickness (SWT), RV s`and RV e`were both inversely correlated with GAA1 , but not with GAA2, whereas anterior and lateral s`were both inversely correlated with GAA2  but not with GAA1. Increasing SWT was the most consistent LV structural correlate of lower s`and e`, whereas age was a consistent inverse correlate of e`but not of s`.FXN gene.There are generalized abnormalities of both LV regional and RV long axis function in FRDA, but there are also regional differences in the association of this dysfunction with the smaller and larger GAA repeats in the  FXN), and in 96% of affected individuals it is due to homozygosity of a GAA repeat expansion in intron 1 of the FXN gene [Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative condition due to a deficiency in the mitochondrial protein frataxin . The study group comprised adult subjects with FRDA due to homozygosity for GAA expansions in the FXN gene who had a normal LV ejection fraction (>50%) and who were free of hypertension and diabetes. Subjects with FRDA were compared to a control group of similar age, sex and blood pressure.To further define the effects of FRDA on myocardial function, we investigated the effects of FRDA on long axis systolic and early diastolic tissue Doppler imaging (TDI) velocities of the RV free wall, and of the septal, inferior, anterior and lateral walls of the left ventricle. In addition, we investigated the relationship of the RV and LV regional velocities with GAA expansion length of both the smaller (GAA1) and larger FXN gene who were seen in a multidisciplinary FRDA clinic and who did not meet the exclusion criteria. FRDA subjects were excluded if they had diabetes, a history of heart failure or hypertension, a cardiac rhythm other than sinus, a blood pressure (BP) greater than 140/90 mmHg at the time of the echocardiographic examination, an ejection fraction ≤50% or more than mild valvular disease. Data from the same echocardiogram for M-mode LV measurements and septal and lateral TDI velocities has been reported previously for 27 of the subjects in the present study [All research involving human participants was approved by the Monash Health Human Research and Ethics Committee and all clinical investigation was conducted according to the principles expressed in the Declaration of Helsinki. The echocardiographic studies of individuals with FRDA who met the study criteria were identified retrospectively, the need for consent was waived, and the analysis was performed on anonymized data. Written informed consent was obtained from all control subjects. The study group comprised 78 adult subjects with FRDA due to homozygosity for a GAA triplet repeat expansions in intron 1 of the Transthoracic echocardiography was performed using a Sonos 5500 ultrasound machine (Philips) and measurements were performed off-line using Xcelera V1.2 L4 SP2 (Philips). M-mode images of the left ventricle were obtained in the parasternal long axis view just distal to the mitral valve leaflet tips after alignment of the cursor perpendicular to the left ventricular wall. 2-D images were also used to facilitate identification of the endocardium and standard M-mode measurements of LV septal wall thickness (SWT), posterior wall thickness (PWT), LV end-diastolic diameter (LVEDD) and LV end-systolic diameter were obtained ,11. FracFour- and two-chamber apical loops of left ventricular contraction were recorded and used for measurement of LV EF using the biplane method of discs. The length of the LV at end-diastole from the plane of the mitral annulus to the apical endocardium in the 4- and 2-chamber views was recorded during the end-diastolic measurement, and the longest dimension from these 2 views was used as the left ventricular end-diastolic length (LVEDL) ,14.Pulsed wave TDI was performed in the apical four- and two-chamber apical views. TDI velocities of longitudinal annular motion were recorded at end expiration apnoea at the septal, lateral, anterior and inferior mitral annular borders and at the lateral tricuspid annular border, all after optimizing parallel alignment of the ultrasound beam. Spectral pulsed wave Doppler was used with instrument settings adjusted to record the high frequency/low velocity tissue signals using an appropriate sample volume size. Peak systolic (s`), and early diastolic (e`) velocities were measured off-line and 3 consecutive beats were averaged. Satisfactory tissue Doppler signals were acquired in all subjects. Interobserver variability for measurements of TDI velocities in control subjects in our laboratory using the Sonos 5500 have been reported previously and varied between 5.5 and 7.7% .FXN gene was measured as previously described [The number of GAA repeats in the escribed .Data were analyzed using standard statistical software (SYSTAT V13). Continuous variables are presented as mean ± SD. Group differences in continuous variables between FRDA subjects and controls were assessed with an unpaired Student t test. Linear regression analysis was performed in FRDA subjects to determine correlations of RV and LV regional TDI velocities with independent variables including age, age at the onset of symptoms (AOS), symptom duration, GAA1, GAA2, heart rate, blood pressure, body surface area (BSA), body mass index (BMI), LVEDD, SWT and LVEDL ,17–19.2) has been provided for multivariate analyses as an estimate of the degree of variance in a dependent variable explained by a multivariate model after adjustment for the number of independent variables in the model. Apart from decisions regarding inclusion of variables in multivariate models, a p value of <0.05 was considered significant.The correlation coefficient (r) is provided for univariate regression analyses and the partial correlation coefficient , positively correlated with BSA (p = 0.033) and inversely correlated with age (p = 0.042) and GAA1 (p = 0.028). LVEDD was also larger in males (p = 0.003) and positively correlated with BSA (p = 0.024), but it was not correlated with age and it was only borderline correlated with GAA1 (p = 0.074). LVM was larger in males (p<0.001), positively correlated with BSA (p = 0.038) and inversely correlated with age (p = 0.004), but was not related to GAA1. SWT was larger in males (p = 0.006) and inversely correlated with age (p = 0.034), but there was no correlation of SWT with BSA or GAA1.Comparison of s`and e`at the tricuspid annulus and the septal, inferior, anterior and lateral borders of the mitral annulus in FRDA and control subjects are shown in For correlations of RV s`with LV regional s`velocities, the highest r values were for the septal and inferior walls  and the lowest were for the anterior and lateral walls . The highest r value for RV e`was with septal e`, and there were only small differences with the correlations of RV e`with the other