The significant progress in cancer treatment, including chemotherapy, immunotherapy, radiotherapy, and combination therapies, has led to higher long-term survival rates in cancer patients, while the cardiotoxicity caused by cancer treatment has become increasingly prominent. Cardiovascular magnetic resonance (CMR) is a non-invasive comprehensive imaging modality that provides not only anatomical information, but also tissue characteristics and cardiometabolic and energetic assessment, leading to its increased use in the early identification of cardiotoxicity, and is of major importance in improving the survival rate of cancer patients. This review focused on CMR techniques, including myocardial strain analysis, T1 mapping, T2 mapping, and extracellular volume fraction (ECV) calculation in the detection of early myocardial injury induced by cancer therapies. We summarized the existing studies and ongoing clinical trials using CMR for the assessment of subclinical ventricular dysfunction and myocardial changes at the tissue level. The main focus was to explore the potential of clinical and preclinical CMR techniques for continuous non-invasive monitoring of myocardial toxicity associated with cancer therapy. The significant progress in cancer treatment has led to higher long-term survival rates in cancer patients ,2, with The clinical diagnosis of cardiotoxicity is mainly based on abnormal left ventricular ejection fraction (LVEF) and the presence of heart failure symptoms . In receStudies have shown that approximately 58–89% of patients do not fully recover from LVEF after the treatment for cardiotoxicity caused by LVEF ,17,18,19CMR is a non-invasive comprehensive imaging modality that provides not only anatomical information, but also tissue characterization, as well as cardiometabolic and energetic assessment. This review focuses on the subclinical ventricular dysfunction and the myocardial changes at the tissue level assessed using CMR in an attempt to summarize the potential imaging biomarkers for the early diagnose of cardiotoxicity associated with cancer therapies. In particular, we highlighted the latest CMR studies investigating the right ventricle, which might be more susceptible to cardiotoxicity than the left ventricle, but has been less evaluated. Moreover, we checked the ongoing registered clinical trials using CMR techniques for the evaluation of cardiotoxicity, and proposed imaging strategies that can be incorporated in future clinical trials with different purposes.Cancer therapies can damage both tumor cells and normal body cells. As myocardial cells are terminally differentiated cells with a limited dividing ability, they are prone to long-term and serious results after being damaged. Based on the presence of structural abnormalities and the degree of functional reversibility, cardiotoxicity can be classified into two types: type I (the injury type) and type II (the dysfunction type) .Type I cardiotoxicity refers to severe myocardium injury that is generally considered irreversible due to the structural damage . The mai+2 release channel and the ryanodine receptor; (2) ROS can mediate myocardial cell apoptosis by activating hypertrophy signal kinases and transcription factors; and (3) excessive ROS stimulate cardiac fibroblast proliferation and activate matrix metalloproteinases, leading to fibrosis and matrix remodeling [In the past three decades, the pathogenesis of anthracycline-induced cardiotoxicity has been studied intensively, but the exact mechanism is not entirely clear. The most widely accepted mechanism is that topoisomerase II beta and reactive oxygen species (ROS) play the key roles . Anthracmodeling ,34. The modeling . The carmodeling .Pathological manifestations of cardiotoxicity include myocardial edema, cytoplasmic vacuolization, necrosis, apoptosis, and eventually myocardial and extracellular fibrosis  37,38,3,338,39. Type II cardiotoxicity, which was defined in the early 2000s, is not dose-dependent and is highly reversible due to the absence of ultrastructural abnormalities . The chaCMR is the non-invasive gold-standard imaging modality to assess the structural and functional changes of the heart by means of a variety of sequences. The changes in ventricular morphology and function, valvular function, the pericardium, and large vessels can be evaluated using dark-blood sequences, cine sequence, and phase-contrast flow sequences. Cine sequence can also be used to quantify functional parameters, such as LVEF, and to identify wall motion abnormalities. Myocardial tissue characterization techniques, such as gadolinium enhancement sequences and mapping techniques, enable the detection of myocardial edema, inflammation, and fibrosis.Conventional left ventricular parameters such as LV mass and LVEF have been essential for the diagnosis and prognosis of cardiotoxicity. Myocardial strain analysis offers the opportunity to detect subclinical dysfunction when LVEF remains normal.LV mass has attracted attention in cardio-oncology as a quantifiable marker for cardiotoxicity. LV mass reduction may represent myocardium atrophy, and the loss in LV cardiomyocytes was associated with the increase in peak cardiac troponin T after anthracycline treatment in a previous study . CMR canLVEF was evaluated using echocardiography and MUGA in early studies of cardiotoxicity. Echocardiography is the first-line imaging modality to assess LVEF in clinical practice. However, the reproducibility can be impacted by its high operator dependency, and the accuracy may be challenged in patients with an inadequate acoustic window, such as breast cancer patients with breast expanders, prostheses, or implants . The varCMR can be used to monitor the changes in LVEF with excellent accuracy and reproducibility due to its high spatial resolution ,55,56, aIn addition, LVEF is insensitive to subtle myocardial injury or subclinical reduce of LV function ,62. EwerStrain refers to the ability of the myocardium to deform. LV strain depicts the LV myocardial deformation in a cardiac cycle as a percentage of its initial length. Measurements of the segmental and global strain of the myocardium in longitudinal, radial, and circumferential directions can partly reflect the internal contractile function of the myocardium . SeveralGLS is the changes in myocardial length from base to apex in a cardiac cycle, and is highly sensitive to subclinical LV dysfunction and has been included in an expert consensus for imaging evaluation of cardiotoxicity . The conCircumferential strain reflects the degree of circumferential shortening of the ventricular myocardial fibers. Narayan et al. found that circumferential strain was one of the strongest predictive parameter of cardiotoxicity, with a 1% difference in the baseline circumferential strain associated with a 38% increase in the odds of cardiotoxicity . Other sWhile myocardium strain is garnering increasing attention, its limitations cannot be ignored. First of all, high inter-observer and intra-observer variability of strain parameters, especially that derived using echocardiography, is a substantial barrier to an extensive clinical application. Moreover, the need for dedicated post-processing consumes additional time and costs. Last but not least, various vendors and post-processing algorithms make it difficult to establish a universal reference range of normal values. A comparative study showed that the absolute difference of GLS among different vendors was up to 3.7% strain units . FurtherRV and biventricular impairment have also been found in cardiotoxicity, in addition to the primary concern for LV dysfunction. A recent study of cardiotoxicity in rats confirmed that histopathological changes occurring in the LV could also be detected in the right ventricle, even with more prevalent interstitial fibrosis . AnotherRV dysfunction is a reliable prognostic marker for adverse outcomes in a variety of cardiovascular diseases. It has been found that patients treated with trastuzumab who demonstrated biventricular dysfunctions had less improvement in LVEF than those without RV dysfunction, as assessed using echocardiography-derived LVEF, RV fractional area change, and peak systolic longitudinal strain (LV and RV) . FurtherRV strain can also be used to evaluate the subclinical dysfunction of the right ventricle. However, the feasibility of RV strain is limited by the thinner ventricular wall and the difficulty in tracking the endocardial boundaries. Only a few studies have analyzed RV strain using echocardiography and demonstrated the value of RV strain in the early detection and prognosis of cardiotoxicity ,80,81. CTissue characterization techniques in CMR enable the detection of microstructural changes in the myocardium in the process of a variety of myocardial diseases, and have been widely used in the diagnosis and follow-up of cardiomyopathy, myocardial infiltration, and inflammatory diseases .Conventional sequences, including T1-weighted, T2-weighted, and cine bright-blood steady-state free-precession sequences, can provide basic morphological information on the myocardium, as well as the surrounding structures , and extra-cardiac information . An early animal study showed that an increase in the myocardial T1 signal intensity may be related to subclinical injury caused by oxidative stress . CMR is The late gadolinium enhancement (LGE) technique is considered pivotal for tissue characterization and can identify regional myocardial fibrosis, providing prognostic information for a variety of cardiovascular diseases ,86,87,88Parametric mapping is an innovative imaging technique that can achieve higher-level tissue features by directly quantifying pixels without reference to putative normal tissue. Parametric mapping techniques, including T1 mapping, T2 mapping, and extracellular volume fraction (ECV), can overcome the limitations of conventional T1-weighted imaging, T2-weighted imaging, and LGE in assessing diffuse myocardial inflammation or fibrosis ,93,94,95T1/T2 mapping has been useful in the diagnosis of myocardial edema and in ruling out active inflammation via quantification of T1/T2 relaxation time, especially T2 relaxation ,97,98, dT1 mapping and ECV quantification provide a non-invasive method to evaluate myocardial fibrosis, which is characterized by extracellular space expansion and collagen deposition. Increases in native T1 and ECV values can be used to assess diffuse myocardial fibrosis that cannot be identified using LGE . A studyECV refers to the volume of extracellular matrix as a percentage of the total volume of myocardial tissue, which can be calculated using pre- and post-contrast T1 mapping with good reproducibility. ECV is mainly affected by the interstitial space and myocellular volume or mass , and hasTo sum up, mapping techniques can non-invasively identify subtle changes in myocardial tissue, and provide promising imaging biomarkers for the early detection and prognosis of cardiotoxicity associated with cancer therapies, but they were included in the expert consensus for the clinical management of cardiotoxicity. Moreover, myocardial T1/T2 mapping and ECV values can be affected by various technical and subject-related factors. The current expert consensus for myocardial parametric mapping techniques recommends local reference ranges for clinical interpretation .CMR has been involved in a number of randomized clinical trials for the assessment of cardiotoxicity in the most recent decade, and was used either as an outcome measure in the evaluation of cancer therapies, or as a diagnostic test for early management of cardiotoxicity. We identified around 20 ongoing or newly completed registered clinical trials involving CMR for cardiotoxicity. Apart from conventional structural and functional evaluation, parametric mapping , LV myocardial strain , RV free wall strain (NCT05349058), two-dimensional flow imaging (NCT04896242), myocardial diffusion weighted imaging (NCT02274480), and hyperpolarized carbon 13-based magnetic resonance spectroscopic imaging (NCT04044872 and NCT03685175) are also involved in the recruiting clinical trials. Moreover, some trials aim to compare the diagnostic value of CMR with other imaging modalities such as CT (NCT04880317) and PET/MRI (NCT04555642). The cancer therapies assessed by these ongoing clinical trials have expanded from chemotherapy to radiotherapy, immunotherapy, and targeted therapy.With the increasing attention paid to the value of CMR in the clinical management of cardiotoxicity, novel biomarkers reflecting the pathological process of cardiotoxicity are expected to provide new insights into the early diagnosis and prognosis of cardiotoxicity. Emerging CMR techniques such as magnetic resonance spectroscopy (MRS), diffusion weighted imaging (DWI), and diffusion tensor imaging (DTI) may provide additional insights into the metabolic status and the organization and integrity of microstructural components in cardiotoxicity.31P-MRS) can be used to detect resonance peaks of seven metabolites, among which the ratio of phosphocreatine (PCr) to adenosine triphosphate (ATP) is the most important parameter for analyzing myocardial energy status [31P-MRS and anthracycline therapy was found in breast cancer patients [31P-MRS in the identification of energetic abnormalities in cardiotoxicity.Phosphorus MRS (y status . The PCry status ,114. Eney status . In a repatients . FurtherMyocardial DWI and DTI have been technically feasible for patients with cardiomyopathy. The value of DWI as an alternative to native T1 and ECV for the detection and quantification of myocardial fibrosis has been validated in patients with hypertrophic cardiomyopathy ,118. WhiDespite the superior qualities of CMR in the assessment of myocardial injury, its application in clinical practice is limited by its relatively high technical requirements and low availability , thus thThe development and application of cancer therapies have resulted in a higher survival rate with inevitable side effects, the most serious of which is cardiotoxicity. Early diagnosis and treatment of cardiotoxicity are of great significance in the prognoses of patients. Existing studies suggest that myocardial strain and mapping technology based on cardiovascular magnetic resonance imaging are promising for the early diagnosis of cardiotoxicity before the left ventricular ejection fraction deteriorates. The ongoing clinical trials involving strain analysis and parametric mapping assessment may provide substantial data regarding the normal ranges and cut-off values for abnormalities for the novel imaging biomarkers. In addition, the introduction of other techniques, including magnetic resonance spectroscopic imaging, myocardial diffusion weighted imaging, and diffusion tensor imaging, may help to elucidate the underlying pathophysiological mechanism, and thus are worthy of further investigation in future studies.


