In recent years, there has been a controversial discussion about whether borderline dysplastic hips should be treated with an arthroscopic procedure or rather with an acetabular reorientation. New research suggests that a classification into stable and unstable hips may be helpful. The aim of the study was to validate (1) the intra- and interobserver reliability of a newly defined radiographic parameter named the Gothic Arch Angle, (2) the association between the GAA and previously existing measurements used to define severity of acetabular dysplasia, and (3) the correlation between radiographic measurements of acetabular dysplasia with MRI findings previously suggestive of hip instability. We defined and validated the GAA in 10 standardized radiographs of asymptomatic hips by two observers and calculated intra- and interobserver coefficients at two individual dates. Subsequently, a consecutive series of 100 patients with dysplastic hips  were evaluated for signs of instability on anteroposterior (a.p.) pelvic radiographs and direct MR arthrography and were divided in two groups: stable and unstable. In these patients the LCEA, the AI, the FEAR index and the GAA were radiographically evaluated. Correlation analyses and a logistic regression analysis was performed to identify the predictive value of instability for each radiographic parameter. Cutoff probabilities analysis was performed using standard receiver operating characteristic (ROC) curves to rate the predictive efficiency value of the GAA. The GAA showed excellent inter- and intraobserver reliability. A correlation was found between GAA and FEAR index. A logistic regression analysis showed that LCEA, FEAR index and GAA are distinct predictors of instability in hip dysplasia. The GAA showed the largest area under the curve (AUC 0.96), indicating it to be the best predictor of instability with an optimal cutoff value of 90° . The GAA is a new available indicator for instability and is thus suggested to be used as a future radiographic parameter for the stability of dysplastic hips. Further studies are needed to understand how this parameter might additionally predict clinical outcome in the treatment of hip dysplasia.Level of evidence: Level III, diagnostic study. While there is general consensus that hip dysplasia with a lateral center–edge angle (LCEA) < 18° should be treated with a reorientation of acetabular coverage through acetabular reorientation8, there is still a controversial discussion about whether milder forms of dysplasia (borderline hip) with an LCEA between 18° and 25° should be treated with arthroscopy or acetabular reorientation14. A few authors have suggested a distinction between stable and unstable hips for this group of patients in order to make the right therapeutic decision15. Wyatt et al. therefore introduced the Femoro-Epiphyseal Acetabular Roof (FEAR) index in 2017 to distinguish between stable and unstable dysplastic hips16. The theory underlying the FEAR index is that epiphyseal growth of the proximal femur is affected by the contact forces during development. According to Pauwels and Maquet, the epiphyseal plate orientates perpendicular to the joint reaction force in accordance with the Hueter–Volkman principle17. This leads to the fact that the angle of the closed epiphyseal plate indicates the balance of forces across the proximal femoral physis18. Wyatt et al. theorized that the angle between the epiphyseal scar of the femoral head growth plate and acetabular index (AI) would reveal the resultant force vector, which could be used to predict the stability of the borderline hip15. However, the originally described threshold of 5° demonstrated just a 79% probability of correctly assigning hips as stable and unstable15. Thus, it must be assumed that unstable hips may not be adequately identified by the FEAR index.Developmental dysplasia of the hip (DDH) is defined as osseous deficiency of the acetabulum with abnormal coverage of the femoral head which may lead to an overload and joint instability with subsequent damage of the acetabular cartilage or labrum20. The gothic arch can be identified as a triangular structure on anteroposterior (ap) radiographs of the pelvis. The base of the triangle is formed by the sourcil while the sides are shaped by condensed arch-like structured trabecular bone. The intersection of these two arches form the tip of the gothic arch. Biomechanically the tip off the gothic arch lies on the line of application of the compressive force, which is perpendicular to the weight-bearing surface (WBS) and passes through the center of rotation. Bombelli hypothesized that hips with an altered gothic arch are mechanically jeopardized. In these hips the tip would therefore point either medially or laterally. In dysplastic hips the tip moves medially and thus the WBS shifts craniolaterally steeper. This in turn leads to a force directed craniolaterally, which results in increased tension on the hip capsule and consequently to craniolateral displacement of the femoral head. Consequently, we assume that the concept of the gothic arch and the FEAR Index should be combined in order to achieve a higher predictive capacity with regard to hip stability. We have therefore revisited Bombelli's concept, additionally amended it by the analysis of the femoral epiphyseal growth plate and defined a new measurement parameter for instability of the hip, called the Gothic Arch Angle (GAA).To integrate a broader range of biomechanical hip joint characteristics, Renato Bombelli, an Italian orthopaedic surgeon, has described the so-called gothic arch of the hip in 1976 and introduced it as the key to correct understanding of the biomechanical propertiesThe aims of this study were (1) to validate the intra- and interobserver reliability of a newly defined radiographic parameter named the Gothic Arch Angle, (2) to validate the association between the GAA and previously existing measurements used to define severity of acetabular dysplasia, and (3) to validate the correlation between radiographic measurements of acetabular dysplasia with MRI findings previously suggestive of hip instability.15 for cohort stratification. Based on these results one patient group matching stable hip criteria (n = 61) and one matching unstable hip criteria (n = 39) were formed. Both groups were compared regarding their clinical case and secondary patient characteristics , a missing dMRA (n = 75), osteoarthritis  or previous hip surgery (n = 26). In brief, a total of 100 patients out of 535 patients could be identified and were included in the analysis  we reviewed our hospital registry to identify all patients who presented in our practice for hip joint preserving surgery between January 2019 and January 2020. From this registry, patients who showed a lateral center edge angle (LCEA) of less than 25° without signs of osteoarthritis (Toennis grade ≤ 1) on the standing a.p. pelvic radiograph and for which direct MR arthrography (dMRA) was available were selected. These patients were analyzed according to the instability criteria described by Wyatt et al.22. An angle between two lines was measured 24, and the FEAR index15 , very good (0.71–0.80), good (0.61–0.70), fair (0.41–0.60), and poor (0.21–0.40). A stepwise forward multivariate logistic regression analysis was performed to identify the predictive value of an instability for each radiographic measurement. Cutoff probabilities and sensitivity/specificity analysis were performed using standard receiver operating characteristic (ROC) curves to determine optimal cutoff values. The threshold for statistical significance was set to 0.05.Continuous variables are presented as means ± SD with ranges, and categorical variables are presented as frequencies and percentages. Data were analyzed by use of R Two observers  independently measured the GAA. Each image was measured at two independent time points (one week apart). The GAA showed excellent inter- and intraobserver agreement. In addition, the reliability of the GAA was compared with the LCEA, the AI, and the FEAR index Table . The meaAfter validation of the GAA, a correlation analysis between LCEA, AI, FEAR index and GAA was performed Table . An exceAll radiographic parameters were significantly different between the stable and unstable hips, except for AI  , FEAR index (p < 0.0001) and GAA (p < 0.0001) were significantly different between the unstable and stable patient group, while the AI p = 0.59) did not indicate significant differences  with respect to discrimination into stable or unstable. Based on the results of our study, it may be feasible for clinicians to use thee GAA as an additional radiologic assessment to identify patients with possible abnormal mechanics leading to hip instability.However, we believe, similar to Wyatt et al.36. Herickhoff et al. demonstrated in patients with unilateral DDH that the tip of the gothic arch pointed significantly more medially on the dysplastic side than on the healthy side 36. We are convinced that the presented concept allows an even more reliable prediction of instability when both aspects (FEAR Index and Gothic Arch) are combined.In our study, the AI was not found to predict hip instability. This may be due to the fact that only a few hips with increased AI are underrepresented in the present analysis. However, the AI is included in the determination of the FEAR index, which was found to be a significant predictor of instability. It can therefore be assumed that the orientation and position of the epiphyseal scar is the more important factor in the FEAR index. Bombelli proposed the theory that a craniomedially aligned tip of the gothic arch must be considered an indication of hip dysplasia, which has been confirmed in the past38. We therefore recommend a standardized approach, which includes patient history and examination as well as diagnostics consisting of radiography and MRI. The GAA can provide significant information regarding hip stability. However, the impact of the GAA on clinical outcomes needs to be demonstrated in further studies.The values for the FEAR index and GAA were significantly higher in the unstable group than in the stable group. Compared to the FEAR index, however, the GAA demonstrated the highest AUC in the ROC analysis and therefore appears to be a better predictor of instability. However, the GAA should not be used as the solely tool, but rather as a further piece in the puzzle on the way to a reliable diagnosis and identification of unstable hips. In recent years, a relationship between femoral torsion and dysplasia has been observed, thus the femoral torsion dimension should be considered in an appropriate assessmentAll patients had symptomatic hip pathologies, hence the study lacks an asymptomatic control group. There is no correlation with clinical results that are based on a therapy decision derived from the use of GAA. Future studies investigating the influence of the GAA on clinical results are therefore mandatory. A further limitation, although it did not apply to any of the radiographs analyzed, is the possibility that the epiphyseal scar or the tip of the gothic arch cannot be identified due to radiograph quality. In such cases it may theoretically not be possible to determine the GAA. However, this limitation also applies to the FEAR index. Furthermore, there is no data on whether the epiphyseal scar changes or remains consistent over time or whether the femoral version has an influence on the assessment of the GAA. Finally, the GAA is evaluated by means of static radiographic images, so that no dynamic assessment and analysis is possible. Prospective studies may be conducted to examine the dynamic motion and the influence on stability.We defined a new radiological parameter to assess the stability of dysplastic hips. The GAA demonstrated excellent intra- and interobserver reliabilities. The optimal cutoff value for the GAA was 90° to differentiate between stable and unstable hips. Further studies are needed to understand how this parameter might additionally predict clinical outcome in the treatment of symptomatic hip dysplasia.