LV walls . For inter-relationships of LV regional s`, the r values were highest between the septal and inferior walls, and between the anterior and lateral walls . There were similar correlations for e`between the septal and inferior walls and the anterior and lateral walls .Prior to multivariate analyses of TDI velocities in FRDA subjects, the possibility of confounding relationships were examined between the potential independent variables. There was the expected strong correlation between age and symptom duration  and inverse correlation between GAA1 and AOS , but no relation between GAA2 and AOS (r = -0.07), despite there being a positive correlation between GAA1 and GAA2 . There were no significant correlations of GAA1 or GAA2 with either age or symptom duration. There was an inverse correlation between GAA1 and systolic BP , but no significant correlation of GAA1 with diastolic BP, or of GAA2 with systolic or diastolic BP. There were no correlations of LVEDD with either SWT or PWT.In univariate analyses of control subjects, BSA was a positive correlate of all the RV and LV s`velocities , whereas age, heart rate, LVEDD and SWT were not correlates of any of the s`velocities. The univariate correlates of RV and LV s`velocities in FRDA subjects with age, GAA1, GAA2, AOS, symptom duration, BSA, heart rate, SWT, LVEDD and LVEDL are shown in On multivariate modeling of RV s`and regional LV s`velocities in FRDA subjects, GAA1, GAA2, AOS, SWT, LVEDD and LVEDL were added stepwise and in that sequence, only significant correlates remained in the model for the next step, and the significant independent correlates are shown in On univariate analysis in control subjects, all the regional LV e`were inversely correlated with age , whereas an inverse correlation of RV e`with age was borderline significant (p = 0.086). All LV e`velocities except inferior e`were also inversely correlated with diastolic BP (0<0.04) in control subjects, whereas septal e`, but none of the other e`velocities, was inversely correlated with BMI (p<0.04). None of the control subject regional e`velocities were correlated with SWT, LVEDD or LVEDL. The univariate correlations in FRDA subjects of the various RV and LV e`velocities with age, GAA1, GAA2, AOS, symptom duration, diastolic BP, BMI, SWT, LVEDD and LVEDL are shown in On multivariate modeling in FRDA subjects of RV e`and regional LV e`velocities, age, GAA1, GAA2, symptom duration, SWT and LVEDD were added stepwise in that sequence, only significant correlates remained in the model for the next step, and the independent correlations in the final models are shown in There are a number of new findings about the cardiac effects of FRDA from the present study performed in subjects with a preserved LVEF and no cardiac symptoms. First, there were reductions in RV long-axis systolic and early diastolic velocities and a generalized reduction of regional LV long axis systolic and early diastolic peak velocities compared to control subjects. Second, both RV s`and e`, but none of the regional LV s`or e`velocities, were independently and inversely correlated with GAA1. Third, anterior and lateral s`and septal e`, but none of the other systolic or early diastolic LV velocities, were independently and inversely correlated with GAA2. Fourth, a higher SWT (without indexation for body size) was an independent predictor of lower s`and e`velocities of most LV walls and was also associated with a lower RV e`. Fifth, a smaller LVEDD  was an independent predictor of a lower anterior and lateral e`, but not a predictor of septal or inferior e`or any of the regional LV s`. These findings demonstrate for the first time that there is early impairment of RV long axis function in FRDA, and that the reduction in LV long-axis function in FRDA affects all walls. Despite this apparent uniformity, there were a number of differences between the left and right ventricles, and between the different LV walls, in the associations of TDI velocities with GAA repeats and LV structural change, and thus possibly, in the mechanisms underlying the lower TDI velocities. Furthermore, while some previous studies have reported correlations of GAA2 with cardiac involvement in FRDA, we believe this to be the first study to describe the presence of different and independent associations of GAA1 and GAA2 with measures of cardiac function in FRDA.There were structural LV changes evident in the FRDA subjects in this study, reflected in LVEDD, SWT, PWT, RWT and LVMI, which are characteristic of the FRDA disease process. The most common abnormality in FRDA is increased RWT, and this is due to the combination of an increase in wall thickness and a reduction in LVEDD –5. LVMI RV function has not been a particular focus of research in FRDA, but there is a previous report that RV regional short-axis contraction can be impaired in FRDA despite preservation of both RV ejection fraction and LV ejection fraction . On the We and others have previously reported that there are abnormalities of LV long-axis systolic and early diastolic motion in FRDA ,6,7. TheGAA1 has been a consistent predictor of AOS in previous studies in FRDA ,16,23–27In the present study GAA1 was an inverse correlate of AOS, but there was no correlation of GAA2 with AOS. Both RV s`and RV e`were inversely correlated with both GAA1 and GAA2 on univariate analysis, but when included together in a multivariate model, only GAA1 remained as an independent predictor of RV s`and RV e`. On the other hand, GAA2 was a predictor of both anterior and lateral s`and that this was independent of GAA1 indicates that the GAA2 association was not due to any colinearity with GAA1 in this circumstance. Furthermore, that this correlation was also independent of SWT and LVEDD is consistent with there being a GAA2 related functional LV change in FRDA which is independent of the LV structural changes. However, no explanation for this observation is apparent at this time, and a causal relationship cannot be assumed. Thus, the GAA1 association with clinical features in FRDA can be attributed to the established correlation of GAA1 with frataxin levels , but a sFXN gene who are yet to develop neurological symptoms, but may already have cardiac changes, cannot currently be part of a cross-sectional cardiac study because there are no screening programs.Analysis of the relationship of TDI velocities with age, AOS and symptomatic duration, and interpretation of the findings, in the present study was necessarily complicated  because of the collinearity between these variables and several specific features of the cohort. Indeed, while often not considered, the following issues apply to varying degrees in all cohort studies in FRDA: 1) Age is the sum of AOS and symptom duration, with AOS reflecting both GAA1 and the severity of the underlying