To quantify the impact of a home-based cardiac rehabilitation intervention (Rehabilitation Enablement in Chronic Heart Failure (REACH-HF)) on objectively assessed physical activity (PA) of patients with heart failure (HF) and explore the extent by which patient characteristics are associated with a change in PA.Secondary analysis of randomised controlled trial data.Five centres in the UK.247 patients with HF .REACH-HF versus usual care (control).PA was assessed over 7 days via GENEActiv triaxial accelerometer at baseline (pre-randomisation), post-intervention (4 months) and final follow-up (6–12 months). Using HF-specific intensity thresholds, intervention effects (REACH-HF vs control) on average min/day PA ) over all days, week days and weekend days were examined using linear regression analysis. Multivariable regression was used to explore associations between baseline patient characteristics and change in PA.Although there was no difference between REACH-HF and control groups in 7-day PA levels post-intervention or at final follow-up, there was evidence of an increase in weekday MVPA , light PA  and decreased inactivity  in favour of REACH-HF. Baseline factors associated with an increase in PA from baseline to final follow-up were reduced MVPA, increased incremental shuttle walk test distance, increased Hospital Anxiety and Depression Scale anxiety score and living with a child >18 years (p<0.05).While participation in the REACH-HF home-based cardiac rehabilitation intervention did not increase overall weekly activity, patient’s behaviour patterns appeared to change with increased weekday PA levels and reduced inactivity. Baseline PA levels were highly predictive of PA change. Future focus should be on robust behavioural changes, improving overall levels of objectively assessed PA of people with HF.ISRCTN78539530 and ISRCTN86234930. The use of population-specific intensity thresholds to derive physical activity (PA) intensity provides a more reliable and robust estimate of PA levels of patients with heart failure.The use of rigorous data processing and analysis methods to look beyond a single PA metric  revealed interesting patterns in the data, however this increase in granularity causes a reduction in statistical power and future studies should consider this in sample size calculations.As this was an exploratory study, there may be an increased risk of type 1 errors with multiple repeated tests, and some frequency counts of variables included in multivariable models were low.Physical activity (PA) has numerous health benefits for patients with heart failure (HF) including reduced HF mortality and HF hospitalisation, and improved quality of life.Traditionally, cardiac rehabilitation (CR) interventions have prioritised increasing exercise capacity rather than PA behaviour, and evidence that CR increases PA toward recommended levels is lacking.Furthermore, although some studies have shown that PA levels are associated with a number of factors including age, body mass index, exercise capacity and disease severity in patients with HF, these have been limited by cross-sectional design that do not measure within-person PA change.Due to the wide range of health benefits associated with increased PA in patients with HF, further studies, using improved, objective and population-specific PA assessment techniques are needed to understand and clarify the impact of CR on PA levels and the relationships between PA and patient level characteristics. Therefore the primary aim of this study was to assess the impact of a home-based CR programme (Rehabilitation Enablement in Chronic Heart Failure (REACH-HF)et alA key element of the REACH-HF intervention development process was the involvement of a local patient and public involvement (PPI) group consisting of nine patients with HF and caregivers of people with HF. The PPI group co-created the REACH-HF intervention, and were involved in the recruitment process, and associated research questions and topic guides  that randomised patients with HF 1:1 to a home-based CR intervention plus usual care (REACH-HF group) or to usual care alone (control group), stratified by site and N-terminal Brain Natriuretic Peptide (NT-proBNP). The first was a pilot RCT of the REACH-HF intervention for patients with HF with preserved ejection fraction  >45%), and the second was a multicentre RCT of the REACH-HF intervention for patients with HF with reduced ejection fraction . Accelerometry-measured PA was a secondary outcome of the original studies, and full details of these trials are presented elsewhere.In summary, REACH-HF is a theory-based, comprehensive self-management programme consisting of four core elements; (1) an HF self-help manual with a choice of two structured exercise programmes; a chair-based exercise DVD, and a progressive walking training programme ; (2) a patient ‘progress tracker’ booklet designed to facilitate learning and record symptoms and other actions related to healthcare; (3) a ‘family and friends resource’ manual for caregivers to increase their understanding of HF and their own physical and mental well-being; and (4) facilitation by specially trained cardiac nurses, physiotherapists or exercise therapists to individually tailor the intervention. Participating patients and caregivers worked through the REACH-HF manual for 12 weeks. Participants in both the pilot RCT and full RCT received the same programme.This study complies with the Declaration of Helsinki.A total of 247 adults (aged ≥18 years) with a confirmed diagnosis of HF , and complete baseline accelerometer data sets (participants were required to have ≥16 hours per day and ≥7 days of wear) were included in this analysis. Participants were recruited and completed the baseline visit between January 2015 and February 2016, from primary and secondary care settings in five UK centres . All participants provided written informed consent.PA data were collected via accelerometry on three occasions: at baseline (pre-randomisation), post-intervention (4 months) and final follow-up (6–12 months). Given the final accelerometry data follow-up for the two trials was at 6 months for patients with HFpEF, and 12 months for patients with HFrEF we have therefore combined data at these two ‘final follow-up’ time points for this study.The following patient level data were collected at baseline: medical history  class, concomitant medication), socio-demographic information , NT-proBNP measurement via blood sample, exercise tolerance via incremental shuttle walk test (ISWT) and health outcome questionnaires, that is, disease-specific health-related quality of life (HRQoL) using the Minnesota Living with Heart Failure Questionnaire, and the Health-Related Quality of Life (HeartQoL) questionnaire; psychological well-being using the Hospital Anxiety and Depression Scale (HADS) questionnaire; generic HRQoL using the EuroQol-5 Dimension-5 level (EQ-5D-5L) questionnaire; and Self-Care of HF Index questionnaire (SCHFI).http://cran.r-project.org). Initial processing included autocalibration, and detection of abnormally high values and non-wear.At the clinical visits, participants were provided with and instructed to wear a GENEActiv triaxial accelerometer  for 24-consecutive hours for 7 days. Accelerometers were returned to the clinical trials unit using postage-paid envelopes. Data were downloaded using GENEActiv PC software  and processed in R  using the GGIR software package : 16.7 mg (left wrist), 18.6 mg (right wrist), MVPA : 43.6 mg (left wrist), 45.5 mg (right wrist)) were applied to calculate the average minutes per day spent inactive, in light PA and MVPA, over all days, weekend days and weekdays. These thresholds were established by a recent accelerometer calibration study in 21 patients with HF.Descriptive statistics were calculated as means and SDs or counts and percentages unless otherwise stated.Data from final follow-up were used for primary analysis in line with the primary endpoints of the two original trials.Univariate linear regression was used to investigate the baseline socio-demographic , medical history , ISWT and health status variables  associated with change in MVPA, adjusting for baseline MVPA, treatment group and trial stratification variables .2 values were used to inform model comparison and selection.In addition to univariate regression, we undertook multivariable regression to explore the association between selected patient characteristics and change in MVPA. Variables with statistical evidence of univariate association with change in MVPA (p<0.15) were selected for entry into a series of multivariable regression models to establish which variables were independently and most strongly associated with change in PA at final follow-up and post-intervention, mutually adjusting for trial stratification variables, baseline MVPA and treatment group. Model 1—socio-demographic and medical history variables only, model 2—exercise capacity and health status variables only and model 3—socio-demographic, medical history, exercise capacity and health status variables identified as significant (p<0.05) predictors in models 1 and 2. Checks and diagnostics were performed for model assumptions, residuals, multicollinearity (variance inflation factor) and influential observations (Cook’s distance). Akaike information criterion (AIC) and RStatistical analyses were performed using Stata .Two hundred and forty-seven patients had accelerometer data at baseline which met the criteria for inclusion in analysis. Post-intervention, 198 patients were included and at final follow-up 173 patients were included in the analysis . Patient10.1136/bmjopen-2022-063284.supp1Supplementary dataThe effects of REACH-HF intervention versus control at final follow-up on PA  over all days, weekdays and weekend days are presented in At post-intervention follow-up, there were no significant differences between REACH-HF group and control for all bouted PA intensities or days  .At final follow-up, using unbouted PA data, there was a small increase in weekday MVPA and decrease in weekday inactivity in the REACH-HF group, with the reverse found in control group, (between group differences showing a trend in favour of REACH-HF (MVPA: 15.18 (95% CI: −0.32 to 30.67), p=0.06; inactivity: −21.25 (95% CI: −43.24 to 0.75), p=0.06; In terms of prevalence of meeting PA guidelines, no differences were found between REACH-HF and control group at either follow-up time point .Post-intervention, presence of diabetes and SCHFI maintenance scores at baseline were associated with a decrease in MVPA (p<0.05), whereas individuals with greater ISWT distance at baseline were more likely to increase their MVPA p<0.05; .Multivariable models to predict change in MVPA post-intervention are presented in Variance inflation factor (VIF) ranged from 1.06 to 1.18 across the six models indicating a low level of multicollinearity.We undertook an in-depth analysis of RCT data of a CR intervention (REACH-HF) objectively assessing PA levels of patients with HF using intensity thresholds specifically developed for this population group. When PA levels were averaged over all 7 days of the week, there was no evidence that participation in REACH-HF impacted daily PA levels compared with control. As some 48% of patients in the REACH-HF trials were already meeting UK PA guidelines at baseline (based on bouted data), it may be that there was a ceiling effect, where those already physically active would have difficulty further improving on MVPA levels, making small changes in PA difficult to pick up statistically. This has often been the case in other CR trials.However, separating weekend and weekdays revealed important patterns in the PA response. Average weekday PA levels showed a consistent trend where MVPA and light PA increased , and inactivity decreased (−38 min/day) in the REACH-HF group compared with the control group. Over weekend days, the reverse appeared to be true, with an increase in inactivity and decrease in PA. This pattern was not evident in either group at baseline, therefore these findings suggest that the REACH-HF participants may have compensated