In children with myocardial ischemia, myocardial fibrosis was observed with greater frequency. Myocardial perfusion defects may reflect an ischemic process which (1) affects the clinical manifestations and (2) is an important predictor of adverse clinical events and risk of death in children with HCM. Myocardial ischemia in HCM patients frequently correlates with myocardial fibrosis.Myocardial ischemia caused by microvascular dysfunction is an important pathophysiologic component of hypertrophic cardiomyopathy (HCM), promoting myocardial fibrosis, adverse left ventricular remodeling, and impacting on clinical course and outcome in HCM patients. The aim of study was to assess the prevalence and clinical significance of myocardial ischemia in children with HCM using 99mTc-MIBI single-photon emission computed tomography (SPECT). Ninety-one children with HCM, median age 13.6 years, underwent SPECT evaluation from 2006 to 2017. Imaging was performed at rest and after maximal exercise. Myocardial perfusion defects were identified in 70 children , median age 13.8 years. Fixed perfusion defects were evident in 22 of them, while reversible at rest in 48. In 21 children , median age 11 years, myocardial perfusion defects were not detected. Patient demographics, echocardiography, resting electrocardiogram (ECG), 24-h Holter ECG, myocardial fibrosis in cardiovascular magnetic resonance imaging, and cardiovascular events were analyzed and compared between the groups. During follow-up at a median of 8.3 years in children with myocardial ischemia, clinical endpoints occurred more often (47 vs. 5;  Hypertrophic cardiomyopathy (HCM) is the second most common cardiomyopathy in children, with an estimated annual incidence of 0.24–0.47 per 100,000 , 4. The From January 2006 to November 2017 we prospectively enrolled pediatric patients with diagnosed HCM hospitalized in the cardiology department. All our HCM patients underwent 99mTc-MIBI SPECT evaluation and then were followed prospectively for a median of 8.3 years to assess the occurrence of cardiovascular events. Criteria for inclusion in the study were age < 18 years at time of diagnosis and echocardiographic evidence of LV hypertrophy defined as a maximal left ventricular wall thickness greater than two standard deviations above the body surface area-corrected mean (z-score ≥ 2) and not explained by abnormal loading conditions , 16. ThePatients demographics, clinical symptoms, as well as the results of echocardiography, resting and ambulatory 12 lead electrocardiograms (ECG), CMR, and 99mTc-MIBI SPECT at rest and after exercise test were collected. Cardiac examinations were repeatedly performed during the follow-up period.In all children, routinely planned cardiac examinations  and clinical evaluation every 6 months were performed. In the case of impairment of the general condition, onset of clinical symptoms and disease progression, cardiac tests, including repeated CMR, were performed more frequently, according to individual indications.For analysis, the most recent or latest results before the endpoint were chosen. The period from diagnosis of HCM to the most recent study was median 10.8 (6.5–13.2) years. The median period between SPECT and recent results was 8.3 (4.3–10.8) years.Sudden cardiac death, unexplained syncope and non-sustained ventricular tachycardia (NSVT) were defined as recommended in the literature . EchocarCardiovascular magnetic resonance imaging (CMR) was performed using a 1.5-T scanner . Cine images were acquired by the breath-hold, electrocardiographic-gated, segmented k-space steady-state free-precession technique using 25 phases per cardiac cycle. LGE images were obtained in the long-axis and short-axis imaging planes using a breath-hold-segmented inversion recovery sequence implemented 10–15 min after intravenous administration of 0.1 mmol/kg of gadobutrol ; gadodiamide  was used instead gadobutrol if the patient was under 2 years of age. The presence of left ventricular LGE and myocardial fibrosis was determined using visual assessment by two independent observers and if positive, quantified. Quantification was performed both as a signal intensity threshold of > 6 SD above remote myocardium. The extent of LGE is presented in grams and as the percentage of total LV mass .The 99mTc-MIBI SPECT was performed for evaluation of MP and prevalence of perfusion defects indicative of myocardial ischemia. The tracer used was sestamibi (MIBI) labeled with technetium 99 m. The 99mTc‑MIBI chelate was administered intravenously at a dose of 111 to 740 MBq per kilogram of body weight . MP scanPatient events were recorded by communication with children‘s parents. Medical records were reviewed after attendance in outpatient clinics or hospital stay. No patient was lost to follow-up. Clinical endpoints included these cardiovascular events: SCD, HF-related death, resuscitated cardiac arrest (rCA), appropriate ICD discharges (ICDdx), heart transplant (HTx), NSVT, syncope, and progression of heart failure from New York Heart Association (NYHA) class I or II to class III. Moreover, arrhythmic endpoints was predefined and included: SCD, rCA, adequate ICDdx, NSVT.All children were divided into group I (gI) with and group II without myocardial ischemia in SPECT (gII). The presence and extent of the perfusion defects were analyzed by two independent experts and relative myocardial perfusion was assessed. In a descriptive way, the presence of perfusion defects was determined in the following projections: short axis , vertical long axis  and horizontal long axis . The presence of perfusion defects indicated a significantly lower concentration of 99mTc-MIBI in the myocardium. In the case of fixed myocardial perfusion defects SPECT images showed significantly lower concentration of 99mTc‑MIBI in stress and in rest images indicating severe myocardial ischemia. In the case of reversible perfusion defects, SPECT scans showed significant radiotracer accumulation improvement in rest images.The demographic, clinical, echocardiographic, CMR parameters, and occurrence of endpoints were analyzed and compared between the two groups.U Mann–Whitney test. Binary variables were compared using Fisher test or chi-square test. The Kaplan–Meier survival curves were constructed to compare the groups with and without myocardial ischemia and with fixed or reversible perfusion defects in terms of reaching endpoints. Values of p < 0.05 were considered statistically significant.Statistical analysis was performed using Statistica software. Continuous variables are described as median with interquartile range (25th to 75th centile). Nominal variables are presented as a numerical value and the percentage of the study group. Continuous variables were compared by A total of 91 patients with HCM, median age 13.6 (10.3–15.8) years, 64% male, in NYHA class I or II, underwent SPECT evaluation from January 2006 to November 2017. Patients were followed prospectively for 8.3 (4.3–10.8) years. MP defects were identified in 70 of the 91 children , median age 13.8 years (10.7–15.9). Fixed perfusion defects were evident in 22 (31.4%) patients . A comparable number of children in both groups experienced LVOTO. The median LA diameter z-score did not differ significantly between the two groups studied (3.4 [gI] and 2.6 [gII]). Fibrosis in CMR was found at a significantly greater frequency in children with perfusion defects compared to children without myocardial ischemia , , while the gII median was 6.6 (p = 0.02) and significantly more patients reached a clinical endpoint .During follow-up, clinical endpoints occurred significantly more often in children with recognized perfusion defects and myocardial ischemia , rCA (n = 1), ICDdx (n = 6), NSVT (n = 15), syncope (n = 10), progression of heart failure from NYHA class I or II to class III (n = 9), HF-related death (n = 1), and HTx (n = 2). In children with myocardial ischemia, significantly more frequent myocardial fibrosis was observed . The data are presented in Table In children with perfusion defects, the following cardiovascular events occurred: SCD ( rCA n = , ICDdx (SVT n = 1, syncopeMyocardial ischemia can occur in patients with HCM in the absence of coronary artery disease  and is aThe LGE CMR sequences identify the persistence of gadolinium-based contrast agents within areas of fibrosis due to their accumulation and delayed washout from an expanded extracellular space . A growiIn agreement with other investigations , 39, 40,During follow-up lasting longer than eight years, 40% of patients with myocardial ischemia had cardiovascular events. Moreover, an association was found between the presence of MP abnormalities and the prevalence of cardiovascular endpoints. It should also be emphasized that the number of endpoints was significantly higher in children with MP defects, which confirms current literature reporting that, in patients with HCM, the degree of microvascular dysfunction is a strong, independent predictor of clinical deterioration and death .The results of our study showed that myocardial ischemia was strongly associated with an unfavorable outcome, which was confirmed by the analysis of the survival curves. This finding is consistent with the results of similar studies by others , 41. It As in the studies of other authors, the maximum LV wall thickness correlated with the presence of perfusion disorders . In chilIn children with hypertrophic cardiomyopathy and diagnosed myocardial perfusion defects in SPECT, we consider extending the cardiac tests to include computed tomography angiography to assess coronary arteries, modify pharmacological treatment by increasing the dose of beta blocker and recommend low or moderate intensity physical activity. We advise against competitive sports in these children. We determine the indications for ICD implantation on an individual basis.In conclusion, we demonstrated that MP defects may reflect an ischemic process which affects clinical manifestations and is an important predictor of adverse clinical events and risk of death in children with HCM. Today's routine diagnostic protocols for HCM do not include testing for myocardial ischemia. It is hoped this and other studies emphasize the value of including this type testing as a key element for developing future risk strategies.