disease process  Age is t, and symThere are other limitations of our study. Our cohort was by design limited to adult FRDA subjects with preserved EF and without symptoms or signs of heart failure. Exclusion of individuals without overt cardiac dysfunction will have reduced the variability of TDI velocities, and thus the degree of correlation observed could underestimate the interdependence between some variables. Because of the associated neurologic dysfunction, FRDA subjects are relatively sedentary, and although this was not associated with an increase in BMI in FRDA subjects compared to control subjects in this study, this would likely have resulted in differences in fitness and fat free mass between FRDA and control subjects. A further limitation of the inclusion of sedentary subjects is that it is possible that some subjects were only free of exertional cardiac symptoms because of their lack of ability to exercise.FXN gene and the extent of LV structural change. Further studies are required to confirm these findings and to investigate possible mechanisms which might explain these regional LV and RV differences.In conclusion, there are generalized abnormalities of RV and LV regional long axis function in FRDA, but there are also regional differences in the association of the various LV walls long-axis TDI velocities with the small and large alleles of the S1 Data(XLSX)Click here for additional data file.


Contrast-induced nephropathy (CIN) becomes more and more frequent after percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI). There have been no reported meta-analyses to determine the role of these risk factors in predicting CIN in patients with STEMI undergoing PCI. So we made this meta-analysis to summarize the incidence of CIN in patients with STEMI undergoing PCI and to study associations between CIN and several risk factors that are mentioned in most prevention guidelines.  The overall incidence of CIN in patients with STEMI undergoing PCI is not low. Many risk factors could influence the occurrence of CIN, such as hypertension, diabetes mellitus (DM), and lower estimated glomerular filtration rate. I2 index).  Databases, including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Chinese BioMedical (CBM), were searched for articles published before May 21, 2019, to identify all relevant studies on CIN. The pooled data were analyzed using either fixed-effects or random-effects models depending on heterogeneity (assessed via the p < 0.00001), 1.83 , 2.14 , 7.79 , 1.92 , 3.12 , −6.15 , −15.06 , and 5.53 , respectively.  Twelve articles encompassing a total of 6342 patients were included. The overall pooled CIN incidence was 13.3% (95% CI: 10.4–17.1). The forest plots showed positive associations between CIN and the presence of hypertension, diabetes mellitus, history of prior myocardial infarction, age, damaged left anterior descending artery, Killip class ≥2, decreased left ventricular ejection fraction, lower estimated glomerular filtration rate, and left ventricular ejection fraction <40%; the odds ratios for these factors were 1.85 (95% CI: 1.57–2.18;  The overall incidence of CIN in patients with STEMI undergoing PCI was not low and was closely associated with hypertension, diabetes mellitus, history of prior myocardial infarction, age, damaged left anterior descending artery, Killip class ≥2, decreased left ventricular ejection fraction, lower estimated glomerular filtration rate, and left ventricular ejection fraction <40%. Percutaneous coronary intervention (PCI) has become increasingly important and common in the treatment of ST-segment elevation myocardial infarction (STEMI), resulting in fewer ischemic complications, more survival myocytes, preserved ventricular function, and improved survival of patients when compared with treatment via pharmacologic reperfusion with fibrinolytic agents , 2. The As a result, contrast-induced nephropathy (CIN), a relatively infrequent complication after PCI in patients with STEMI, has attracted increasing attention . CIN mayWe searched many databases, including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Chinese BioMedical (CBM), for articles published before May 21, 2019, to identify all relevant studies on CIN. We searched studies using the following key words: contrast-induced nephropathy , contrast induced acute kidney injury , cardiac catherization , and percutaneous coronary intervention . The detailed searching strategy is shown in the Appendix.The inclusion criteria were as follows: (1) written in English or Chinese, (2) patients with STEMI underwent PCI, (3) a prospective follow-up study, and (4) CIN incidence, and risk factors were clearly presented.The exclusion criteria were as follows: (1) duplicate publication , (2) ICU patients included, and their data could not be separately identified; (3) animal experiment, case report, meeting report, review, and studies on prevention , 12.Two reviewers (Huan He and Xiao-Rui Chen) independently searched databases, included and excluded papers, and assessed the data on methodological assessment. A third reviewer (Yun-Qing Chen) was consulted if the two reviewers could not reach the same conclusion.We used the Delphi list for randomized controlled trials (RCTs) and the QUADAS-2 tool to finish the methodological assessment of the included studies , 13. TheI2 index to test the heterogeneity of the incidence. A random-effects model was used to pool the CIN incidence when I2 ≥ 25%, while a fixed-effects model was used when I2 < 25%. We carried out this analysis on logit-transformed incidence because it is assumed to follow a normal distribution in each study, and therefore, we calculated the mean logit CIN incidence with corresponding standard errors. After antilogit transformation, we obtained pooled estimate of CIN incidence (95% CI). All of the abovementioned analyses were executed by using Stata/SE 12.0 software  <60 mL/min/1.73 mμmol/L or >50%. CIN was defined within 48–72 h after PCI in twelve papers.Three papers defined CIN as an increase in serum creatinine ≥25% from the baseline value within the 72-hour period; four papers defined CIN as an increase in serum creatinine ≥0.5 mg/dL; three papers defined CIN as an increase in serum creatinine of ≥25% or ≥0.5 mg/dL; one paper defined CIN as an increase in serum creatinine >25% or a decrease in the estimated glomerular filtration rate (eGFR) <25%; and one paper defined CIN as a rise in serum creatinine >26.5 The overall pooled incidence of CIN was 13.3% (95% CI: 10.4–17.1). We did not present the subgroup analysis of the incidence of CIN in different contrast mediums because there were only 12 papers.In analyzing the risk factors of CIN, not all twelve papers provided complete data. To acquire the original data, we tried our best to communicate with the