for increased PA during the week by being less active at the weekend, which could account for the lack of overall PA increase found. Compensation for increased exercise with increased inactivity in the subsequent days has been demonstrated in other populations such as older adults,Traditionally, CR programmes have been developed with a focus on increasing exercise capacity rather than PA promotion. In its current format we have shown modest positive influences of a home-based CR programme on weekday PA levels of patients with HF. In order to achieve greater PA benefits to patients, CR programmes may need to adapt, placing stronger emphasis on increasing unstructured daily PA behaviour or targeting both PA and sedentary behaviour. This could be facilitated by simplified PA messaging such as sit less, move more, every day, which might be easier for patients to understand and sustain in the longer-term, leading to higher levels of total PA and reduced sedentary time and is likely to have significant health benefits to patients with HF.Given the large variation in PA differences from baseline up to final follow-up in MVPA, we were interested to investigate potential factors associated with a change in MVPA. To our knowledge, this is the first study to explore this. Our results showed that particular living situations of the patient were associated with PA change (living with a parent or child >18 years), which may indicate involvement of family members is associated with PA behaviour change and self-care of patients with HF.This study has a number of strengths. First, the objective measurement of PA, and robust and rigorous accelerometer data processing and analysis. Literature reporting accelerometer measured PA in patients with HF with CR intervention is limited, especially in large, representative samples. The use of population-specific intensity thresholds provides a more reliable estimate of PA levels of patients with HF, compared with application of commonly used thresholds based on healthy adults.This study highlights the benefit of extracting more detailed PA data, looking beyond a single PA metric  and considering within-week differences in PA patterns. In line with updated PA guidelines that acknowledge bouts less than 10 min can also be beneficial for health,As this was an exploratory study, multiple repeated independent tests were conducted comparing treatment groups and between baseline characteristics and change in MVPA. Given the dangers of multiple testing, which may have led to increased risk of type 1 errors, our results must be treated with caution. In addition, variables associated with MVPA change were inconsistent across the two follow-up points and explained only a small proportion (10–15%) of the variance in MVPA change and combining the final follow-up data sets from 6 and 12 months may have introduced variation to the data. While the sample size was sufficient for this exploratory study, some of the frequency counts of variables included in the multivariable models were low. Further studies using objective PA assessment are needed to clarify the impact of exercise-based CR interventions in patients with HF and the patient factors associated with change in PA.This pooled analysis of RCTs shows that participation in a home-based CR intervention did not impact 7-day PA compared with control. However, participating in CR did appear to increase weekday PA levels and participants may have compensated for this by becoming more inactive during the weekend. Understanding of the behavioural effects of a home-based CR intervention could provide key targets for clinicians and researchers to adapt CR focus and PA messaging, in order to encourage patients to increase overall weekly PA and reduce inactivity. Understanding the factors associated with change in PA with CR intervention could potentially enhance development of more intense interventions specifically tailored or targeted at those with lower baseline PA or exercise capacity levels, as these patients will have the most to gain from increasing their PA.


Heart failure with reduced ejection fraction (HFrEF) is the inability of the heart to adequately contract or eject blood. This heart is unable to produce adequate cardiac output to perfuse vital tissues. At a fundamental level, it is known that the cardioprotective pathway of nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate is impaired in heart failure patients. Vericiguat is a novel, orally used, small molecule, and direct stimulator of the soluble guanylate cyclase, and thus, it enhances the production of cyclic guanosine monophosphate. Vericiguat was approved by the FDA in January of 2021 to reduce the risk of cardiovascular death and heart failure hospitalization following a hospitalization for heart failure or need for outpatient IV diuretics, in adults with symptomatic chronic heart failure and ejection fraction less than 45%. In this review, we describe the chemical and mechanistic aspects, pharmacokinetics, adverse effects, and contraindications of vericiguat so as to facilitate its optimal therapeutic use. Heart failure is a severe disease that affects more than 60 million people worldwide. Its prevalence is increasing because of the aging population. Heart failure can be chronic and progressive, and despite recent advances, patients with symptomatic heart failure have very poor prognosis. An important aspect of the heart function is the ejection fraction which represents the volume of blood pumped from the main chamber with each contraction. Typically, normal left ventricular ejection fraction (LVEF) is between 50% and 70% of its total volume  1–4]. H–4. H1–4]Common causes of HFrEF include coronary artery disease and cardiomyopathy, high blood pressure, aortic stenosis, and arrhythmia , 10. ComUnder normal conditions, the endothelium generates nitric oxide (NO) which stimulates the production of cyclic guanosine monophosphate (cGMP) via the action of soluble guanylate cyclase (sGC). Intracellular cGMP is important to regulate the heart's contractibility. Until recently, endothelial dysfunction has been unrecognized in heart failure patients .β-blockers, angiotensin receptor blockers, angiotensin receptor-neprilysin inhibitor, angiotensin-converting enzyme inhibitors, sodium-glucose cotransporter-2 inhibitors, and aldosterone antagonists. Vasodilators and diuretics may also be used. Furthermore, lifestyle changes have also been shown to decrease symptoms of heart failure. These include eating healthy, maintaining healthy weight, limiting caffeine and alcohol intake, and physical activity. Several devices and surgical procedures can also be used to treat HFrEF. Left ventricular assist devices (LVADs) assist in the heart's pumping action by pumping blood to the aorta and are used in long-term management until heart transplantation becomes feasible or as a bridge therapy. Implantable cardioverter-defibrillators (ICDs) can also be used. ICDs are small devices placed in the chest to monitor heart rhythm and to send electrical pulses to correct any abnormal heart rhythms. ICDs are recommended in heart failure patients with a high risk of sudden cardiac arrest. In severe cases when medications provide no benefits, heart transplantation may be required pyridin-3-yl)pyrimidin-5-yl) carbamate  is an orally bioavailable drug. It is chemically known as methyl -arbamate  13]. As. As1H-pyIn particular, intracellular cGMP is important for the regulation of vascular tone, cardiac contractility, and cardiac remodeling. cGMP deficiency has been shown to be detrimental to the heart and contributes to the progression of heart failure. Heart failure has been found to be associated with impaired synthesis of NO and decreased activity of sGC, which may contribute to myocardial and vascular dysfunction. When NO binds to sGC, the enzyme catalyzes the synthesis of intracellular cGMP. Vericiguat is a direct and indirect stimulator of sGC. By stimulating sGC, independently of and synergistically with NO, vericiguat augments levels of intracellular cGMP, leading to smooth muscle relaxation and vasodilation. Overall, oral administration of vericiguat has been found to increase cardiac output and index and to decrease systemic vascular resistance. Vericiguat is not associated with tolerance upon long-term use , 16. VerN = 92) or 1 of 4 daily doses of oral vericiguat (1.25 mg (N = 91), 2.5 mg (N = 91), 5 mg (N = 91), and 10 mg (N = 91)) for 12 weeks. In this trial, treatment with vericiguat from baseline to week 12 was not significantly different from the placebo group regarding reducing the biomarker of heart failure of N-terminal pro-B-type natriuretic peptide. It was then concluded that a different clinical trial where higher doses of vericiguat would be highly likely to yield more meaningful results , 22N-glu2 at treatment initiation or on dialysis. No clinically relevant increases in exposure were observed for individuals with mild and moderate hepatic impairment. Mean exposures were 21% and 47% higher, respectively, compared to individuals with normal hepatic function. The pharmacokinetics of vericiguat have not been studied in patients with severe hepatic impairment. Interestingly, no clinically significant variations in the pharmacokinetics of vericiguat were observed based on sex, age, body weight, race/ethnicity, or baseline N-terminal pro-B-type natriuretic peptide [Compared to patients with normal renal function, the AUC of vericiguat is increased by 5%, 13%, and 20% in patients with heart failure with mild, moderate, and severe renal impairment not requiring dialysis, respectively. Yet, these differences in exposure are not considered clinically relevant. Unfortunately, the pharmacokinetics of vericiguat have not been studied in patients with eGFR < 15 mL/min/1.73 m peptide , 20.Given its basicity, vericiguat is less soluble at neutral than at acidic pH. Thus, pre- and cotreatment with antacids or proton pump inhibitors decreases vericiguat exposure by about 30% following fasted administration. Nevertheless, cotreatment with these drugs did not affect vericiguat exposure in patients with heart failure when vericiguat was taken as directed with food , 20. No In VICTORIA trial, the mean drug exposure duration was 1 year, and the maximum exposure duration was about 2.6 years. During the study, the mean reduction in systolic blood pressure of patients who received the drug was about 1-2 mmHg more than those who received the placebo. This decreased blood pressure appears to have caused tachycardia in some patients . Few patVericiguat has US Boxed Warning of embryo-fetal toxicity. This was based on data obtained from reproduction studies in animals. This warning indicates that administering this medication to a pregnant female can be fatally harmful, and therefore, the absence of pregnancy before the treatment start should be confirmed for females of reproductive potential. To prevent pregnancy, the patients are recommended to use contraceptives during treatment and for at least one month after treatment discontinuation , 20.Vericiguat is contraindicated in patients taking other sGC stimulators such as riociguat. Because of hypotension, riociguat is contraindicated in patients using nitrates such as isosorbide dinitrate, isosorbide mononitrate, nitroglycerin, pentaerythritol tetranitrate, and erythritol tetranitrate. In VICTORIA trial, patients with concurrent or anticipated use of long-acting nitrates were excluded . However2 who are not on dialysis. Vericiguat has not been studied in patients with eGFR < 15 mL/min/1.73m2 at treatment initiation or on dialysis. No dosage adjustment of vericiguat is recommended in patients with mild or moderate hepatic impairment. The drug has not been studied in patients with severe hepatic impairment [Because there is no data on the presence of vericiguat in human milk or on its effects in breastfed infants, breastfeeding during treatment is not recommended because of the potential of serious adverse effects . A patiepairment , 20. Safpairment , 20.Limited data are available regarding overdosage in patients treated with vericiguat. In VICTORIA trial, doses up to 10 mg have been studied. In a study of patients with preserved ejection fraction heart failure (LVEF ≥ 45%), multiple doses of vericiguat 15 mg have been studied and were generally well tolerated. In the case of an overdose, patients may get hypotension which requires symptomatic treatment. Because of its high protein binding, vericiguat is less likely to be removed by hemodialysis , 20.HFrEF is a debilitating, chronic, and progressive disease. Research on the disease's pathophysiology and pharmacotherapy has realized an incredible success in the last 30 years. However, the morbidity and mortality rates after hospitalization remain significantly high , 20. VerMechanistically, the sGC stimulator vericiguat bypasses the conventional model and offers a new paradigm-shifting therapy by affecting the NO-sGC-cGMP pathway . This no