Cardiorenal syndrome (CRS) is defined as a disorder resulting from the abnormal interaction between the heart and kidney, in which acute or chronic dysfunction of one organ may lead to acute and/or chronic dysfunction of the other. The functional interplay between the heart and kidney is characterized by a complex bidirectional symbiotic interaction, regulated by a wide array of both genetic and environmental mechanisms. There are at least five known subtypes of CRS, based on the severity of clinical features and the degree of heart/renal failure. The fourth subtype ) is characterized by a primary chronic kidney disease (CKD), which in turn leads to a decreased cardiac function. Impairment of renal function is among the most important pathophysiological factors contributing to heart failure (HF) in the pediatric age group, and cardiovascular complications could be one of the most important causes of mortality in pediatric patients with advanced CKD. In this context, a loss of glomerular filtration rate directly correlates with both the progression of cardiovascular complications in CRS and the risk of HF. This review describes the interaction pathways between the heart and kidney and the recently identified pathophysiological mechanisms underlying pediatric CRS, with a special focus on CRS4, which encompasses both primary CKD and cardiovascular disease (CVD). The heart and kidneys interact through several intricate cellular and subcellular processes and molecular pathways . These iIn recent years, next-generation sequencing technologies, including exome and mRNA sequencing studies, have shed new light on the complex molecular mechanisms underlying CRS ,5. This In recent years, studies based on next-generation sequencing and omics-related sciences have revealed an expanding complexity underlying rare pediatric disorders associated with chronic organ failure. The molecular dissection of these conditions and the underlying genetic and/or immune-mediated possible causes may explain the frequent multisystemic, metabolic, and neurological abnormalities associated with these rare pediatric disorders ,8,9,10. In 2004, the Working Group of the National Heart, Lung, and Blood Institute proposed the first definition of CRS. CRS was described as a consequence of abnormal functional connections between the kidneys and other circulatory compartments, leading to increased circulating blood volume and exacerbating the symptoms of heart failure (HF) and CVD progression. This initial definition was extremely cardiocentric, thus not explaining the real complexity underlying the interplay between the two organ systems. In 2008, the Acute Dialysis Quality Group proposed a new classification in a Consensus Conference. This classification divided CRS into two key sets, cardiorenal and renocardiac CRS, according to the primum movens of disease . Both cardiorenal and renocardiac CRS were then subsequently organized into five subtypes based on disease acuity and according to the beginning and duration of the organ dysfunction . The newThe lack of univocal terminology in the research literature and the difficulties to reach a broadly accepted definition for this condition represent an unsolved issue, which complicates epidemiological studies of CRS. The use of uniform terminology is needed to: (i) better compare data across disease subtypes and different patients; (ii) understand the epidemiology underlying CRS and investigate demographic and age- and gender-related factors and their contribution to the disease initiation and progression; (iii) dissect the underlying pathomechanisms of kidney dysfunction and HF and to fully characterize the specific subtype of heart/kidney disorder according to the individual clinical scenario . Based oThe pathophysiological interactions and feedback mechanisms between the cardiovascular and renal systems are complex and bidirectional. There are three major mechanisms beyond the development and the evolution of cardiorenal and renocardiac dysfunction: hemodynamic alterations, neurohormonal mechanisms, and other factors such as biochemical perturbations and structural changes . These iThe conventional hypothesis for CRS focuses on the hemodynamic adaptations of the kidney to heart failure as an initial insult. CRS results from the heart’s inability to generate forward flow leading to hypoperfusion of the kidneys (low flow) . Renal hNeurohormonal mechanisms play a significant role in CRS pathophysiology. The regulation of the heart and kidneys involves a complex interaction between neurohormones, the sympathetic nervous system (SNS), and filling status. The neurohormonal pathway is linked to RAAS and SNS activation, which, together with hemodynamic mechanisms, lead to systemic vasoconstriction, salt and water retention, and preservation of GFR. The concomitant activity of SNS can exacerbate RAAS-mediated fluid overload and increase systemic vasoconstriction, which, in patients with cardiac dysfunction, can lead to a congestive state with peripheral edema. RAAS axis activation, in these patients, leads also, indirectly, to angiotensin II activation and the formation of oxygen reactive species (ROS) ,28. CompRare pediatric disorders associated with chronic organ failure may be involved in several molecular pathways, including the regulation of transcription, translation, and post-translational processes at the subcellular level. These disorders include a variety of monogenic and polygenic/genetically complex and/or environmental conditions with expanding clinical differential diagnosis, molecular heterogeneity, and associated (underlying) disease mechanisms ,30,31,32Several other molecular pathways have been implicated in CRS, including chronic inflammation, comorbidities ,34 such CRS includes all the disorders involved in the bidirectional interactions between the heart and kidneys, in which the dysfunction of one organ can significantly impair the function of the other. CRS is divided into two main categories based on the initial insult and into five subcategories according to the direction of the effect and the acuity of the initiating insult (acute or chronic) ,5 Table CRS type 1  is characterized by the fast deterioration of cardiac function, which leads to acute renal injury (AKI). Type 1 CRS is relatively prevalent. It is usually present in the setting of acute decompensated heart failure (ADHF), often after an ischemic  or nonischemic heart disease , which may be divided into four subtypes: hypertensive pulmonary edema with preserved left ventricular systolic function, acutely decompensated chronic HF, cardiogenic shock, and predominant right ventricular failure. Pathophysiology. Hemodynamic mechanisms. In the presence of ADHF, hemodynamic processes play a prominent role in CRS type 1, resulting in decreased renal artery flow and, as a result, a decrease in GFR. Different hemodynamic profiles have been proposed: in “cold” pattern patients, the predominant hemodynamic change is a drop in effective circulating fluid volume, whereas in “wet” pattern patients, there is a significant increase in central venous pressure. Nonhemodynamic mechanisms. CRS type 1 has been linked to SNS and RAAS activation, chronic inflammation, and an imbalance in the percentage of reactive oxygen species (ROS)/nitric oxide (NO) generation. The beginning of AKI has an impact on the prognosis of HF in CRS type 1, but early detection of AKI is difficult [ifficult . The preChronic anomalies in heart function  contribute to progressive kidney failure in CRS type 2 .Pathophysiology. Hemodynamic mechanism. The most important pathophysiological processes of CRS type 2 are renal hypoperfusion and persistent elevations in renal venous pressure. Nonhemodynamic mechanisms: Maladaptive activation of the RAAS axis and the SNS, as well as a chronic inflammatory state, are important pathophysiological causes of renal disease progression. Structure injury, such as glomerulosclerosis and tubulointerstitial fibrosis, is precipitated by intrarenal oxidative stress and proinflammatory signaling. Chronic HF and renal illness can coexist for a long time, making it difficult to determine which of the two disease states is predominant (or secondary). Even a small drop in glomerular filtration rate (GFR) results in a markedly poor prognosis, increasing the mortality rate in these individuals, and it can be used as a marker of cardiovascular disease severity [severity . Diabeteseverity . When AKI leads to the development of acute HF, CRS type 3 (acute renocardiac syndrome) ensues. It is less prevalent than type 1 CRS and has not been thoroughly researched in the literature. AKI can impact the heart directly or indirectly, and through numerous distinct pathways, it can cause an abrupt cardiac event .Pathophysiology. Hemodynamic mechanisms. Renal dysfunction can cause severe pathophysiological derangement, which can lead to heart damage. Oliguria can cause sodium and water retention, resulting in fluid overload and the development of hypertension, pulmonary edema, and myocardial injury. Nonhemodynamic mechanisms. Electrolyte abnormalities that cause arrhythmias and cardiac arrest, metabolic acidosis that causes vasoconstriction, coronary artery disease, and left ventricular dysfunction can be also associated with CRS type 3. Renal ischemia can cause myocardial inflammation and apoptosis on its own [ its own . FurtherCRS type 5 (secondary CRS) is characterized by the presence of cardiac and renal dysfunction in the same patient, and it can occur in a variety of clinical settings as a result of acute or chronic systemic illnesses . Type 5 CRS has a scarcity of information in the literature. It is obvious that some systemic diseases affect both organs at the same time, and that the