authors but did not receive any responses. Therefore, we performed data analyses if 2 × 2 data could be extracted from the studies.p < 0.00001), and the I2 value was 0%, which indicated a homogeneous dataset. The forest plot is summarized in When analyzing the association between hypertension and CIN, we obtained a positive outcome. The OR was 1.85  was obtained, with an I2 value of 35%. These data are shown in In datasets evaluating the association between diabetes mellitus and CIN, an OR of 1.83 , and the I2 value was 0%. These data are shown in We found that the incidence of CIN was higher in people who had a history of prior myocardial infarction; the OR was 2.14  and a positive association, OR 7.79 . These data are shown in The pooled analysis of the relationship between age and CIN showed a nonhomogeneous dataset (p=0.01), and the I2 value was 67%. These data are shown in If the target vessels included left anterior descending in patients, then CIN was more likely to occur. In the meta-analysis of the association between damaged left anterior descending and CIN, the OR was 1.92 , and the I2 value was 0% when evaluating the association between Killip class ≥2 and CIN. The forest plot is shown in We found that the OR was 3.12 , as shown in the forest plot. The I2 value was 92%. These data are shown in We found that the left ventricular injection fraction (%) was lower in the CIN group, with an OR of −6.15 , and the I2 value was 49%. These data are shown in A lower estimated glomerular filtration rate led to an increased likelihood of developing CIN. The OR was −15.06 , as shown in the forest plot. The I2 value was 95%. These data are shown in Similar to those with a decreased left ventricular ejection fraction, those with a left ventricular ejection fraction less than 40% were more likely to develop CIN, with an OR of 5.53 , −5.64 , 4.30 , 1.55 , 5.99 , and −1.85 , respectively. The I2 values were 71%, 0%, 0%, 15%, 0%, and 95%, respectively. Gender , smoking, family history of coronary atherosclerotic heart disease, damaged right coronary artery (RCA), and damaged left circumflex artery (LCA) were not significantly associated with the incidence of CIN. All the data are shown in We found that anemia, triglyceride, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and hemoglobin could not predict the incidence of CIN; the ORs were 2.21 .By analyzing many risk factors that we extracted from previous studies, we only found a few risk factors associated with CIN: hypertension, diabetes mellitus, a history of prior myocardial infarction, age, damaged left anterior descending artery, Killip class ≥2, decreased left ventricular ejection fraction, lower estimated glomerular filtration rate, and left ventricular ejection fraction <40%.Other risk factors such as gender , smoking, anemia, family history of coronary atherosclerotic heart disease, triglyceride, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), hemoglobin, damaged RCA, and damaged LCA do not appear to have a significant association with the incidence of CIN.CM (contrast medium) plays a predominant role in CIN, yet specific underlying mechanisms have not been fully elucidated , 21. A dSimilar to other studies, our meta-analysis also has some limitations. First, there is no uniform definition of CIN, which may influence the incidence of CIN across studies. We did not perform a subgroup analysis of the incidence of CIN because of the low number of studies available for analysis. Second, we also did not take CM into account when analyzing the risk factors due to an insufficient amount of data. Third, compared with elective PCI, primary PCI is associated with a higher incidence of CIN, a complication that is associated with increased in-hospital and long-term morbidity and mortality . We alsoThe overall incidence of CIN in patients with STEMI undergoing PCI does not seem low. The main risk factors that are likely associated with CIN in patients with STEMI undergoing PCI are hypertension, diabetes mellitus, history of prior myocardial infarction, age, damaged left anterior descending artery, Killip class ≥2, decreased left ventricular ejection fraction, lower estimated glomerular filtration rate, and left ventricular ejection fraction >40%. A large sample size randomized controlled study is needed to support our conclusion.


Tetralogy of Fallot (ToF) is the most common type of cyanotic congenital heart disease. Since the first surgical repair in 1954, treatment has continuously improved. The treatment strategies currently used in the treatment of ToF result in excellent long-term survival . However, residual problems such as right ventricular outflow tract obstruction, pulmonary regurgitation, and (ventricular) arrhythmia are common and often require re-interventions. Right ventricular dysfunction can be seen following longstanding pulmonary regurgitation and/or stenosis. Performing pulmonary valve replacement or relief of pulmonary stenosis before irreversible right ventricular dysfunction occurs is important, but determining the optimal timing of pulmonary valve replacement is challenging for several reasons. The biological mechanisms underlying dysfunction of the right ventricle as seen in longstanding pulmonary regurgitation are poorly understood. Different methods of assessing the right ventricle are used to predict impending dysfunction. The atrioventricular, ventriculo-arterial and interventricular interactions of the right ventricle play an important role in right ventricle performance, but are not fully elucidated. In this review we present a brief overview of the history of ToF, describe the treatment strategies currently used, and outline the long-term survival, residual lesions, and re-interventions following repair. We discuss important remaining challenges and present the current state of the art regarding these challenges. The classic tetrad (3. Patients with ToF have varying degrees of cyanosis depending on the severity of right ventricular outflow tract (RVOT) stenosis and pulmonary artery (PA) anatomy. The anatomic abnormalities seen in ToF vary from milder to more severe phenotypes, such as ToF with pulmonary atresia and Fallot-type double outlet right ventricle (RV). These more severe forms may require different management and treatment strategies. This review focuses on the “classic” ToF, with right ventricular outflow (pulmonary) stenosis, rather than atresia, and excluding double outlet right ventricle.Tetralogy of Fallot (ToF), the most common type of cyanotic congenital heart disease (CHD), has an incidence of 0.34 per 1000 live births tetrad  was firset al.5. The right ventricular outflow tract obstruction (RVOTO) was approached by a ventriculotomy into the right ventricular anterior wall and relief included inserting a transannular patch (TAP) if required  was reported in the majority of patients, more commonly in those with TAPs12. PR initially was thought to be a relatively benign hemodynamic residual lesion but subsequently was found to be predictive of decreased exercise performance and progressive RV dilation. RV dilation, in turn, was associated with ventricular arrhythmia and biventricular dysfunction15. Furthermore, patients were noted to be at higher risk of sudden cardiac death17.Surgical repair of ToF was first described in 1955 by Lilleheiequired , left. A22. In patients with a small pulmonary valve annulus, a TAP is still necessary for adequate RVOTO relief. Other techniques to preserve or replace pulmonary valve competence include pulmonary valvuloplasty with patching limited to the infundibulum24, implantation of a monocusp valve26, a valved RV-to-PA conduit28, or a homograft valve27. A survival benefit of these valve-sparing or valve-replacing techniques has not yet been demonstrated32.Different surgical techniques were developed minimizing the extent of the ventriculotomy and trying to preserve competence of the pulmonary valve without causing significant residual RVOTO. Via a transatrial or transatrial-transpulmonary approach, the need for a ventriculotomy can be reduced , right. 33 and brain34 function. However, there is no consensus on the definition of “early” versus later repair. Neonatal repair  is feasible with acceptable results but is not widely used and this is because of better short-term outcomes of non-neonatal repair35. Neonatal repair more often requires TAP compared with repair beyond the neonatal period, resulting in worse event-free survival35. In the majority of patients, primary repair can be postponed to 3 to 6 months of age with excellent outcomes37.In general, it is thought that earlier primary repair of ToF can limit prolonged exposure to RV pressure loading and reduced oxygen saturations, preserving cardiovascular39. The superiority of a staged approach versus primary neonatal repair has not been demonstrated41.Symptomatic ToF patients may require an intervention in the neonatal period. Different strategies can be used if primary repair is judged not to be the best option. Historically, a systemic-to-pulmonary shunt—typically a modified Blalock-Taussig (mBT) shunt—has been used to increase pulmonary flow, reduce hypoxemia, and allow time for PA growth. This allows repair to be performed at an older age and has the potential advantage of using no, or less extensive, TAP. However, palliative shunt procedures are associated with a 3% to 5% early mortality rate42. Procedural success is estimated to be 83%43. Recently published multicenter studies compared outcomes following DA stenting and mBT shunting using propensity score–adjusted models44. Clinical status, assessed by saturation, hemoglobin levels, and PA size, was more favorable following DA stenting compared with mBT shunting44. Benthamet al. found better survival  0.07–0.85) for DA stent compared with mBT43, whereas Glatzet al. found no difference in survival 44. A trend toward higher re-intervention rate in the DA stent group was observed in both studies44. DA stenting appears to be a feasible strategy for selected cases.Stenting of the ductus arteriosus (DA) is another strategy to warrant pulmonary blood flow after birth by inducing a systemic-to-pulmonary shunt. However, in cyanotic CHD, the anatomy of the DA might be complex and unsuited for stenting46. Whether this strategy ultimately reduces TAP use or improves long-term outcomes remains controversial46.Alternatively, palliative balloon dilation of the pulmonary annulus can be used to increase oxygen saturation and promote growth of the pulmonary vasculature and as bridge to later complete repair in selected patients48. Experience with this strategy is still relatively limited but it has been demonstrated to be a relatively safe procedure promoting growth of the pulmonary arteries as a bridge to repair50. Quandtet al. compared medium-term outcomes of RVOT stent with systemic-to-pulmonary shunt and found no difference in survival between strategies49. Intensive care and hospital stay duration and peri-operative complications were more favorable for the RVOT stenting group but the re-intervention rate was higher for this group49. The most common re-interventions in this group were re-stenting and re-ballooning. (Re)shunt surgery or early complete repair was less common in this group compared with patients who underwent primary mBT. Comparisons between neonatal repair and RVOT stenting have shown comparable short-term and long-term outcomes52. During 10 years of follow-up, Wilderet al. demonstrated a similar increased rate of catheter-based re-interventions in the RVOT stent group compared with neonatal repair52. More studies are needed to determine the best strategy for the patient group requiring early intervention. Management strategies likely need to be individualized for optimal outcome.Similarly, RVOT stenting can be used as a palliative strategy or bridge to repair in neonatal life65. Early mortality has significantly decreased in more recent eras. European and American congenital cardiothoracic surgery registries have reported a peri-operative mortality below 3% in recent years68. Peri-operative outcomes are determined largely by the severity of the ToF described by, for example, the pre-operative size of the pulmonary valve and pulmonary arteries, RV-PA pressure gradient, and oxygen saturation71. Patients with repair including TAP have higher peri-operative mortality66. As most centers consider a TAP only when the pulmonary annulus z-score is lower than −2 or −3, this in part reflects more severe ToF72. Furthermore, co-morbidities, such as coronary abnormalities, prematurity, small body size–associated lesions, and genetic abnormalities, have been associated with increased peri-operative mortality73.Overall survival following ToF repair has significantly improved in recent eras.65. Survival at 30 years ranges from 68.5% to 90.5%65. Long-term (20 to 30 years) survival from large cohorts of patients operated on with more recent surgical modifications of ToF repair  is still lacking. Important factors determining long-term outcome are residual RVOTO and severity of PR54.Mortality rates at medium-term follow-up have not changed much across the different surgical eras 65. Surv77. Re-interventions are common in these patients. Cuyperset al. found that 44% of patients underwent at least one surgical or catheter re-intervention after 35 years of follow-up63. D’Udekemet al. found that 24 ± 5% of patients underwent re-operation after 30 years of follow-up64. Following transatrial transpulmonary repair, lower rates of re-interventions have been reported. Luijtenet al.12 found a 80% freedom of re-intervention and death