Certain variables reportedly are associated with a change in left ventricular ejection fraction (LVEF) in heart failure (HF) with reduced ejection fraction (HFrEF). However, literature describing the association between the recovery potential of LVEF and parameters of ventricular remodeling in echocardiography remains sparse.We recruited 2,148 HF patients with LVEF < 35%. All patients underwent at least two echocardiographic images. The study aimed to compare LVEF alterations and their association with patient characteristics and echocardiographic findings.p-value < 0.05 in Kaplan–Meier estimates of the cumulative hazard curves.Patients with “recovery” of LVEF (follow-up LVEF ≥ 50%) were less likely to have prior myocardial infarction (MI), had a higher prevalence of atrial fibrillation (Af), were less likely to have diabetes and hypertension, and had a smaller left atrium (LA) diameter, left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD), both in crude and in adjusted models (adjustment for age and sex). LVEDD cutoff values of 59.5 mm in men and 52.5 mm in women and LVESD cutoff values of 48.5 mm in men and 46.5 mm in women showed a year-to-year increase in the rate of recovery (follow-up LVEF ≥ 50%)/improvement (follow-up LVEF ≥ 35%), Our study shows that LVEDD and LVESD increments in echocardiography can be predictors of changes in LVEF in in HF patients with LVEF < 35%. They may be used to identify patients who require more aggressive therapeutic interventions. Heart failure (HF) is a major public health problem associated with substantial morbidity, high mortality, and poor quality of life , 2. The In a meta-analysis, improvement in LVEF and left ventricular (LV) volume was associated with lower rates of mortality among patients with HFrEF . FurtherShorter HF duration, lower baseline LVEF, non-ischemic cardiomyopathy, female sex, and no prior myocardial infarction (MI) were reportedly associated with an increase in LVEF in HFrEF patients , 10. HowThis study was approved by the Institutional Review Board (TSGH-C202105049). It retrospectively and consecutively examined HF patients who were treated between April 2010 and September 2020 at a medical teaching hospital in northern Taiwan. Patients' clinical data were retrospectively reviewed without patients' written consent. Patients aged more than 18 years old with a primary or secondary diagnosis of HF at the time of the most recent office visit were included in the study. Participants were required to have an LVEF of <35% based on previous echocardiogram measurement and more than two echocardiographic images. That is, patients were required to have an echocardiogram showing LVEF < 35% as the baseline and one echocardiogram after that as the follow up image for analysis. Echocardiographic images were retrospectively collected in our hospital's database. The follow-up timing of echocardiography was the physicians' clinical decision. We were not involved in the decision making. We then excluded patients who had the following events or procedures between the baseline and follow-up assessment of LVEF: major cardiovascular surgery, cardiac device implantation, cancer, or heart transplant.Recovery of LVEF was defined as an LVEF ≥ 50% on echocardiography follow-up, and improvement of LVEF was defined as an LVEF ≥ 35% but <50% on echocardiography follow-up in our analysis.Echocardiographic findings, baseline demographics, clinical characteristics, comorbidities, and laboratory findings were obtained from patient charts and electronic health records by trained chart review specialists. Echocardiography was acquired by experienced cardiologists or technicians using standardized methods. LVEF was determined using the M-mode in the parasternal long-axis view or Simpson's biplane method. Parameters of ventricular and atrial remodeling, including changes in left atrium (LA) diameter, LV end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), interventricular septum (IVS), left ventricular posterior wall (LVPW), estimated pulmonary artery systolic pressure (PASP), and severity of valvular regurgitation from baseline, were also collected using the American Society of Echocardiography guidelines . LVEDD wTo further investigate the predictive performance of the recovery potential of LVEF and LVESD/LVEDD, Kaplan–Meier analysis was performed using follow-up data available in the echocardiography database for the chosen cutoff values, based on the Youden index . Time 0 t-test. Categorical variables of the comorbidity described were analyzed using the χ2 or Fisher's exact test, as appropriate. A Cox proportional hazard model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) as measures of associations with LVEF improvement and LVEF recovery. The multivariable Cox proportional hazard model was used to adjust the potential confounding factors, and the adjusted variables were age and sex. A p-value < 0.05 was considered significant. Normality of distribution was tested by the Shapiro Wilk test in all continuous variables. If the distributions were skewed, we categorized these variables and reanalyzed their HRs. Statistical analyses were conducted using R software, version 3.4.4. In addition, we evaluated a Kaplan–Meier hazard curve to capture the hazard of the improvement of LVEF and recovery of LVEF, stratified by LVEDD and LVESD.Continuous variables of the general demographic data were expressed as the mean and standard deviation using Student's A total of 2,148 patients with baseline LVEF < 35% were included in this study. Among these patients, 516 (24%) had “no recovery” (follow-up LVEF < 35%), 714 (33.2%) had “improvement” (50% > follow-up LVEF ≥ 35%), and 918 (42.7%) patients had “recovery” (follow-up LVEF ≥ 50%). Compared to the other two groups of patients , patientWe checked normality in all continuous variables, and all the continuous variables were in skewed distributions. Therefore, we categorized these variables by normal values and reanalyzed their HRs in The factors associated with LVEF improvement (LVEF ≥ 35%) are shown in The factors associated with LVEF recovery (LVEF ≥ 50%) are shown in p-value < 0.05). Male patients with LVESD < 48.5 mm and female patients with LVESD < 46.5 mm exhibited a higher hazard for improvement of LVEF and recovery of LVEF .Kaplan–Meier estimates of the cumulative hazard curves for possible LVEF improvement (LVEF ≥ 35%) and recovery (LVEF ≥ 50%) during the follow-up period are depicted in The two major findings of the present study are as follows:Certain variables can be used to predict the response of change in LVEF. The data in our study showed that hyperlipidemia, prior MI, diabetes mellitus, hypertension, baseline LVEDD/LVESD and LA diameter were negatively associated with the recovery of LVEF. And Af, hypoalbuminemia, and anemia were positively associated with the recovery of LVEF.Both LVEDD and LVESD were associated with the recovery of LVEF. Furthermore, LVEDD cutoff values of 59.5 mm in men and 52.5 mm in women, and LVESD cutoff values of 48.5 mm in men and 46.5 mm in women predicted the improvement of LVEF and recovery of LVEF and can help physicians identify patients who are more likely to have a change in LVEF.A correlation between the therapeutic effect of LVEF and mortality was reported in a meta-analysis. The regression analyses showed that a 5% increase in the mean EF change corresponded to a decreased odds ratio (OR) for mortality and favorable outcomes . FurtherCertain variables reportedly predict the change in LVEF after treatment. However, the relationship between echocardiography features and the recovery potential of LVEF remains unclear. Shorter HF duration, lower baseline LVEF, non-ischemic cardiomyopathy or no prior myocardial infarction, and female sex were associated with LVEF improvement in previous studies , 10. HowTo the best of our knowledge, this is the first study to examine the link between parameters of LV structure remodeling, such as LVEDD and LVESD, and LVEF increments in HFrEF patients. In addition, LVEDD cutoff values of 59.5 mm in men and 52.5 mm in women, and LVESD cutoff values of 48.5 mm in men and 46.5 mm in women may be useful and simple tools for the assessment of LVEF recovery potential.In our study, we found prior MI, LA enlargement, dyslipidemia, diabetes, and hypertension are negatively association with recovery of LVEF.The association of LA enlargement with HF has been well established. LA is correlated with LV function and change in LV filling pressure is associated with LA size . Thus, LNon-ischemic cardiomyopathy and no prior MI were more likely to increase LVEF in our study and previous reports. These results might be explained by different cardiac remodeling processes due to diverse pathological conditions. Necropsy studies have demonstrated that patients with congestive heart failure and significant coronary artery disease have gross myocardial scarring at autopsy, even in those without a clinical history of MI, angina, or Q waves , and scaWe also found patients with recovery of LVEF tend to have Af, hypoalbuminemia, and anemia.An increasing prevalence of Af was observed with increasing EF (higher in HFpEF and HFmrEF compared to HFrEF) , 25. We Several studies demonstrated that there is an association between anemia, hypoalbuminemia and worse outcomes in HF patients regardless of LVEF, although it is unclear why these factors are associated with worse outcomes –33. WhicAn add-on strategy of drugs and devices is suggested in current HF treatment guidelines for HF patients with persistent low ejection fraction. The 2015 European Society of Cardiology (ESC) guidelines recommend ICD therapy in symptomatic patients with LVEF ≤ 35% after ≥3 months of optimal medical therapy. Despite the minor differences between their recommendations depending on the underlying heart disease, LVEF thresholds ≤ 35% were used to guide device-based therapy, including implantation of primary prevention ICDs and cardiac resynchronization therapy (CRT), both in American College of Cardiology (ACC) guidelines and ESC guidelines , 35. TheHF medications at baseline showed no significant difference in each groups in Our study drew its strength from a large sample size, a longitudinal design rather than a cross-sectional design, and a well-validated echocardiographic finding.However, our analysis has some limitations that need to be acknowledged. First, all patients were from a center in Taiwan using a longitudinal design. Sampling bias and selection bias are deemed inevitable. We could not assure the generalizability of the results to other populations and could not establish a cause–effect relationship. Second, the duration and etiology of HF, which are reportedly associated with LVEF improvement in previous literature, were not mentioned in our study. Although it is unclear why the duration of heart failure modifies recovery potential, it may be related to scar burden and the cumulative level of myocyte injury . Third, In our study, no previous MI history, no hyperlipidemia, no hypertension, non-diabetic, smaller baseline LVEDD/LVESD and LA diameter were associated with 50% or greater LVEF recovery. LVEDD cutoff values of 59.5 mm in men and 52.5 mm in women and LVESD cutoff values of 48.5 mm in men and 46.5 mm in women were associated with LVEF increments. These data may inform discussions on therapies for HFrEF and can be the bases for future research on parameters of ventricular remodeling.