malfunction of one might have an impact on the other. The most common cause of CRS type 5 is sepsis, which causes cell ultrastructural changes and organ failure. Sepsis can cause AKI and severe cardiac depression at the same time. Many mediators and pathways have been implicated in the pathogenesis of sepsis-induced cardiac depression; however, the exact etiopathogenetic mechanism remains unknown.Pathophysiology. Hemodynamic mechanisms. Pathophysiological abnormalities in sepsis-related CRS type 5 are influenced by the sepsis’s systemic effects and direct cross-talk between the injured heart and kidney. Despite good systemic hemodynamics, microcirculation is frequently involved in the early stages of sepsis. With dilatation and decreased ejection fraction, both the left and right ventricles can be affected in septic cardiomyopathy. There are obvious changes in intraparenchymal blood flow in sepsis-associated AKI, independent of systemic hemodynamic abnormalities due to the septic process. Nonhemodynamic mechanisms. The pathophysiology of septic cardiomyopathy does not appear to include myocardial blood flow or oxygen consumption. The role of proinflammatory mediators and complement factors in the development of cardiac involvement during sepsis has been suggested. Sepsis can influence the autonomic nervous system (ANS), the RAAS, and the hypothalamus–pituitary–adrenal axis (HPA) independently, affecting cardiac and/or renal function in numerous, separate processes. Several physiological and molecular alterations occur in both tissues with combined heart and kidney dysfunction, as in sepsis. Activation and elevation of cytokines (TNF-a and IL-6), as well as leukocytes  in the heart and kidney during sepsis, has been well documented.CRS type 4 (chronic renocardiac syndrome) is defined by cardiovascular involvement  in patients with primary CKD  . Figure CKD is a major public health problem. It accounts for at least 11% of the U.S. adult population . The Natn = 656) revealed that 38% have anemia, 63% have serum phosphorus >5.5 mg/dL, and 55% have a calcium–phosphorus product >55 mg2/dL2 [Children with CKD have a high prevalence of conventional cardiovascular risk factors  . Modern  mg2/dL2 . DespitePathophysiology. Hemodynamic mechanisms. Ischemic heart disease is accelerated by CKD, which also contributes to pressure and volume overload, resulting in left ventricular hypertrophy (LVH). Congestive HF is worsened by volume overload central to CKD, with underlying anemia of chronic illness and the occurrence of hemodialysis arteriovenous fistulas being typical contributing factors. Nonhemodynamic mechanisms. Traditional risk factors of CVD, such as hemodynamic derangements, hypertension, and RAAS and SNS activation, do not completely explain the high rates of HF in CKD patients [patients . As a coAccording to recent experimental and clinical studies, CKD leads to an accumulation of uremic toxins . Huang et al. recently demonstrated in an experimental study that a uremic molecule, known as high phosphate (HP), contributes to CKD-associated HF . HP is cIndeed, HP upregulates IRF1 through acetylation of the H3K9 histone, which mediates HP-induced PGC1α downregulation by binding directly to its promoter region. PGC1α is downregulated in the hearts of CKD mice, implying that it mediates myocardial energy metabolism dysfunction and leads to CKD-related HP. On the other hand, genetic knockdown of IRF1or PGC1α restoration significantly improves HP-induced changes. Huang et al. demonstrated that myocardial energy metabolism dysfunction induced by the IRF1-PGC1α axisplays a crucial role in the pathogenesis of type 4 CRS and suggested that hyperphosphatemia management or targeted intervention on HP-mediated IRF1 elevation and PGC1α downregulation could represent a future treatment able to reduce cardiovascular risk in CKD patients .The activation of the local renin–angiotensin system has recently been discovered to have a vital role in the course of illnesses. Both the heart and kidney’s local renin–angiotensin systems are linked to cardiovascular disease and kidney disease, respectively. Angiotensin II production in the tissues is just as significant as circulating angiotensin II. These local RAAS have both autocrine (cell to cell) and paracrine (cell to cell) actions. As a result, the RAAS is more complex than a simple blood volume and blood pressure control mechanism. Target-organ damage is mediated by AT1 activation at the local level, which includes remodeling, endothelial dysfunction, and collagen deposition, resulting in fibrosis. Furthermore, angiotensin II is synthesized locally, and the amount of angiotensin II produced locally increases in direct proportion to the severity of HF. In HF patients, angiotensin II synthesis increases sodium reabsorption, causes systemic and renal vasoconstriction, cardiac hypertrophy, apoptosis, and changes in the interstitium.Evidence of early cardiovascular abnormalities can be found even in patients with mild kidney dysfunction. Common findings are abnormalities of the left ventricular (LV)  and LV dysfunction) regions, large artery structural alterations , and coronary and cardiac valve calcifications . These fThe correct treatment of CRS type 4 necessitates a comprehensive and combined approach, considering the pathological mechanisms. Currently, the treatment of type 4 CRS is mainly based on the correction of the traditional and nontraditional cardiovascular risk factors and on the prevention of CKD progression. Once diagnosed, heart disease should be treated according to current HF treatment guidelines, such as those published by the European Society of Cardiology.In patients with mild to moderate renal impairment, angiotensin-converting enzyme inhibitors (ACEIs) have been shown to be effective in improving the cardiovascular survival rate of patients with myocardial disease ,59.Moreover, ACEIs help dialysis patients avoid arrhythmic events thanks to their action on neurohormonal stimulation, ventricular remodeling, and hemodynamics. In addition, Pun et al.  demonstrLittle is known in the literature on the use of ARBs in dialysis patients to reduce cardiac mortality. Candesartan was tested in a small randomized study in dialysis patients. Candesartan was shown to reduce cardiovascular events and fatal arrhythmias in dialysis patients in a small, randomized trial , though It has been demonstrated that after myocardial infarction or heart failure, BBs reduce the risk of cardiovascular death. BBs minimize cardiac risk in CAD patients with or without CKD, as shown in the Bezafibrate Infarction Prevention study . A totalIn conclusion, there is no definitive clinical guideline for the best mode of coronary intervention in CRS type 4 patients at this time.The theory of “cardioprotective dialysis” states that advances in dialysis can enhance hemodynamic stability, minimize oxidative and inflammatory stress, and result in the more effective removal of low and middle toxins. New technologies include the use of new biomaterials that can help minimize inflammatory reactions and increase membrane performance, as well as machines with well-integrated safety, therapy effectiveness, performance, and monitoring functions.Patient-monitoring improvements during hemodialysis (HD) can increase safety and tolerability, which is critical. The ultrafiltration rate and conductivity have been regulated to modify blood volume and plasma refilling utilizing biofeedback devices. In contrast to conventional HD, Peritoneal dialysis (PD) may be able to escape the hemodynamic instability that comes with normal and rapid ultrafiltration.However, some evidence indicates that although PD has a lower mortality rate than HD in the first 1–2 years, it has a higher mortality rate after that. On the other hand, other registry data contradict this conclusion ,68. A Cochrane meta-analysis to assess the effects of different hemodialysis membrane materials in patients with ESRD showed that biocompatible membranes were associated with a reduction in the beta-2-microglobulin (β2M) level, an increase in albumin concentration, and improvement in Kt/V, but mortality was not affected .House et al.  found noSeveral studies have linked “hemodiafiltration” or “hemofiltration” care to improve blood pressure regulation, improve β2M and phosphate clearance, decrease intradialytic hypotension or arrhythmia, reduce inflammation and oxidative stress, and a lower hospitalization rate ,73.Chronic kidney disease–mineral and bone disorder (CKD–MBD) is a dialysis consequence that is especially noteworthy in children, as it can interfere with growth and cardiovascular health. Furthermore, all-cause mortality rates are greater for children on dialysis: at least 30 times higher than the overall pediatric population, and much higher than the transplant population.CRS patients have a higher risk of death and morbidity than those with each disease entity alone. The heart and kidneys interact bidirectionally and interdependently through several mechanisms. A better understanding of the interactions between these organs is important for his practical clinical implications. Patients with CKD have the highest cardiovascular risk of any pediatric demographic, and dialysis is a primary factor linked to poor outcomes in children with ESRD. These data suggest that long-term dialysis should be avoided in these patients, with preemptive transplantation as the best management strategy when feasible. When compared to long-term dialysis, successful transplantation can considerably alleviate uremia-related risk factors and, most importantly, enhance life expectancy by 20–30 years. More research is needed to better understand the pathogenetic process and best therapies in this pediatric population.