after 10 years and D’Udekemet al.64 found 75% freedom of re-operation after 25 years. A small case-control study found a lower pulmonary valve replacement (PVR) rate following transatrial repair compared with transventricular repair. The use of a TAP is associated with a higher re-intervention rate54, as is severity of ToF at repair65. Specific indications for re-interventions will be discussed later in this article.Survival into adulthood is currently expected following ToF repair, leading to a growing population of adults with corrected ToF who require lifelong specialized medical care78. Current guidelines provide clear indications for re-intervention for residual RVOTO . PA branch stenosis can be safely relieved by balloon dilation, stenting, or PA reconstruction79. In several large studies, 1% to 7% of patients have undergone PA dilation or stenting at long-term follow-up (median of 5.8 to 36 years)81. Surgical relief of the RVOT and PA plasties were performed in 1% to 5% of patients at long-term follow-up81.Residual RVOTO is common following repair and results in residual or progressive concentric hypertrophy of the RV. Data obtained from the INDICATOR study suggest that RV hypertrophy, due to increased mass-to-volume ratio, is a more important long-term risk factor for ventricular tachycardia (VT) and death than severity of RV dilation (RV end-diastolic volume index)l RVOTO 75–77. 84. PR induces RV volume overload of the RV with often progressive RV dilation, which may include the development of tricuspid regurgitation (TR) and RV dysfunction. It is often accompanied by prolongation of the QRS complex, and RV dyssynchrony could contribute to the progression of dysfunction87. There generally is a long period in a compensated state, during which RV function is maintained. In some patients, these compensatory mechanisms fail, leading to progressive RV dysfunction86. The mechanisms of RV adaptation and remodeling, as well as the molecular events contributing to the transition from a compensated to a decompensated state, are still poorly understood. Timely restoration of pulmonary valve competence is considered to halt the progressive adverse RV remodeling resulting in RV dysfunction seen in chronic PR.PR is very common at medium- to long-term follow-up. Five to ten years after repair, 40% to 85% of patients have moderate to severe PR88. Staged repair and TAP are risk factors for late PVR80, whereas mild residual PS seems to reduce risk89. As more patients with ToF survive into adulthood, PVRs are increasingly being performed90.Thirty-five years after ToF repair, PVR will have been performed in about 40% of patients92. It should be noted that no improvement in survival following PVR compared with medical management has been demonstrated to date94.PVR is effective in decreasing RV volumes, reducing TR, decreasing QRS duration, increasing left ventricle (LV) ejection fraction (EF), and improving functional status95. The current 10-year re-PVR–free survival of ToF patients undergoing homograft PVR ranges from 74% to 89%96.Homograft or bioprosthetic valves are currently the preferred valves for PVR97.In situ tissue engineering techniques, in which a decellularized “starter scaffold” of polymers can be used to provide shape and structure to the valve, are of particular interest. This scaffold is infiltrated by endogenous cells to provide a regenerating functional valve. As the scaffold would be non-immunogenic, this could provide a relatively cheap “off the shelf” valve. Current studies evaluating tissue-engineered valves in animals and humans show promising early results98.Tissue-engineered valves with a non-synthetic and non-immunogenic surface have the potential to provide lifelong valve replacement99. However, clinical experience compared with  homograft PVR is limited99. Procedural success of transcatheter PVR is generally good (>95%)100. The hazard rate for re-intervention following transcatheter PVR ranges from 0.4% to 5.9% per patient-year100. However, high rates of infective endocarditis during follow-up have been described101. Recent results from the MELODY Registry estimate the infective endocarditis risk to be 2.3% per patient-year102. In comparison, the infective endocarditis risk in surgical PVR has been estimated to be 0.3% per patient-year103. Transcatheter PVR has been shown to increase exercise capacity and quality of life 6 months after the procedure105. Direct comparisons with surgical PVR are still lacking.Several transcatheter PVR strategies have been developed and are increasingly used in a clinical  settingVentricular tachycardia. VT is a common arrhythmia in the repaired ToF population. Cuyperset al. reported a 5% cumulative incidence of sustained VT after a median of 35 years after ToF repair63 and these figures are similar to those of most reports106. However, cumulative incidences of up to 15% have been reported in some adult populations107. Predictors of sustained VT include higher age, number of prior cardiac surgeries, presence of a TAP, LV diastolic dysfunction, and QRS width108. Most guidelines recommend implantable cardioverter defibrillators (ICDs) for patients who have had sustained VT or cardiac arrest77. ICDs are also employed for primary prevention, although selecting high-risk patients who would benefit from ICD implantation remains challenging77. Pacemaker and ICD prevalences in adult ToF populations both range from 5% to 10%109.110. Another study found a similar recurrence rate (19%) 10 years after ablation111.Electrophysiological studies can help to determine the underlying substrate, and radiofrequency ablation can be performed. Ablation of monomorphic VT substrates has excellent short-term outcomes with recurrent VT in 18% of patients after a mean follow-up of 34 monthsSupraventricular tachycardia. The prevalence or cumulative incidence of supraventricular tachycardia (SVT) in adult patients ranges from 4% to 20%112. In the first 10 to 15 years following ToF repair, SVT is relatively uncommon but the incidence rises steadily after this period107. Intra-atrial re-entrant tachycardia, typically involving the right atrium, is the most common type of SVT in patients with ToF107. Two large studies found that SVT was an independent predictor of death or VT108. Few studies have assessed the efficacy of ablation of atrial arrhythmias in corrected ToF, and long-term follow-up is lacking115.118. In patients with aortic dilation, aortic root size seems to progressively increase over a period of years. Aortic dissection following ToF appears to be a rare complication119. A population-based study in Texas demonstrated no increased risk for thoracic aortic dissection for patients with ToF compared with the general population119. However, progressive aortic root dilation can lead to malcoaptation