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Tri-Service General Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.Y-CC contributed to drafting of the manuscript and critical revision of the manuscript. S-CH contributed to algorithm development, drafting of the manuscript, and submission process. Y-PC contributed to data acquisition, concept generation, and the methodology. Y-WC contributed to data acquisition and concept generation. C-SL contributed to concept generation and the methodology. CL contributed to the methodology, data acquisition, and interpretation. W-HF contributed to concept generation, the methodology, data acquisition and interpretation, and approval of the article authors. All authors contributed to the article and approved the submitted version.This study was funded by the Ministry of Science and Technology, Taiwan (110-2314-B-016-008 to W-HF), the Tri-Service General Hospital, Taiwan (TSGH-E-111217 to W-HF), and National Defense Medical Center (MND-MAB-D-111143 to W-HF).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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Lumped parameter modelling has been widely used to simulate cardiac function and physiological scenarios in cardiovascular research. Whereas several patient-specific lumped parameter models have been reported for adults, there is a limited number of studies aiming to simulate cardiac function in children. The aim of this study is to simulate patient-specific cardiovascular dynamics in children diagnosed with dilated cardiomyopathy, using a lumped parameter model.Patient data including age, gender, heart rate, left and right ventricular end-systolic and end-diastolic volumes, cardiac output, systolic and diastolic aortic pressures were collected from 3 patients at Great Ormond Street Hospital for Children, London, UK. Ventricular geometrical data were additionally retrieved from cardiovascular magnetic resonance images. 23 parameters in the lumped parameter model were optimised to simulate systolic and diastolic pressures, end-systolic and end-diastolic volumes, cardiac output and left and right ventricular diameters in the patients using a direct search optimisation method.Difference between the haemodynamic parameters in the optimised cardiovascular system models and clinical data was less than 10%.The simulation results show the potential of patient-specific lumped parameter modelling to simulate clinical cases. Modelling patient specific cardiac function and blood flow in the paediatric patients would allow us to evaluate a variety of physiological scenarios and treatment options. For instance, Gross et al.12 evaluated the effect of left ventricular assist device speed increase during exercise in a model simulating heart failure. Liu et al.20 evaluated varying speed modulation algorithms for continuous-flow left ventricular assist devices based on a cardiovascular coupling numerical model. Modelling of cardiac function and simulation of physiological cases in adults have been studied extensively and detailed information can be found in the literature.18Lumped parameter modelling has been widely adopted to simulate cardiac function and physiological scenarios in cardiovascular research as they allow to study complex conditions in a simplified manner. For instance, heart failure has been simulated using this method by reducing systolic elastance, which describe the relationship between left ventricular pressure and volume.7 developed a patient-specific model of cardiovascular and respiratory systems during hypercapnia. Pope et al.26 showed how sensitivity analysis and subset selection can be employed in a cardiovascular model to estimate system parameters for healthy young and elderly subjects. Neal and Bassingthwaighte22 developed a method to estimate subject-specific cardiac output and blood volume during haemorrhage. There is a limited number of studies aiming to simulate physiological cases in children where there is a need for such models. Schiavazzi et al.29 estimated parameters of patient-specific in single-ventricle lumped circulation models under uncertainty. Goodwin et al.10 developed a model simulating infant cardiovascular physiology for educational purposes. Sá Couto et al.28 developed a cardiovascular system model to simulate neonatal physiology. Giridharan et al.9 developed a computer model of the paediatric circulatory system to test ventricular assist devices. Petukhov and Telyshev24 developed a cardiovascular system model for paediatric patients with congenital heart diseases. Bozkurt3 developed a cardiovascular system model capable of simulating cardiac function and heart chamber dimensions over a cardiac cycle in adults and children.Lumped parameter models simulating patient-specific cardiac dynamics in adults have already been developed. For instance, Ellwein et al.14 Moreover, in children, clinical decisions are often dependant on results recorded in adult heart failure trials.6 Therefore, treatment is negatively affected as there are substantial difficulties in adapting adult data to paediatric patients. Patient-specific numerical models simulating cardiac function may help to evaluate treatment options for children. Our previous model3 presents a concept model in which the parameters were not optimized to simulate patient-specific clinical data. It simulates hemodynamic variables in adults and children within a physiological interval. The aim in this study is to simulate patient-specific cardiovascular dynamics in children diagnosed with dilated cardiomyopathy using a new optimisation strategy which can be applied without computational cost for parameter identification.Mostly, average models describing generalised physiology in adults and children have been utilised to simulate physiological scenarios such as heart failure. However, causes of heart failure vary significantly from patient to patient and indeed, several different therapies, including digoxin, beta-blockers, diuretics or angiotensin-converting enzyme inhibitors, are used to improve heart failure.The following demographics and hemodynamic parameters were collected from 3 patients diagnosed with dilated cardiomyopathy at Great Ormond Street Hospital for Children, London, UK, by searching the clinical database: age, gender, heart rate, cardiac output, left and right ventricular end-systolic and end-diastolic volumes, systolic and diastolic aortic pressures. The patients were selected to simulate mild and severe dilated cardiomyopathy in the left ventricle and biventricular dysfunction.Cardiac magnetic resonance images  were reviewed for these patients. The steady-state free precession sequences acquired at both end-diastole, and end-systole, were used to measure cardiac dimensions in Simpleware ScanIP 2018 . Four-chamber view was used to measure left and right ventricular long axis length and right ventricular basal diameter; the short-axis view was used to measure left ventricular lateral-septal diameter.31In children, dilated cardiomyopathy is diagnosed considering z-scores for ventricular ejection fraction, ventricular volume and ventricular end-diastolic and end-systolic diameters indexed on body surface area and measurements of the ventricular systolic function (z-score>2).2) was diagnosed with mild dilated cardiomyopathy. There were no signs of left ventricular hypertrophy, atrial dilation, atrio-ventricular valve regurgitation, and outflow tracts’ obstruction. Both aortic and pulmonary valves were competent, with no stenosis. The right ventricle had normal global systolic function and volume. Cardiac output was 5.3 L/min, and systolic and diastolic pressures were 109 mmHg and 60 mmHg, respectively. End-diastolic volume was 106 mmHg (z-score=2.1).Patient 1  was diagnosed with severe dilated cardiomyopathy. She presented with global thinning of the myocardium with no left ventricular hypertrophy. There was no left atrial dilatation and no mitral regurgitation on volume measurements. There was no left ventricular outflow tract obstruction and the aortic valve had normal function. The right atrium was not dilated. There was no tricuspid valve regurgitation. There was no right ventricular outflow tract obstruction. The pulmonary valve was competent with no stenosis. Cardiac output was 2.6 L/min, and systolic and diastolic pressures were 84 mmHg and 49 mmHg, respectively.Patient 2  was diagnosed with severe cardiomyopathy with biventricular dysfunction and raised pulmonary pressure. The right atrium was dilated, whilst the left atrial chamber remained normal. There was 37% tricuspid valve regurgitation. The right ventricular myocardium was moderately hypertrophied, with globally poor contractility and evidence of severely impaired diastolic function. The right ventricle was dilated at both end-diastole and end-systole. There was no left ventricular hypertrophy. The left ventricular chamber was of low-normal body surface area indexed volume at end-diastole, and normal volume at end-systole, appearing under-filled, with a global impairment of systolic function. The pulmonary valve was unobstructed whilst there was 11% pulmonary valve regurgitation. The aortic valve was competent. Cardiac output was 2.6 L/min, and systolic and diastolic pressures were 118 mmHg and 64 mmHg, respectively.Patient 3  was described using the active and passive contraction components . The ventricular active pressure component was described using systolic ventricular elastance , ventricular volume and zero-pressure volume , and the activation function . The ventricular passive pressure component  was modelled using an exponential relationship including volume (Vlv) and additional coefficients . Detailed information about the cardiovascular system model can be found in.3The cardiovascular system model used in this study simulates pressures, volumes and diameters in the heart chambers, flow rate through the heart valves, and pressures and flow rates in the systemic and pulmonary circulations. The left ventricular pressure (Vlv) was described using the left ventricular radius (rlv), long axis length (llv) and an additional coefficient (Klv), which includes effects of the contraction in the long axis and scales the proportion between the left ventricular radius and volume over a cardiac cycle. Change of the left ventricular radius (rlv) were described utilising the flow rates through the aortic and mitral valves , the left ventricular volume (Vlv) and long axis length (llv), and the coefficient Klv.Left ventricular volume (pla) and volume (Vla) relationship was described using the elastance (Ela).The left atrial pressure (Vla) was described using the left atrial radius (rla) and long axis length (lla), and an additional coefficient (Kla). Changes of the left atrial radius (rla) were described utilising the flow rates through the mitral valve and pulmonary vein , the left atrial volume (Vla) and long axis length (lla), and the coefficient Kla.The left atrial volume  to simulate regurgitant valve flow in the patients. The flow rate expression through the mitral valve is provided below.Heart valves were modelled using the pressure across the valve and the characteristic resistances for the forward and backward flows , compliance (C) and inertia (L). The aortic blood pressure (pao) and flow rate signals (Qao) are provided below.Qav and pas represent the aortic valve flow rate and systemic arteriolar pressure, respectively, and Cao, Rao and Lao representing compliance, resistance and inertance in the aorta, respectively. The electric-analogue of the cardiovascular system model is represented in Figure The circulatory system included the aorta, the systemic arteries and veins, and the pulmonary arteries and veins. Blood flow in the circulatory system was described using a lumped parameter model, which included electrical analogues for resistance (EF) in the cardiovascular system models were calculated as given below.Ejection fraction  in the optimisation process aimed to