A 0D model of the cardiovascular system, including a wide range of LVAD settings and incorporating the whole spectrum of heart failure, was used to generate data for the training procedure of the DNN. The DNN predicted Emax,lv with a mean relative error of 10.1%, and all other parameters of LV function with a mean relative error of <13%. The framework was then able to retrieve a number of LV physiological variables  with a mean relative error of <5%. Our method provides an innovative tool to assess LV hemodynamics under device assistance, which could be helpful for a better understanding of LV-LVAD interactions, and for therapeutic optimization.Characterizing left ventricle (LV) systolic function in the presence of an LV assist device (LVAD) is extremely challenging. We developed a framework comprising a deep neural network (DNN) and a 0D model of the cardiovascular system to predict parameters of LV systolic function. DNN input data were systemic and pulmonary arterial pressure signals, and rotation speeds of the device. Output data were parameters of LV systolic function, including end-systolic maximal elastance (E Left Ventricular Assist Device (LVAD), a subset of mechanical circulatory support, assists the failing left ventricle (LV) by pumping blood from the LV into the ascending aorta. In recent years, LVAD has become a crucial therapeutic solution for patients with end-stage heart failure . CurrentThe assisted LV may retain a certain amount of residual native function. Therefore, complex and reciprocal interactions occur between the heart and the LVAD. The systemic blood flow, i.e., total cardiac output, represents the sum of the flows generated by the LVAD and the native LV, dependent on respective loading conditions (preload and afterload) and inherent function. The latter corresponds to the rotational speed for the device  and residual systolic function (contractility or inotropy) of the native LV . UnderstEmax,lv), which is the maximal slope of the end-systolic pressure volume relationship of the LV  to predict Emax,lv and other variables relevant to LV systolic function. The presence of the LVAD strongly affects the arterial pressure waveforms, it is therefore not possible to employ the same DNN considered in Bonnemain et al. , to predict isted LV . In the n et al.  to recovn et al.  can be eEmax,lv and other parameters of LV systolic function) and (ii) various physiological LV quantities , by employing a lumped parameter model of the cardiovascular system (see description below). Our framework makes use of a deep neural network (DNN) which infers, given systemic and pulmonary arterial pressure measurements and the RPM of the LVAD as inputs, an estimation of LV systolic parameters . The DNN was trained with a lumped model of the cardiovascular system  and a compliance (Ci) to account for viscous and elastic effects, respectively, and is further characterized by its unstressed volumes. Inertance (Li) is considered only in large systemic and pulmonary arteries, i.e., blood acceleration is neglected in the rest of the vascular tree. Mass conservation (1), momentum conservation (2), and pressure-flow relationship (3) equations are applied to each compartment i, assuming that blood is an incompressible, isotropic, and Newtonian fluid:The model comprises eight vascular compartments. The pulmonary circulation is represented by a serial arrangement of arterial, peripheral, and venous circulations. The systemic circulation begins with arteries and further subdivides into splanchnic and extrasplanchnic circulations, each having a peripheral and venous compartment in series. Each compartment Vi is the volume of ith compartment, Vi,0 the unstressed volume of ith compartment , Qi,in and Qi,out the inlet and outlet flow rates of ith compartment, Pi,in and Pi,out the inlet and outlet pressures of ith compartment.where The heart model comprises ventricles and atria as a four-compartment system, each of which is modeled by a serial arrangement of a compliance, a resistance, and an ideal valve, i.e., blood flows without viscous loss from inlet to outlet compartments when pressure of the former exceeds pressure of the latter. Atria are passive elements, whereas contractility of ventricles is characterized by a time-varying elastance. Autoregulation occurs through the carotid baroreflex. The vagal afferent activity is modulated by the absolute systemic arterial pressure and its rate of change. Sympathetic and vagal efferent activities then modulate systemic peripheral resistances, systemic venous compliances, heart period, and ventricles resistances and compliances.Emax,lv and Emax,lv,0, respectively, the maximum baroreceptor gain GEmax,lv, and kE,lv, which describes the end-diastolic pressure-volume relationship for the left ventricle. Ranges for each parameters are shown in Different stages of left ventricle systolic failure severity were represented by modifying values of the following parameters: end-systolic elastance of the left ventricle with and without autoregulation, c, and a pump speed modulation feature, namely the artificial pulse, which periodically modifies the pump speed from its preset value ωc. More specifically, every 2 s the pump speed decreases by 2,000 RPM during 0.15 s and then increases by 4,000 RPM during the following 0.2 s. This aims at promoting pump washout  and which outputs a scalar a = g(w0 + w1x1 + w2x2 + … + wdxd), where the vector g is the activation function, which is typically non-linear. Here, we focus on a simple and widely-used class of DNNs, namely multi-layer perceptrons (MLPs). A MLP is made of layers composed of artificial neurons in which each neuron receives input from all neurons in the previous layer; for this reason, this structure is commonly referred to as fully-connected. In matrix form, the output of the lth layer readsA DNN is a parametric machine learning algorithm used to capture complex nonlinear relationships between inputs and outputs, which needs to be trained on a large number data points. In contrast to other parametric models, DNNs do not require strong assumptions about the nature of the data distribution. The fundamental building block of a DNN is an artificial neuron, that is a simple function which takes a Wl)( and bl) and the bias vector, respectively. We denote by L the total number of layers of the DNN. Layer 0 is the DNN input, and layer L is the output, whereas layers 0 < l < L are called hidden layers.where l in a MLP depends on the parameters contained in the weight matrix Wl)( and in the bias vector bl) = aL)( when a(0) = xi, where Θ = {W(1), …, WL), …, bL) ≈ yi. See  and a set of four heart-failure-characterizing parameters  with N interpolation equidistant points. We set the simulation time to T = 30 s, allowing signals to reach a steady state after initialization, with N = 2, 000. The resulting output was a set of evenly-spaced time series. We note tm = mT/N, m ∈ {0, 1, …,N}, for the ith sample of the dataset. The pressure curves were represented in the frequency domain. That is, we computed the trigonometric Fourier coefficients A simulation was performed over a time range  Fourier coefficients of the signal ui,X, which are stored in a vector We fixed the activation functions of the DNN and trained a model for various number of layers and neurons per layer. In addition to the Fourier coefficients of the signals, we provided the pump setting The 0D model has been implemented in the object-oriented and equation-based Modelica programming language, on the open-source OpenModelica framework. Pre- and post-processing procedures were implemented in the Python and Matlab languages. The DNN architecture was implemented with the Keras library within TensorFlow.K required to accurately reconstruct the pressure signals. These are in turn given as input to the DNN. We provide in K for a complex curve, as obtained with low RPM  and severe LV failure. Indeed, in these conditions, LV preload is little reduced, allowing the native LV to contract and eject through the aortic valve. Thus, ejection through the LVAD and the native aorta induced a complex signal ((x) = max for l < L and gL)((x) = ex/(1 + ex). For training, we used the typical mean squared error loss function B = 32 being the batch size. Learning rate was set to 0.001. 5% of the samples in the dataset were kept for the test set, while 80% and 20% of the remaining samples were used in the training and validation sets, respectively.We used the rectified linear unit and sigmoid activation functions for the hidden and output layers, respectively. That is, We evaluated 28 different DNN architectures. For each architecture, the training and validation values of the loss and the mean absolute error were computed, as shown in Emax,lv, Emax,lv,0, and kE,lv . The predictive accuracy was slightly lower for GEmax,lv (mean relative error 12.43%), which is consistent with the sensitivity analysis performed in Bonnemain et al.  for each sample of the test set, using the following output measures: LV end-systolic pressure and volume, LV end-diastolic pressure and volume, LV ejection fraction, and pulmonary artery wedge pressure . For each variable, the minimal, maximal, and mean values, as well as the standard deviation, were obtained using alternatively the exact and predicted values of the 4 parameters of LV systolic function, and the differences between obtained data were computed as the error, presented as mean ±SD, 95% confidence interval, and relative error. The results of this analysis are presented in LVAD has become a frequently used therapeutic option in end-stage heart failure. Although this type of mechanical circulatory support significantly improves clinical condition and outcome of patients , some isOur present work provides a novel approach to help address such complex issues by implementing a DNN and by using a 0D model of the cardiovascular system, which incorporates the mathematical description of a last generation LVAD. We developed an automated framework to accurately recover LV hemodynamic parameters from data available in the clinical practice, namely systemic and pulmonary arterial pressures. These signals were represented in their frequency domain and were then given as input to the DNN. An appropriate selection of the number of Fourier coefficient allowed to retain only relevant physiological frequencies, control size of input, and clean possible noise. In addition to the pressure signals, the input of the DNN included information about the device setting (RPM).Emax,lv with a mean relative error of <10%. Furthermore, the 0D model allowed to precisely recover values of LVEF, ventricular volumes, and ventricular pressures, as indicated by the small relative error (<5%) between their actual and predicted values. Moreover, the average time to predict LV parameters from input signal was fast (<1 s) using a personal computer. Thus, real-time implementation could be easily considered.Owing to this architecture, only one DNN has to be trained to include every possibility of the working range of the device. This makes our framework suitable for a fast and automated implementation. Our DNN proved excellent reliability, being able to predict Emax,lv is challenging, requiring left-side heart chambers catheterization, a technique whose implementation is not realistic in the daily clinical practice. Non-invasive methods, including echocardiography and magnetic resonance imaging, coupled to measurement of arterial blood pressure have been proposed  and with the rotation speed of the device, allowing to predict end-systolic elastance and other parameters of left ventricular function with excellent accuracy. Our method could represent a useful tool to optimize LV-LVAD interactions early after implantation as well as during chronic therapy, and to evaluate the possible functional recovery of the left ventricle.https://github.com/matthiaszeller/VAD-0D-DNN.The code used to support the findings of this study has been deposited in the following repository: JB: design and implementation of the work, data acquisition and interpretation, and manuscript drafting. MZ: implementation of the work, data acquisition and interpretation, and manuscript drafting. LP: data interpretation and manuscript drafting. SD: design of the work, data interpretation, final manuscript drafting, and financial support. LL: data interpretation, final manuscript drafting, and financial support. All authors critically reviewed and approved the final version of the manuscript.This work was supported in part by the Emma Muschamp Foundation, Lausanne, the Mahmoud Darvish Foundation, Lausanne, to JB, and from the Swiss National Science Foundation under project FNS-200021_197021 to SD.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.