of the aortic valve and aortic regurgitation. Furthermore, the elasticity of the dilated aortic root was shown to be reduced in patients with ToF, possibly hampering circulatory function120. The importance of aortopathy in circulatory function and mortality remains incompletely understood.Dilation of the aorta is seen in 12% to 24% of adult patients with ToF121. In young pig models, chronic PR affects biventricular systolic function, RV myocardial contractility, and LV diastolic performance122. Histopathology of several animal models displays early hypertrophy of the chronically volume-loaded RV and, in a later stage, myocardial fibrosis121. The molecular responses to increased volume or pressure loading of the RV are different from those in the LV125. In a pig model of repaired ToF with induced PR, PS, and an RVOT scar, RV hypertrophy and dilation were found after 23 weeks. The myocardium was characterized by increased collagen deposition, leading to decreased impulse conduction velocity and dispersion126. Similar findings were found in the LV, despite preserved LV function at this stage. This demonstrates biventricular adverse effects are present early in the adverse remodeling process127.The mechanisms of RV adaptation and remodeling in response to chronic RV volume overload, resulting from PR, are poorly understood125. Volume loading and pressure loading increase myocardial metabolic demand. This metabolic stress induces an increased amount of reactive oxygen species. Compensatory anti-oxidant production in the RV is impaired compared with the LV125. This might imply that the RV is more vulnerable to oxidative stress, as seen in abnormal loading conditions.Basic research into RV remodeling has focused mainly on the response to increased pressure loading rather than the predominantly volume-loaded RV as seen in PR128. Gene expression patterns of the cardiomyocyte in the compensated state differ from those of healthy controls. Several molecular pathways, such as transforming growth factor beta (TGF-β) signaling, p53 signaling, and cytoskeleton-related pathways, are downregulated in the early compensated state but show late upregulation as the RV progressively remodels128. However, the exact cellular and molecular mechanisms of transition from a compensated to a decompensated state of the volume-loaded RV have not been fully elucidated129.In volume-loaded RV mouse models, a clinical course similar to RV dysfunction with volume-loaded RV in humans is observed. RV function is maintained during a compensated phase, followed by RV dysfunction130. Adverse clinical events have been related to larger RV volumes, PR severity, biventricular EF, and mass-to-volume ratio132. Increased RV volumes, most commonly end-diastolic volume index (EDVi), have been considered a sign of prolonged high PR burden and thus a predictor of RV dysfunction. However, exercise capacity can be preserved even in severely dilated ventricles, demonstrating that compensatory mechanisms can still be adequate to maintain performance of large RVs133. In the INDICATOR cohort, increased RV wall mass-to-volume ratio, among other factors, was found to be an independent predictor of VT and all-cause mortality, whereas RV EDV and end-systolic volume were not predictive of the end-points78. RV hypertrophy could be a more sensitive marker of pending dysfunction than EDV, although this might be particularly true for patients with residual PS.Our limited understanding of the pathophysiology of RV failure hampers our ability to adequately detect failure in the early stages in clinical practice. Imaging techniques are used to assess the RV and follow patients serially, aiming to detect early changes in biventricular size and performance. Cardiovascular magnetic resonance (CMR) imaging is routinely used to reliably quantify RV volumes and function, wall mass, and PR134. The predictive value of global longitudinal or circumferential strain in ToF is still uncertain: Orwatet al. found that RV global longitudinal strain assessed by CMR was a superior independent predictor for death, cardiac arrest, or VT compared with RV volumes135. RV global circumferential strain was not predictive of outcome in that study135. Dilleret al. found a similar relation for LV global longitudinal strain assessed by echocardiography136.Regional myocardial performance and mechanical synchrony can be assessed by strain imaging studies. Global circumferential or longitudinal strain has been used to assess RV function. Under normal circumstances, the RV ejects mainly by longitudinal shortening while, with increased RV pressure loading, circumferential contraction is increased137. The contributions of this mechano-electrical interaction to RV function remain uncertain, as studies assessing mechanical dyssynchrony report conflicting results141. RV circumferential dyssynchrony was shown to negatively predict exercise capacity in one study140. This association has not been confirmed in other studies141. Cardiac resynchronization therapy is increasingly used in ToF. A recent study found that 12 out of 15 adult patients with ToF had an improved NYHA (New York Heart Association) class or LV function after 2.6 years (median) of cardiac resynchronization therapy142. Procedural success was high and adverse events were rare.Mechanical dyssynchrony has been demonstrated to relate to prolonged or fragmented  QRS complexesAtrio-ventricular interactions. Diastolic function after ToF repair is a determinant of the amount of PR. In some patients, end-diastolic forward flow (EDFF) in the main PA during right atrial contraction can be observed143. This is considered a sign of “restrictive RV physiology” as the non-compliant RV acts as a conduit during atrial contraction as RV diastolic pressure exceeds PA diastolic pressure145. Restrictive physiology could limit the amount of PR as elevated diastolic RV pressure reduces the amount of PR. A recent study found no relationship between the presence of EDFF and other markers of diastolic dysfunction 146. Different mechanisms, such as pulmonary arterial capacitance and atrial function147, may play significant roles in the occurrence of EDFF. Luijnenburget al. found that bi-atrial function, but not diastolic ventricular function, differed between patients with EDFF and those without it147. In that study, abnormal atrial function was related to worse exercise capacity and higher N-terminal pro brain natriuretic peptide (NT-proBNP). Kuttyet al. found that right atrial longitudinal strain predicted RV performance but not exercise capacity148.146, exercise capacity147, and EDV147. The presence of EDFF might have a different etiology and clinical importance early versus late after repair or in severely dilated versus non-dilated ventricles.The effect of EDFF on circulatory function is