minimise the difference in mean arterial pressure (MAP) and cardiac output (CO) between clinical data and the cardiovascular system model. The optimisation algorithm was designed to find a quick and effective solution for parameter estimation problem with multiple variables such as in the presented cardiovascular system model. The utilised optimisation method evaluates multiple variables in each simulation and effectively finds optimal solutions without computational cost.The objective function (CO) and pressure (MAP) terms to ensure that objective function is sensitive to the parameter set in the x vector. MAP in the cardiovascular system model is the time-averaged aortic pressure (pao) over a cardiac cycle in each patient.fMAP and fCO are the relative error functions for mean arterial pressure and cardiac output. The parameter set (x) included left and right ventricular end-systolic elastances , left and right ventricular zero-pressure volumes , the coefficients used in the passive pressure components of the ventricular pressures , the compliances and resistances of the aorta, systemic arteries, and veins, pulmonary artery, arterioles and veins  and the circulating blood volume (Vblood).The utilised electric analogue model of blood vessels simulates blood flow by solving ordinary differential equations for pressures and flow rates in each compartment. Heart chambers simulate pressure and volume which in turn affects the cardiac output the cardiovascular system. Error functions and objective function includes flow rate  were chosen around the values from the concept model published in.3 Step-size (h) in the optimisation was defined using xub, xlb and iteration number (n) in each simulation, and the parameters were updated using the initial lower bounds of the parameters and the step size, except for the coefficients A and B. These were updated starting with the upper bounds. Because arterial pressure and cardiac output decrease with the increasing A and B. Step size (h) and parameter updates are given in the Equations Upper and lower bounds of the optimised parameters (f(x)≤0.05, fMAP(x)≥-0.1 and fMAP(x)≤0.1, fCO(x)≥-0.1 and fCO(x)≤0.1.The optimisation algorithm was set to complete 10 iterations in one simulation. The upper and lower bounds of the parameters were updated according to the values of the objective and error functions. The simulations were repeated to complete 10 iterations in each simulation with updated upper and lower bounds until Klv and Krv.The left and right ventricular diameters were estimated by optimising the coefficients in The error function for the diastolic and systolic diameters of the left and right ventricles were defined as:k vector  were chosen around the values from the concept model published in.3 Again, the step-size (h) in the optimisation was defined using kub, klb, and the iteration number (n) in each simulation and the parameters were updated using the initial lower bounds of the parameters and the step size. Klv and Krv do not affect any other variable but ventricular diameters, depending on the ventricular volumes. Therefore, first ventricular volumes were optimized and then Klv and Krv were tuned according to the ventricular volumes. Initial upper and lower bound of the parameters in the k vector are reported in Table Upper and lower bounds of the fD(k)>-0.1 and fD(k)≤0.1. Initial upper and lower bounds of the parameters in the x and k vectors are reported in Table Again, the optimisation algorithm was run to complete 10 iterations in each simulation. The upper and lower bounds of the parameters were updated according to the values of the error functions. The simulations were repeated to complete 10 iterations in each simulation with updated upper and lower bounds until 27 However, most of the blood volume consists of unstressed blood and constitutes a blood volume reserve.11 Circulating blood volume is less than the total blood volume, therefore, optimised values for the circulating blood volume were less than the total blood volume in the cardiovascular system models.Blood volume optimised in this study is the circulating blood volume. Total blood volume in children for the studied ages changes between 2000 mL and 4000 mL.lv) were used as input values in the model. Ventricular long axis lengths were kept constant in the simulations and calculated using systolic and diastolic long axis lengths  in each patient as:Patient-specific heart rates and left and right ventricular long axis lengths ; for ventricular volumes, in Patient 3 for the left ventricle in diastole (6 mL); for stroke volume, in Patient 1 for the right ventricle (7 mL). Ventricular diameters were also in good agreement, with the largest difference being 0.3 cm in diastolic right ventricular diameter in Patient 3. The upper and lower bounds of the parameters in the x and k vectors, as given in the Table The difference between the upper and lower bounds were narrowed down after the first optimisation with the initial upper and lower bounds of the parameters. The second optimisation allowed us to calculate optimal values satisfying conditions defined in the objective function and the error functions for the parameters in the f was ≤0.050 for all models in the optimisation. Moreover, the error function remained between -0.1 and 0.1. The plots of left and right ventricular pressures, and aortic and pulmonary arterial pressures from the three models are shown in Figure The objective function Systolic and diastolic aortic pressures were around 106 mmHg and 57 mmHg correlating with the patient data in Patient 1. Systolic right ventricle and pulmonary arterial pressures were around 35 mmHg whereas diastolic pulmonary arterial pressure was around 20 mmHg. Reduced systolic left ventricular and aortic pressures Patient 2 were simulated as in the patient data. Right ventricular and pulmonary arterial pressures were above 30 mmHg at systole, whilst diastolic pulmonary arterial pressure was slightly above 10 mmHg. Systolic left ventricular and aortic pressures were around 118 mmHg in Patient 3. Both systolic and diastolic pressures were remarkably high in the right ventricle showing the effects of both systolic and diastolic dysfunctions in the right ventricle. Left and right ventricular volumes and basal diameters extracted from the models are plotted over 2 cardiac cycles in Figure The left ventricular volume was larger than the right ventricular volume during the entire cardiac cycle in both Patient 1 and 2. The right ventricle was remarkably dilated in Patient 3, whereas the left ventricular volume remained below 100 mL over the cardiac cycle. Moreover, the right ventricular stroke volume was larger than the left ventricular stoke volume in Patient 3 because of the reverse flow through the tricuspid and pulmonary valves. Left ventricular basal diameter was higher than the right ventricular basal diameter in Patient 1 and 2, whilst right ventricular basal diameter was relatively high in Patient 3.The left and right ventricular pressure-volume loops from the models are given in Figure The left ventricular pressure-volume loop shifted to the right in Patient 1 and Patient 2 due to systolic dysfunction in the left ventricle. In Patient 3, the right ventricular pressure-volume loop shifted to the right, indicating impaired right ventricular function.19 Left ventricular systolic elastance  in adults is around 2.5 mmHg/mL whereas it is reported to be above 3 mmHg/mL in children between 6 and 15 ages.15 Relatively high systolic elastance values in Patient 1 and Patient 3 show the effect of a mildly affected left ventricular function; whilst for Patient 2, diagnosed with severe left ventricular cardiomyopathy, left ventricular systolic elastance  was the lowest  is around 1 mmHg/mL in adults,4 whilst 1.4 mmHg/mL has been used for children between 8-12 years age.3 1.040 mmHg/mL right ventricular elastance  shows impaired right ventricular systolic function in Patient 2  in Patient 3  can be seen in Patient 2 and 3 as the cardiac output and mean arterial pressure in these patient were relatively low. Upper and lower bounds of the other parameters were selected considering the concept model and haemodynamic variables such as ventricular volumes and arterial pressures reported in the patient clinical data. For instance, the interval between the upper and lower bounds in the ventricular zero-pressure volumes (V0) were selected higher for the relatively high ventricular volumes clinically reported. Moreover, the right ventricular zero-pressure volumes  were higher in the concept model reported in.3 Therefore, ventricular zero-pressure volumes (V0) were the same for left and right ventricles in the cardiovascular system model simulating Patient 1 where right ventricular zero-pressure volumes  were higher as in the cardiovascular system model simulating Patients 2 and 3.Systemic vascular resistance increases in heart failure as a response to neurohumoral pathways to maintain perfusion level.x vector contained 21 parameters and the k vector contained 2 parameters. The optimal solution depends on the selected upper and lower bounds , and on the step-size (h). It may be possible to obtain the global solution or local minima which provide better solutions by changing the initial upper and lower bounds, step size or interval for the error functions. However, it should be noted that the aim of the study was to simulate clinical conditions within the specified limits for the error functions (fMAP and fCO) and show that it could be possible to simulate clinical values in the patients using lumped parameter models. Also, relatively small step-sizes may allow to find an optimal solution in one run, whilst larger step-sizes updates the upper and lower bounds of the parameters and require running the optimisation algorithm more than once. Therefore, an initial simulation would be required for relatively large upper and lower bound intervals to narrow down the intervals for lower and upper bounds of the parameters. A numerical model utilising relatively large intervals for upper and lower bounds would take more time to find an optimal solution. The used optimisation method allowed us to optimise a parameter set containing several parameters without additional computational cost, as it utilised the parameter values simultaneously to find the optimal solution. Therefore, it is also suitable for low configuration computers.The V0) values, the utilised model simulate left ventricular pressures within the physiological limits. Utilising also V0 in the ventricular passive pressure component will allow ventricular pressures to become zero at the specified V0 values.21Ventricular passive pressure component uses left ventricular volume as its independent variable. Although the ventricular pressures may not be zero at the specified zero-pressure volumes (32 Another application would be simulations of therapies, such as ventricular assist device support that are becoming a viable treatment option for end-stage heart failure paediatric patients,30 albeit often causing complications which may require additional intervention.8 Computational techniques have been utilised widely to evaluate clinical scenarios in children.23 In those cases, where flow and pressure data cannot be retrieved from conventional imaging modalities, patient specific lumped parameter models, as presented in this study, can be used to simulate patient specific boundary conditions for finite element models.Patient-specific lumped parameter models simulating cardiac function in children can be used to evaluate several different scenarios. In this study, dilated cardiomyopathy was considered, but the framework presented could be easily adapted to simulate for example restrictive or hypertrophic cardiomyopathy.This study shows the potential of patient specific lumped parameter models to simulate clinical cases of dilated cardiomyopathy in children. Modelling patient specific cardiac function and blood flow in paediatric patients allows assessment of a variety of conditions for better understanding of the complex hemodynamic and cardiovascular function in these cases.