Myocardial layer-specific strain can identify myocardial ischemia. Global myocardial work efficiency (GWE) based on non-invasive left ventricular (LV) pressure-strain loops is a novel parameter to determine LV function considering afterload. The study aimed to compare the diagnostic value of GWE and myocardial layer-specific strain during treadmill exercise stress testing to detect significant coronary artery disease (CAD) with normal baseline wall motion.Eighty-nine patients who referred for coronary angiography due to suspected of CAD were included. Forty patients with severe coronary artery stenosis were diagnosed with significant CAD, and 49 were defined as non-significant CAD. Stress echocardiography was performed 24 h before angiography. Layer-specific longitudinal strains were assessed from the endocardium, mid-myocardium, and epicardium by 2D speckle-tracking echocardiography. Binary logistic regression analyses were performed to evaluate the association between significant CAD and echocardiographic parameters. A receiver operating characteristic curve was used to assess the capability of layer-specific strain and GWE to diagnose significant CAD.p = 0.006) and peak GWE  were associated with significant CAD. Receiver operating characteristic curves showed peak GWE to be superior to mid-myocardial, epicardial, and endocardial GLS in identifying significant CAD. Further, adding peak GWE to endocardial GLS could improve diagnostic capabilities.Patients with significant CAD had the worse function in all three myocardial layers at peak exercise compared with those with non-significant CAD when assessed with global longitudinal strain (GLS). At the peak exercise and recovery periods, GWE was lower in patients with significant CAD than in patients with non-significant CAD. In multivariable binary logistic regression analysis, peak endocardial GLS (OR: 1.35, Both GWE and endocardial GLS contribute to improving the diagnostic performance of exercise stress echocardiography. Furthermore, adding peak GWE to peak endocardial GLS provides incremental diagnostic value during a non-invasive screening of significant CAD before radioactive or invasive examinations. Coronary artery disease (CAD) is one of the leading global causes of mortality and morbidity. Concerning the diagnostics of CAD, coronary angiography (CAG), which despite being considered the gold standard, only confirmed significant CAD in 38% of suspected patients . Stress The newly developed and explored –5 quantiHowever, as strain is load-dependent, increasing the afterload may underestimate the left ventricular (LV) function; therefore, myocardial work (MW), which combines strain and non-invasive LV pressure, could overcome the limitation. Global myocardial work efficiency (GWE) is one of the major MW parameters and is derived from the percentage ratio of constructive work to the sum of constructive work and wasted work. Recently, significantly lower GWE values were reported in patients with CAD, heart failure, hypertension with left ventricle hypertrophy, and COVID-19 –10, and Due to the limited data available, this study aims to compare the diagnostic value of GWE with myocardial layer-specific global longitudinal strain during exercise stress to detect significant CAD with normal baseline wall motion.The study was conducted in a single tertiary coronary care center with 89 patients without known ischemic heart disease who were referred with angina pectoris and had plans to undergo treadmill exercise stress testing and CAG. Patients with the following criteria were excluded: age <18 years; baseline LV ejection fraction <50%; abnormal baseline wall motion; previous myocardial infarction; prior coronary artery bypass grafting or coronary interventional therapy; left bundle branch block; atrial fibrillation; sustained severe arrhythmia; severe valvular dysfunction; inability to undergo exercise testing; absence of any of apical four-chamber, three-chamber, and two-chamber views; and inadequate image quality. All patients underwent two-dimensional (2D) echocardiography , and a treadmill exercise stress test followed by CAG.Written informed consent was given by all study participants or their legal representatives. The study complied with the Declaration of Helsinki and was approved by the Ethics Committees of Fuwai Hospital (no. 2018-1121).3 – (LV end-diastolic diameter)3] + 0.6}. LV mass was then indexed for body surface area to generate the LV mass index. LV ejection fraction was measured using Simpson's biplane method from apical four- and two-chamber views. Early trans-mitral velocity (E wave) and late trans-mitral velocity (A wave) were measured by pulsed-wave Doppler from the apical four-chamber view with the sample volume positioned at the tip of the mitral leaflets. Mitral inflow E/A ratio was calculated as E wave divided by A wave.Comprehensive conventional echocardiography was performed  using a The treadmill exercise stress test was conducted utilizing the standard Bruce protocol  whereby From each of the three apical views at rest and during exercise, the cardiac loop with the best representation of the LV wall was identified and analyzed in the commercially available software ; initially with automated function imaging (AFI) and subsequently with the 2D strain software. AFI identified and tracked the endocardium automatically to generate the LV global longitudinal strain (GLS), and the regional speckle area of interest was adjusted manually where the tracking was poor. For 2D strain analysis, the endocardial borders were manually delineated by the operator and then traced by the software in the end-systolic frame for the analyses of longitudinal endocardial, mid-myocardial, and epicardial strains . Images Global myocardial work efficiency was calculated from a combination of the 2D LV GLS (based on AFI) and a non-invasively estimated LV pressure, using the commercially obtained software  . BrachiaThe images from CAG were interpreted visually by an experienced cardiologist blinded to patients' echocardiographic data. Significant CAD was defined as ≥70% luminal diameter narrowing in one or more major epicardial vessels or ≥50% in the left main coronary .Intra- and interobserver variabilities were determined with 15 randomly selected patients, where the analysis was repeated by the same investigator 2 weeks later and by a second investigator blinded to the initial results of the first investigator, respectively.t-test or Mann–Whitney U-test, as appropriate, whereas categorical variables were compared with the chi-squared test or Fisher's exact test. Correlation between continuous variables was performed using Pearson's or Spearman's correlation coefficient. Univariate binary logistic regression analyses were performed to evaluate the association between the presence of significant CAD and the echocardiographic variables. After excluding variables that showed collinearity (Pearson's or Spearman's correlation coefficient ≥ 0.60 or variance inflation factor > 10), all variables that found to be significant on univariate binary logistic regression were considered for multiple binary regression analysis using the forward selection method. Receiver operating characteristic curve analysis and Youden's index were used to assess the optimal cutoff points for layer-specific strain and GWE in predicting significant CAD. The comparisons of AUCs were performed using the method described by DeLong et al.  when not normally distributed. Categorical variables are presented as absolute numbers and percentages. Normal distribution was verified by the Shapiro–Wilk test. Continuous variables were compared using Student's g et al. . Intraclp < 0.05 was considered statistically significant.Analyses were performed using SPSS, version 25.0 , MedCalc, version 18.2.1 , and GraphPad Prism 8 . All statistical tests were two-sided, and a p > 0.05) between the two groups regarding age, gender, heart rate, blood pressure, coronary dominance, and exercise ECG results. Patients with significant CAD showed a larger body surface area and body mass index (both p < 0.05) and a higher incidence of dyslipidemia (p < 0.05) compared with those in the non-significant CAD group  between the two groups for the conventional echocardiographic parameters of LV end-diastolic or end-systolic dimensions, LV septal thickness in end-diastole, LV mass index, mitral early-diastole velocity, mitral late-diastole velocity, and the ratio of mitral early-diastole velocity to late-diastole velocity. LV posterior wall thickness in end-diastole was significantly larger in the significant CAD group than that of the non-significant CAD group  compared with those in the non-significant group, although there were no significant differences observed during the rest or recovery periods  had significantly lower absolute values during peak exercise in the significant CAD group (p < 0.001), although the differences between the two groups were not significant at rest or during recovery , although at rest, the values of the two groups had no significant differences  and a good negative correlation with peak GLS using AFI  all presented modest positive correlations with peak GLS using AFI .Peak GWE showed modest negative correlations with peak endocardial, mid-myocardial, and epicardial GLS , peak GWE, and recovery GWE were significantly associated with significant CAD .p = 0.006) and peak GWE  were significantly associated with significant CAD  that was superior to peak mid-myocardial and epicardial GLS . However, the addition of peak GWE to peak endocardial GLS significantly increased the AUC over that of peak endocardial GLS  for the detection of significant CAD . The participants or their legal representatives provided their written informed consent to participate in this study.WW, ZZ, and HW contributed to the conception, design, supervision of the study, and revised the manuscript critically for intellectual content. JL drafted the manuscript. LG, JH, LN, YZ, XL, and JW contributed to the collection and interpretation of data. JL, ML, and YC contributed to statistical analysis. All authors contributed to the article and approved the submitted version.This study was supported by the Beijing Municipal Science and Technology Commission (Grant No. Z171100001017213) and Construction Research Project of Key Laboratory (Cultivation) of Chinese Academy of Medical Sciences (Grant No. 2019PT310025).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.