controversial. Studies found conflicting results regarding the relationship between EDFF and the amount of PRVentriculo-arterial interactions. Adequate atrio-ventricular coupling and ventriculo-arterial (VA) coupling are required for an energetically efficient transfer of blood through the right heart. VA coupling has not been studied extensively in ToF. Latuset al. assessed VA coupling as the relationship between pulmonary arterial elastance and ventricular end-systolic elastance in adult patients with ToF by using CMR and catheter-derived measurements both in resting conditions and during dobutamine stress149. VA coupling was impaired during resting conditions. EF and load-independent parameters of RV contractility increased during dobutamine stress. Pulmonary arterial elastance increased accordingly and the impaired VA coupling that resulted during dobutamine stress was similar to that under resting conditions.Interventricular interactions. Interactions between the RV and LV have been extensively described. The LV and RV have common myocardial fibers, the interventricular septum, the anatomic space confined by the pericardium, and a common neurohumoral system150. Not unexpectedly, the effects of chronic PR are not limited to the RV, although the mechanisms of this ventriculo–ventriculo interaction in chronic PR remain poorly understood. A linear correlation between LV and RV EF has been described151. Severe RV dilation causes abnormal diastolic septal positioning, influencing LV filling152. The role of the LV in outcomes in ToF is increasingly appreciated, as LV function has been associated with increased mortality and increased risk of VT153. In the INDICATOR registry, LV EF was one of three independent predictors of mortality and VT154. Gevaet al. found that LV EF, independent of RV parameters, predicted poor functional status151. Remarkably, parameters of LV function are not considered in current guidelines for the timing of PVR  inhibitors do not appear to influence RV EF or exercise capacity158. In a randomized controlled trial of 33 patients with ToF, beta blockers showed no beneficial effects after 6 months of treatment and an increase in NT-proBNP was noted159. Increasing our understanding of the pathophysiology of RV failure might elucidate new targets for medical treatment unique to the RV.Pharmacotherapy is important in the treatment of LV failure and improves outcomes. However, the effects of the use of heart failure medication for RV failure have been disappointing77. These indications are summarized inRestoring pulmonary valve function before irreversible RV dysfunction occurs could be important to prevent RV failure. However, the durability of currently used pulmonary prosthetic valves is limited. Therefore, the timing of PVR always is a compromise: It should be timed early enough to prevent irreversible adverse remodeling but late enough to limit the number of re-interventions. Because of the difficulties in assessing RV function, predicting decline in RV function is difficult, and the optimal timing of PVR is controversial. Guidelines by the European Society of Cardiology, the Canadian Cardiovascular Society (CCS), and the American College of Cardiology/American Heart Association provide some recommendations on indications for performing PVR160. End-systolic volume index and RV mass-to-volume ratio have been proposed as superior predictors compared with EDV161. Progressive RV dilation is considered an indication for PVR, but there is no consensus on what too much progression is165. Longitudinal changes in RV size and function following ToF repair have been reported in several studies173. RV volumes increase non-linearly and seem to stabilize in adolescence. These factors need to be taken into account when assessing progressive RV dilation.Indications differ between guidelines and have several limitations. Most guidelines do not provide specific cutoff points since these are statistical constructs that do not work for individual patients. The 2009 CCS guideline provides an absolute cutoff value for EDVi but does not take into account the considerable differences in normal (indexed) RV volumes between genders and ageFurthermore, the recommendations in current guidelines are often based on long-term outcomes of studies in patients who have been operated at a much older age than has been the practice in the past 20 years. This warrants caution when extrapolating these results to current adolescent or younger patients.174.Careful interpretation of current guidelines seems to be justified. Individual patient parameters and views should always be taken into consideration. In clinical practice, an approach using information from different sources, including history, physical examination, electrocardiogram, imaging techniques, exercise testing, and blood biomarkers, may be most usefulToF can be repaired with low short-term and long-term mortality. This has caused a demographic shift such that many patients survive well into adulthood. Long-term follow-up of older cohorts has shown the detrimental effects of PR in the long-term. However, residual lesions cause significant morbidity. Surgical modifications to preserve pulmonary valve function, such as the transatrial (and transpulmonary) approaches and restricted use of TAPs, have been widely adopted. Despite improvements in morbidity, follow-up duration for these techniques is probably too limited to demonstrate a survival benefit.Our limited understanding of RV adaptation and the pathophysiology of RV heart failure hampers the ability to detect failure in early stages in clinical practice and to predict future decline of RV function. While a large proportion of adult ToF survivors require one or multiple PVRs in their lifetimes, selecting optimal candidates and optimal timing for PVR remains challenging. Increasing our understanding of RV failure seems key to answer these difficult questions. This might provide treatment options to attain optimal long-term health outcomes for patients with ToF.CCS, Canadian Cardiovascular Society; CHD, congenital heart disease; CMR, cardiovascular magnetic resonance; DA, ductus arteriosus; EDFF, end-diastolic forward flow; EDV, end-diastolic volume; EDVi, end-diastolic volume index; EF, ejection fraction; ICD, implantable cardioverter defibrillator; LV, left ventricle; mBT, modified Blalock-Taussig; NT-proBNP, N-terminal pro brain natriuretic peptide; PA, pulmonary artery; PR, pulmonary regurgitation; PS, pulmonary stenosis; PVR, pulmonary valve replacement; RV, right ventricle; RVOT, right ventricular outflow tract; RVOTO, right ventricular outflow tract obstruction; SVT, supraventricular tachycardia; TAP, transannular patch; ToF, tetralogy of Fallot; TR, tricuspid regurgitation; VA, ventriculo-arterial; VT, ventricular tachycardia