This study aimed to explore the effect of sex on left atrial (LA) remodeling and its relationship with myocardial fibrosis in patients with hypertrophic obstructive cardiomyopathy (HOCM).P = 0.027). Compared with men, the PER-E (P < 0.001) and the PER-E indexes (P = 0.012) in women were lower. In CVF-stratified subgroups, a sex difference in the PER-E index was eliminated (P > 0.05). The CVF was correlated with the PER-E and PER-E indexes in both sexes . In multivariate regression analysis, sex (P = 0.007) and CVF (P < 0.001) were independently correlated with PER-E .A total of 85 patients with HOCM were enrolled. Myocardial fibrosis was quantified by the collagen volume fraction (CVF) in myocardial samples. The early atrial peak of emptying rate (PER-E) was assessed by LA volume/time (V/t) curves derived from cardiac magnetic resonance (CMR) imaging analysis. The PER-E index was PER-E normalized by left ventricular (LV) filling volume. Patients with HOCM showed a lower PER-E index than healthy controls (Patients with HOCM presented LA reverse remodeling. Impaired LA function was more common in female patients with HOCM due to their susceptibility to myocardial fibrosis. Hypertrophic cardiomyopathy (HCM) is a complex and relatively common genetic cardiac disorder . Many paSex is an important factor contributing to disease heterogeneity. Interestingly, female patients with HCM have been described to show less ventricular remodeling compared with male patients , 9, wherTherefore, the current study aimed to investigate the effect of sex on LA remodeling and the association between LA remodeling and myocardial fibrosis in patients with HOCM.This study was carried out in accordance with the Declaration of Helsinki. Written informed consent was obtained from every patient. The study protocol was approved by the Ethics Committee.We consecutively recruited 85 symptomatic adult patients with HOCM who underwent surgical myectomy consecutively from 2016 to 2019. All patients underwent a detailed cardiovascular evaluation, including medical history, clinical examination, 12-lead ECG, and cardiac magnetic resonance (CMR) imaging.Hypertrophic cardiomyopathy was diagnosed by the presence of a non-dilated and hypertrophied LV on CMR imaging in the absence of other diseases that could account for the hypertrophy. Obstructive HCM was defined as a left ventricular outflow tract (LVOT) gradient either ≥40 mmHg at rest and/or ≥50 mmHg during provocation using Doppler echocardiography . PatientControl myocardium from the LV septal wall was collected at autopsy of nine individuals  who died from accidents without any cardiac medical history and their hearts showed no signs of macroscopic or microscopic cardiac lesions. CMR images from 35 age- and gender-matched healthy people  were used as control subjects.Cardiac magnetic resonance was performed on a 1.5-T magnetic resonance scanner . All imaging acquisitions were captured under breath control. CMR images were analyzed using the standard ventricular analysis software . For all patients, septal wall thickness, and posterior and LV end-diastolic dimensions were all determined in the short-axis view (at the midpapillary level). To evaluate functional parameters, cine images were acquired in three long-axis views  and continuous short-axis planes encompassing the entire LV using a balanced steady-state free precession sequence. Typical parameters include field of view: 320 × 320 mm; matrix: 192 × 224; slice thickness: 8 mm; slice gap: 2 mm; repetition time: 2.8–3.0 ms; echo time: 1.1–1.5 ms; flip angle: 60–70°; bandwidth: 930 Hz; views per segment: 12–20; temporal resolution: 30–55 ms (depending on the heart rate); cardiac phases: 25; SENSE factor: ×2. Epicardial and endocardial borders of the LV myocardium were manually traced during the whole cardiac phase on each cine short-axis image to obtain LV end-diastolic and end-systolic volumes, ejection fractions, and myocardial mass. Myocardial mass was calculated by multiplying the volume of the myocardium calculated at end-diastole by the specific gravity of the myocardium (1.05 g/ml). The end-diastolic volume index, end-systolic volume index, and mass index were indexed to body surface area (BSA). Late gadolinium enhancement  was performed on 67 patients. LGE images were acquired 15 min after intravenous administration of 0.2 mmol/kg gadolinium-DTPA  using a phase-sensitive inversion recovery-spoiled gradient echo sequence. LGE images were determined automatically by computer counting all hyper-enhanced pixels in the LV myocardium on each of the short-axis images. LGE images were defined as those with image intensities of 6 SDs above the mean of image intensities in a remote myocardial region in the same image.2). PER-E and PER-A were also normalized by the LV filling volume (difference between LV end-diastolic and end-systolic volumes), obtaining the PER-E index and the PER-A index. The isovolumetric pulmonary vein transit  was defined as the amount of LV filling volume flowing directly from the pulmonary veins into the LV cavity without significant change in LA volume . The isovolumetric pulmonary vein transit ratio (IPVTR) was defined as the ratio between IPVT and the atrial emptying volume , as previously described . LA endocardial contour was manually traced at the phase of the maximal LA volume before mitral valve opening and at the phase of the minimum LA volume after atrial contraction in the two-chambered and four-chambered views. The atrial and ventricular volume/time (V/t) and dV/dt curves were obtained by plotting the cavity volumes over time . From atescribed .The septal myocardium samples were immediately fixed in 10% buffered formalin and embedded in paraffin. The samples were sectioned and stained with Masson’s trichrome staining for evaluating myocardial fibrosis . Four imt-test or the Mann–Whitney U test, whereas the chi-squared test or Fisher’s exact test was used for categorical variables. Pearson’s correlation test or Spearman’s correlation test was used to examine correlations between two continuous variables when indicated. A multivariate analysis was performed with logistic regression analysis using block entry to evaluate if the variables were independent predictors for PER-E, provided to have a p-value of <0.1 in a univariate analysis. All p-values were two-sided. Statistical analysis was performed using the SPSS software package .Continuous variables are shown as mean ± SD. Categorical variables are presented as frequencies (percentages). Patients with HOCM were divided into two subgroups according to the upper limit of CVF normality . Of these patients, 51 patients showed high CVF (23 men and 28 women) and 34 patients showed normal CVF (26 men and 8 men). Comparisons of the groups for continuous variables were performed with the unpaired A total of 85 patients were enrolled in our study. The baseline clinical characteristics of patients with HOCM are summarized in P = 0.002). Women showed more extensive fibrosis than men . LA diameters, LAV max, and LAV min indices were larger  in patients with HOCM than in the controls. In addition, patients with HOCM had a lower PER-E index and LAEF  than the controls.Compared with healthy controls, patients with HOCM showed greater septal wall thickness, LV mass index (LVMI), LV end-diastolic diameter (LVEDD), and LV end-diastolic volume index (LVEDVI) . However, women showed lower PER-E, PER-E index, and PER-E/PER-A than men . The results of the CVF-stratified analyses revealed that female patients with high CVF showed lower LVEDD , LVMI , and PER-E , and IVPTR  were lower in female patients than in male patients with high CVF, although the difference was not significant between the two sexes. However, there was no sex-specific difference in CMR parameters in the subgroup with normal CVF.As shown in r = −0.604, P < 0.001; women: r = −0.727, P < 0.001, r = −0.482, P < 0.001, r = −0.568, P < 0.001; women: r = −0.653, P < 0.001, r = −0.460, P = 0.001, r = −0.464, P = 0.008; women: r = −0.693, P < 0.001; men: r = −0.269, P = 0.061). However, the extent of LGE was not correlated with any LA remodeling parameters.The CVF value was inversely correlated with PER-E (whole cohort: P = 0.033), sex (P < 0.001), EDVI (P = 0.098), ESVI (P = 0.071), and CVF (P < 0.001) were associated with PER-E. After multivariate adjustment, only sex (P = 0.007), EDVI (P = 0.012), and CVF (P < 0.001) remained significant  Compared with the healthy controls, patients with HOCM showed worse LA remodeling. (2) Female patients were more likely to develop impaired LA deformation rates than male patients. (3) The female sex and myocardial fibrosis were independent predictors for LA deformation rate after adjusting for clinical confounders in patients with HOCM.Patients with HOCM are characterized by early LVDD, mitral regurgitation, and outflow tract obstruction . The abnCardiovascular magnetic resonance imaging-feature tracking (CMR-FT) is a new quantitative method for wall motion assessment, with a high spatial resolution and large field of view. The details for the change rates of LAV during conduit  and booster phases  can be provided by the analysis of LA dV/dt curves plotting by CMR-FT. In this study, patients with HOCM showed a lower PER-E index in the conduit phase than controls, but there was no difference in the booster phase. A previous study has also found that patients with non-obstructive HCM were likely to have LA conduit dysfunction, compared to healthy controls . The posIn addition, our study showed that the PER-E and PER-E index of female patients is lower than male patients. A previous study has demonstrated that female patients presented more severe atrial stiffness than male patients with heart failure, which was assessed with pulse wave analysis of the radial artery and carotid-femoral pulse wave velocity using commercially available radial artery tonometry. The effect of atrial stiffness can increase LV afterload and impair LV relaxation, which may contribute to a greater susceptibility to heart failure with preserved LV ejection fraction in female patients . To explThe mechanisms underlying sex-specific differences in myocardial fibrosis are unknown, but in our study, despite worse LA function in female patients, they showed smaller LV diameters and lower septal wall thickness. The LV geometry in female patients could underlie a greater prevalence of obstructive hemodynamics , which wOur study still has several limitations. First, owing to the observational nature of our study, there may be less insight into the causality between LA function and myocardial fibrosis, and it is still unclear how sex modifies the relationship. Second, we only enrolled patients with HOCM, which limited the appliance to other morphological types of HCM. Third, this study is a cross-sectional analysis and may have inherent limitations; the findings must be confirmed by further studies with a longitudinal design.Patients with HOCM presented LA reverse remodeling. Impaired LA function was more common in female patients with HOCM due to their susceptibility to myocardial fibrosis.The original contributions presented in this study are included in the article/The studies involving human participants were reviewed and approved by Ethics Committee of Fuwai Hospital. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.XB, YYS, and CY contributed to the conception and design of the study and wrote the first draft of the manuscript. XB organized the database and performed data analysis. All authors contributed to the interpretation of the results and manuscript revision, read, and approved the submitted version.