Left bundle branch block (LBBB) is an uncommon complication of myocardial perfusion imaging using Regadenoson, a vasodilatory agent. The mechanism is poorly understood at this time but could be related to ongoing ischemia. The use of a Regadenoson with the subsequent occurrence of LBBB could be a predictor of coronary artery disease or conduction abnormalities and should be understood by the physician to diagnose and risk stratify patients undergoing myocardial perfusion imaging properly. Myocardial perfusion imaging (MPI) stress test is performed using exercise or vasodilatory agents such as dipyridamole (a vasodilatory agent which achieves vasodilation through the activity of adenosine deaminase and phosphodiesterase) or Regadenoson . Regadenoson is also known to cause significantly higher peak, absolute and relative heart rates than dipyridamole during MPI. The incidence of exercise stress test-induced left bundle branch block (LBBB) is rare and reportedly occurs in approximately 0.5-1% of all patients undergoing exercise testing [We present a 56-year-old Caucasian male with a past medical history of hypertension and hyperlipidemia presenting with a one-month history of atypical chest pain. The patient specified that the pain was a burning sensation along the right side of the chest without aggravating or alleviating factors. The patient admitted to numbness and tingling of his right hand in an ulnar nerve distribution and denied shortness of breath. His social history was remarkable for chewing tobacco for over 50 years and a strong family history of myocardial infarction, stating his mother had two heart attacks before the age of 45. With a baseline heart rate of 84, the patient subsequently underwent treadmill exercise stress testing and was found to have new-onset LBBB Figure  at a heaThe presence of LBBB on a resting electrocardiogram (ECG) and at low work levels on a stress test essentially exclude exercise-induced LBBB . EI-LBBBWhen LBBB occurs, it may produce a partially reversible or fixed septal defect on perfusion imaging . This peSome studies have documented a strong association between stress-induced LBBB and coronary artery disease (CAD) or heart failure . Such paLBBB is an uncommon complication of Regadenoson stress tests and should be recognized as it may predict the presence of CAD and the probability of permanent LBBB and conduction abnormalities. When this occurs, patients may benefit from CA to rule out existing CAD.


Objective: Sympathetic nervous system (SNS) reaction to exercise is gender dependent. Nevertheless, clinically applicable methods to identify this difference are still missing. An organ largely sensitive to SNS is the spleen whose response to exercise can be easily evaluated, being included in the field of view of myocardial perfusion imaging (MPI). Here, we aimed to verify whether gender interferes with the spleen perfusion and its response to exercise.Methods: For this purpose, we evaluated 286 original scans of consecutive patients submitted to MPI in the course of 2019. Our standard procedure implies a single-day stress-rest sequence with a gap of ≥2 h between the administrations of 180 and 500 MBq of 99mTc-Sestamibi, respectively. Imaging is performed 30 min after radiotracer administration, with scan duration set at 25 and 35 s per view, respectively. Non-gated scans were reconstructed with the filtered back-projection method. A volume of interest was drawn on the spleen and heart to estimate the dose-normalized average counting rate that was expressed in normalized counts per seconds (NCPS).Results: In all subjects submitted to exercise MPI (n = 228), NCPS were higher during stress than at rest . This effect was not detected in the 58 patients submitted to dipyridamole-stress. The response to exercise selectively involved the spleen, since NCPS in heart were unchanged irrespective of the used stressor. This same response was dependent upon gender, indeed spleen NCPS during stress were significantly higher in the 75 women than in the 153 men . Again, this variance was not reproduced by heart. Finally, spleen NCPS were lower in the 173 patients with myocardial reversible perfusion defects (summed difference score ≥3) than in the remaining 55, despite similar values of rate pressure product at tracer injection.Conclusion: Thus, exercise interference on spleen perfusion can be detected during MPI. This effect is dependent upon gender and ischemia confirming the high sensitivity of this organ to SNS activation. In patients with coronary artery disease (CAD), the activation of the sympathetic nervous system (SNS) contributes to trigger ischemic episodes during physical effort, since the sudden increase in arterial pressure, heart rate, and cardiac contractility augment myocardial oxygen consumption, possibly leading to an inadequate blood flow supply downstream from a severe coronary stenosis  of vasculature and capsule . This inclusion allows the measurement of organ uptake of Stress and rest original scans of all 286 consecutive patients, submitted to MPI in the course of the year 2019, were collected and evaluated. All patients were in sinus rhythm. Subjects with atrial fibrillation or pacemaker were excluded from the analysis as to warrant a precise measurement of scan duration. Tracer was injected with the patient approaching the maximal workload or 2 min after the administration of standard dipyridamole dose (0.56 mg/Kg body weight over 4 min). Both stresses were performed under continuous electrocardiographic monitoring (EKG). A 12-derivations printout and arterial pressure were recorded each minute. In all cases, the following clinical parameters were recorded: rate pressure product (RPP) at baseline and at tracer injection, occurrence of chest pain or dyspnea as well as appearance of ST segment depression.99mTc-Sestamibi, respectively. Imaging was performed 30 min after radiotracer administration, with scan duration set at 35 and 25 s per view for stress and rest acquisition, respectively. In all cases, single photon computerized tomography (SPECT) was acquired using a dual-head SPECT gamma camera  equipped with parallel hole low-energy high-resolution collimators.According to our standard procedure, all patients underwent a single-day stress-rest sequence with a gap of ≥2 h between the administrations of 180 and 500 MBq of 99mTc photopeak. An automated body-contour orbit was used, with image acquisition every 3 degrees, through a 180 degrees arc starting from 45 degrees right anterior oblique to 45 degrees left posterior oblique view, with heads configured in L mode. No attenuation or motion correction was applied. According to the current guidelines  was centered over the 140 keV All scans were analyzed by using a commercial software . To minimize the possible differences in reconstruction parameters, non-gated images were reconstructed using the filtered back-projection method with Butterworth filter set at 0.5 frequency and 8th order.Radioactivity content was only measured in non-gated transaxial images. To this purpose, two volumes of interest (≥10 ml) were drawn to estimate average counts of spleen and left ventricular (LV) myocardium. Obtained values were thus divided for the injected dose, and the scan duration to obtain the normalized counting rate . No attenuation-correction was performed.Myocardial perfusion imaging was semi-quantitatively evaluated using the commercial QPS/QGS software . The left ventricle was divided into 20 segments to automatically calculate the summed stress score (SSS), summed rest score (SRS), and summed difference score (SDS) for each patient. Ischemia was defined by a SDS value ≥3.The EKG-gated images were reconstructed using the ordered subset expectation maximization method and applying the correction for the line-spread function. LV end-diastolic volume (EDV) and ejection fraction (EF) values were thus estimated using the dedicated routine of QGS software.n and percentage. For continuous variables, differences between the groups were tested using the Student's t-test for unpaired or paired data as appropriate. Difference in prevalence was tested by chi-square test. Univariate regression was performed to assess the value of clinical and imaging data in predicting spleen uptake after exercise-induced stress. Thereafter, all variables were tentatively included in a multivariate regression model by means of a step-back (backward) procedure, based on the likelihood ratio test and thus using a p < 0.15 for the inclusion of each variable. Data analysis was performed by using the IBM Statistical Package SPSS version 26 . Statistical significance was set at p < 0.05.Continuous data are expressed as mean ± SD, prevalence is described as Among the entire population, 185 (65%) patients were men and 101 (35%) women. Exercise was accomplished in 228 subjects: 153 (67%) of them were men and 75 (33%) women. Fifty-eight patients were submitted to pharmacologic vasodilation: 32 (55%) men and 26 (45%) women.Contractile function was not different in the two groups, since post-stress and baseline LV EF were similar in subjects submitted to exercise or dipyridamole. Likewise, prevalence of positive MPI as well as numerical descriptions of MPI results  were independent of the used stressors.99mTc-labeled Sestamibi uptake was clearly visible in all studied patients both in stress and rest images (p < 0.0001) (p = ns) (p < 0.01) (Spleen t images . In the  0.0001) , 2A. Thi(p = ns) , 2B. The < 0.01) .99mTc-labeled Sestamibi retention was selectively increased by physical effort and focused our attention on the determinants of organ radioactivity content in the 228 patients submitted to exercise MPI.As shown in Reversible perfusion defects, defined by an SDS ≥ 3, occurred in 173/228 (76%) patients submitted to exercise MPI. As reported in 99mTc-labeled Sestamibi uptake in ischemic patients  with the organ blood content. This observation extends to humans as the previous evidence of an almost six-fold increase in splenic blood flow during exercise obtained using the microsphere method in rats  that were gender independent. This observation suggests that SNS response to exercise might be more variegate than commonly assumed, with differential activations of sympathetic neurons regulating the splanchnic district with respect to the heart function.99mTc-Sestamibi uptake during exercise. This response was not shared by patients submitted to dipyridamole stress. It is coherent with previous experimental evidence about an increased flow rate during physical effort and most likely reflects the consequence of an empowered adrenergic and noradrenergic signaling by the sympathetic fibers.In conclusion, the present proof of concept study documented a marked increase in spleen Differently from the myocardium, spleen response to exercise was at least partially dependent upon gender and occurrence of ischemia, possibly indicating a divergent reaction to exercise by cardiac and splanchnic SNS. Should these data be confirmed, the evaluation of SNS regulation of perfusion and metabolic function of the spleen might represent a new window to study the reasons underlying the higher risk of women with coronary artery disease (Dart and Du, The datasets generated for this study are available on request to the corresponding author.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.FL, FD, GS, and CM: conceptualization and original draft preparation. SR, MP, MD, AM, SC, SM, and CD: images acquisition. FL and FD: data collection and analysis. All authors contributed to writing and editing and approved the definitive version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