Electromechanical dyssynchrony, manifested by right bundle branch block and regional wall mechanical dysfunction, contributes to inefficient RV function in repaired Tetralogy of Fallot (ToF). This study aims to evaluate the synchronicity of multiple RV walls using two-dimensional multi-plane echocardiography (2D-MPE) in order to augment current understanding of the mechanisms behind RV dyssynchrony.Sixty-nine adult ToF patients  and twenty-five matched healthy controls underwent deformational analysis of the RV lateral, anterior, inferior and septal walls following 2D-MPE acquisitions. RV synchronicity was assessed by the intra-RV deformation delay between each basal RV wall and mid-septal segment in addition to mechanical dispersion calculated across four, six and eight segments (MD).p < 0.001–0.03). In ToF patients, the lateral and anterior RV walls were last to reach peak deformation and anterior wall longitudinal strain was lower (p = 0.001). Post systolic shortening of at least one RV wall segment was identified in 19 (28%) ToF patients. Despite similar ECG characteristics, lateral and anterior wall-septum delays were significantly longer in patients with greater degrees of dyssynchrony , although RV ejection fraction (RVEF) was not significantly lower. MD-4 and MD-8 indices displayed moderate negative associations with RVEF, strengthened by inclusion of lateral wall longitudinal strain .All RV wall-septum delays plus MD-4 and MD-6 indices were significantly greater in ToF patients compared to healthy controls (RV dyssynchrony in ToF is characterised by electromechanical delays between the lateral, anterior and septal walls, with anterior wall dysfunction likely associated with surgical repair of the RV outflow tract. Prospectively, 2D-MPE may have an emerging role evaluating RV mechanical response to electrical resynchronisation therapy RV elec2.2.1.ToF patients who had undergone detailed imaging of the RV with 2D-MPE during routine outpatient follow up at our ACHD centre were included in this study. In addition to two- and three-dimensional trans-thoracic echocardiogram (2D/3D-TTE), all individuals on the same day had a 12 lead electrocardiogram (ECG). Cardiovascular magnetic resonance (CMR), Holter and exercise test data were included if performed within ninety days of the TTE and ECG. Patients were excluded from analysis when RV free wall strain was only measurable in one wall. A control group of age and gender matched healthy individuals was used for comparison of RV deformational and synchronicity parameters, none of whom underwent CMR. The study was carried out according to the principles of the Declaration of Helsinki, was approved by the local medical ethics committee and written informed consent was obtained from all subjects.2.2.An extensive TTE protocol was carried out according to international guidelines  with add2.3.The evaluation of regional RV wall function by 2D multi-plane echocardiography has been well documented in our previous publications , 16. In 2.4.Parameters used to measure RV dyssynchrony are detailed in 2.5.CMR images were acquired using a Sigma 1.5-T whole-body scanner  with dedicated phased-array cardiac surface coils. Details of the MR sequence used have been reported previously . Analysi2.6.Clinically relevant arrhythmias were defined as the presence of >100 isolated ventricular ectopic beats or >20 couplets/non-sustained runs documented over a 24 h period . Exercis2.6.1.p-value < 0.05 was considered statistically significant.The distribution of data was assessed using histograms and the Shapiro–Wilk test. Depending on the data distribution, continuous data is presented as mean ± standard deviation (SD) or median [inter-quartile range], whilst categorical data is presented as frequencies and percentages. For comparison of normally distributed continuous variables the independent samples T-test was used and in case of skewed distribution, the Mann–Whitney U-test was applied. For comparison of frequencies the X² test was used. The paired T-test was used for comparison of within-subject continuous parameters which were normally distributed, whilst the Wilcoxon Signed Rank test was used in case of skewed distribution. The Pearson correlation coefficient (r) was used to correlate measures of RV mechanical dispersion with CMR-derived RVEF. Multivariable linear regression analysis was undertaken with selected parameters . If parameters were suspected to be collinear, the multivariable analysis only included the parameter with the highest univariable correlation. Intra-observer agreement was assessed by repeated analysis in a random sample of twenty ToF study subjects performed at least six months after the initial analysis and blinded to the initial results. Assessment of inter-observer agreement was performed by a second experienced observer in the same sample (BB). The agreement between two measurements was determined as the mean of the differences +1.96 SD. Additionally, the intra-class correlation coefficient (ICC) was provided. All statistical analyses were performed using the Statistical Package for Social Sciences version 25 . The statistical tests were two-sided and a 3.3.1.One hundred and one ToF patients who had undergone detailed imaging of the RV with 2D-MPE in our ACHD centre were evaluated for study inclusion. Sixty-nine patients  were ultimately included in the study whereby RV free wall strain was measurable in two or more RV walls, in addition to the RV septum. Thirty-two patients were excluded, predominantly due to poor image quality for strain analysis . Thirty-3.2.n = 67 (97%)]. Of the ToF patients who underwent CMR, RVEF was 46 ± 9%.Demographic, ECG, CMR and TTE data are detailed in 3.3.p < 0.001). In ToF patients, LS was lower in the anterior wall (−18 ± 4%) compared to the lateral [−20 ± 4% (p = 0.001)] and inferior walls [−20 ± 4% (p = 0.008)]. p < 0.001). Furthermore, TTP-LS was longer in the lateral (409 ± 68 ms) and anterior (415 ± 80 ms) walls compared to the inferior wall [394 ± 68 ms ]. This resulted in long intra-RV delays between the basal wall and mid-septal segments . MD-4 and MD-6 values were significantly higher in ToF patients compared to healthy controls , whilst MD-8 values were not significantly different. PSS of at least one RV wall segment was identified in nineteen (28%) ToF patients and one control subject . PS was less prevalent, identified in nine (13%) ToF patients and one control subject (4%). Both PS and PSS were present in five (7%) ToF patients.3.4.p = 0.56). Exercise intolerance from available exercise–ECG or CPET was evident in one patient with greater RV dyssynchrony and in two patients with less RV dyssynchrony (p = 0.77). There was no relationship between percentage of predicted peak oxygen consumption and MD-4 value . Lateral and anterior wall-septum delays were significantly longer in ToF patients with greater RV dyssynchrony , although there were no significant differences in RV wall LS. Furthermore, there was a trend towards a higher incidence of PSS in patients with greater RV dyssynchrony . These findings did not however translate to a significant difference between groups in RVEF as measured by either 3D-TTE  or CMR . In seventeen patients who underwent CMR with gadolinium, late gadolinium enhancement (LGE) was predominantly seen at the inferior RV insertion point. Four patients with an MD-4 value >38 ms also had extensive LGE in the RVOT, compared to none with MD-4 < 38 ms (p = 0.18).A greater degree of RV dyssynchrony in ToF patients was defined as an MD-4 value above 38 ms. According to this criterion, greater RV dyssynchrony was present in 38 (55%) patients . There w3.5.r = −0.38, p = 0.017; MD-8: r = −0.51, p = 0.007). Associations were strengthened in a multiple regression model, predominantly by the inclusion of lateral wall longitudinal strain . Further inclusion of pulmonary regurgitation severity and incidence of pulmonary valve re-intervention only marginally increased the r value . Weaker associations were identified between 3D-TTE-derived RVEF and mechanical dispersion values . No associations were found between RV wall to septum delays and CMR-RVEF . Furthermore, very weak associations were found between indices of RV dyssynchrony and QRS duration or with RV wall LS .MD-4 and MD-8 values displayed moderate negative associations with CMR-derived RVEF , reflecting differences in TTP-LS between basal to mid segments of the septum and lateral wall, compared favourably with that of the study by Yim et al. . It is hSegmental post systolic shortening after pulmonary valve closure was present in one third of ToF patients and was more prevalent in those with greater RV dyssynchrony. Pre-stretch was however less prevalent in our study population than has been described in RV dyssynchrony studies performed in children , 4, 6. T5.2.As the population of ToF patients continues to grow and age worldwide, incidence of right ventricular failure is increasing and treatment options are limited. In cases of significant dysfunction associated with RV dyssynchrony, there is evidence that some patients may benefit from cardiac resynchronisation therapy . In EP s5.3.Limitations of this study include a relatively small sample size, particularly for comparison of RV dyssynchrony parameters with CMR-derived function. Furthermore, 14/31 (45%) patients underwent CMR without gadolinium, which limited the evaluation of corresponding scar burden in the RV myocardium. These findings should be interpreted on this basis and thus further robust research is required. RV deformation was only measured in the longitudinal direction and thus components of radial and circumferential shortening were not considered. Furthermore, LV deformation was not quantified therefore the effect of ventricular interdependence on RV mechanics , 31 was 6.A high proportion of ToF patients will develop RV dysfunction following initial or subsequent reparative surgery and treatment options are limited. 2D-MPE imaging enables a more global quantification of RV deformation, providing insights into regional electromechanical function and mechanisms of dyssynchrony. We found that RV dyssynchrony is characterised by electromechanical delays between the lateral, anterior and septal walls, resulting in increased intra-RV mechanical dispersion. Prospectively, 2D-MPE imaging may have an emerging role evaluating RV mechanical response to electrical resynchronisation therapy.