The objective of this study was to determine the relationship between heart rate and relapse among patients in the TRED-HF .Understanding markers and mechanisms of relapse among patients with recovered dilated cardiomyopathy (DCM) may enable personalized management.The relationship between serial heart rate measurements and relapse was examined among patients in the TRED-HF trial, a randomized trial which examined the safety and feasibility of withdrawing heart failure therapy from 51 patients with recovered DCM over 6 months. In total, 25 patients were randomized to therapy withdrawal and 26 to continue therapy, of whom 25 subsequently began therapy withdrawal in a single arm crossover phase.P = 0.002). After data were adjusted for age, log N-terminal pro–B-type natriuretic peptide, and left ventricular ejection fraction (LVEF), heart rate  and change in heart rate from baseline  were associated with relapse. The results remained qualitatively the same after adjusting for beta-blocker dose.The mean ± SD heart rate for those who had therapy withdrawn and did not relapse was 64.6 ± 10.7 beats/min at baseline and 74.7 ± 10.4 beats/min at follow-up, compared to 68.3 ± 11.3 beats/min at baseline and 86.1 ± 11.8 beats/min at follow-up for those who relapsed. After adjusting for differences in heart rate at baseline, patients who had therapy withdrawn and relapsed had a 10.4 beats/min (95% CI: 4.0–16.8) greater rise in heart rate than patients who had therapy withdrawn and did not relapse (NCT02859311)For patients with DCM and improved LVEF, the rise in heart rate after treatment is withdrawn treatment identifies patients who are more likely to relapse. Whether the increase in heart rate is a marker or a mediator of relapse requires investigation. (Therapy withdrawal in REcovered Dilated cardiomyopathy trial [TRED];   Dilated cardiomyopathy (DCM) refers to a common phenotype that is the result of a diverse range of genetic and environmental triggers . A propoDespite such recommendations, some patients remain interested in finding out if their medication can be stopped or reduced, accepting the risk of relapse. Clinicians may prefer to try to help their patients do this cautiously rather than let them experiment on their own. There may be specific situations, such as peripartum cardiomyopathy, where clinicians and patients agree to a trial of therapy withdrawal or dose reduction. The best way to monitor withdrawal or reduction of therapy to predict and prevent relapse is unknown ,6.Data from TRED-HF  demonstrated that deterioration in cardiac function, determined by cardiovascular magnetic resonance (CMR), often preceded a rise in plasma concentrations of N-terminal pro–B-type natriuretic peptide (NT-proBNP). This suggests that this biomarker may not be a good early marker of relapse. However, frequent follow-up using CMR is rarely feasible in clinical practice. Integrating readily available non-invasive variables that can be measured frequently, such as heart rate, with periodic assessment using advanced imaging techniques may be a feasible and robust monitoring strategy. A strong association among achieved heart rate, temporal changes in heart rate, and outcome among patients with heart failure is well established , 9, 10. NCT02859311) study was an open-label, randomized trial examining the safety and feasibility of phased withdrawal of heart failure therapy in patients recovered DCM. A comprehensive description of the methods is provided elsewhere  of <40% that had subsequently improved to ≥50% and who now had normal LV end diastolic volume (LVEDV) and an NT-proBNP concentration of <250 ng/l and who were still taking at least 1 heart failure therapy  were randomized 1:1 to phased withdrawal or continuation of pharmacological heart failure therapy for 6 months. At baseline, 16 weeks, and 6 months, all patients underwent comprehensive CMR assessment. After 6 months, patients assigned to the control arm subsequently entered a single-arm cross-over phase and had therapy withdrawn between months 6 and 12. Those patients were followed in the same way as the randomized phase of the study.Therapy was withdrawn in a supervised, step-wise fashion over a maximum of 16 weeks. Changes were made every 2 weeks following clinic or telephone review. Heart rate, weight, and NT-proBNP concentrations were measured every 4 weeks with interim reviews taking place by telephone, provided patients remained asymptomatic. Loop diuretic drugs were withdrawn first, followed by MRAs, beta-blockers, and finally ACE inhibitors or ARBs. The medication was stopped if the participant was taking 40 mg or less of furosemide , 50 mg or less of spironolactone, or 25% or less of the recommended dose of beta-blocker or ACE inhibitor or ARB. If participants were prescribed larger doses of any of the above, the dosages were reduced by 50% every 2 weeks.At each clinic visit, resting heart rate was recorded in beats/min by using a 12-lead electrocardiogram performed following 5 min of rest in the supine position. The primary endpoint was a relapse of DCM defined by any 1 of the following: 1) a reduction in LVEF by >10% and to <50%; or 2) an increase in LVEDV by >10% and to above the normal range; or 3) a two-fold rise in NT-proBNP from baseline and to >400 ng/l; or 4) clinical evidence of heart failure. Therapy was reintroduced as soon as any of the primary endpoint criteria were fulfilled. The management of patients who did not meet the primary endpoint but experienced adverse events was determined by the study team and the participant’s routine physicians.The main analyses were nonrandomized comparisons of heart rate measurements according to whether patients relapsed following therapy withdrawal. Accordingly, data from the therapy withdrawal arm were used during the randomized phase of TRED-HF  and from the control group during the cross-over phase (with baseline at month 6 and end of follow-up at month 12). As background, data from control patients are presented during the randomized phase of the trial when patients remained taking therapy, although these data were not used for formal statistical comparisons.Three main analyses were performed. First, heart rate measurements at the end of the study or the time of relapse were compared between patients who did relapse and those who did not. Differences were estimated between these groups by fitting an analysis of covariance (ANCOVA) model with the heart rate at the end of the study (or relapse), 4 weeks and 8 weeks as the dependent variables and baseline heart rate and relapse status as the independent variables. Second, serial heart rate measurements taken at each study visit following therapy withdrawal was modeled separately according to whether or not a patient relapsed. To do this, fractional polynomial models with 4 knots were used. Third, the association between heart rates at each visit and relapses at either the same visit or until the time of the next heart rate measurement was estimated. To do that, Cox proportional hazards model was used, fitting heart rates at each visit as the time-updated covariate . SimilarA p value of <0.05 was taken as significant throughout. Statistical analyses were performed using Stata version 16.0 software (StatCorp). The investigators had complete access to all raw and derived datasets.Of 51 patients randomized, 26 were assigned to continue therapy and 25 to have therapy withdrawn. One patient randomized to the therapy withdrawal arm withdrew from the study shortly after enrolment. Another patient completed follow-up in the control arm but did not enter the single-arm cross-over phase thereafter. Therefore, heart rate data were available for 49 patients who had therapy withdrawn, 24 from the randomized phase, and 25 from the cross-over phase . Of thosThe mean ± SD heart rate at baseline and follow-up was 64.6 ± 10.7 beats/min and 74.7 ± 10.4 beats/min for those who had therapy withdrawn but did not relapse and 68.3 ± 11.3 and 86.1 ± 11.8 beats/min for those who had therapy withdrawn and relapsed. For those who continued therapy in the control arm, the baseline and follow-up heart rates were 69.9 ± 9.8 beats/min and 65.9 ± 9.1 beats/min .Table 2CAmong patients who had therapy withdrawn, the latest time points at which loop diuretics, MRAs, beta-blockers, and ACE inhibitors and ARBs were discontinued was 14, 28, 84, and 112 days, respectively. Among patients who had therapy withdrawn and relapsed, there was a persistent and steady rise in mean heart rate between baseline and 112 days . Among pAfter adjusting for differences in heart rate at baseline, patients who had therapy withdrawn and relapsed had a 10.4 beats/min (95% CI: 4.0 to 16.8) greater rise in heart rate over the follow-up period than patients who had therapy withdrawn and did not relapse (p = 0.002) . The chaThe mean rise in heart rate after withdrawal of loop diuretics, MRAs, beta-blockers, ACE inhibitors, and ARBs was 6.7 ± 6.6 beats/min, 4.0 ± 9.8 beats/min, 14.5 ± 9.8 beats/min, and 7.0 ± 12.3 beats/min. The adjusted mean change in heart rate after withdrawal of each medication was not significantly different between patients who relapsed and those who did not . There wTTN gene .There were no differences in heart rate changes over follow-up among carriers versus among non-carriers of truncating variants in the In proportional hazard modeling, time-updated heart rate (or attained heart rate) and change in heart rate from baseline were associated with the occurrence of the primary relapse endpoint at the same visit  . There wIn supplemental models, time-updated heart rate (or attained heart rate), change in heart rate from baseline and change in heart rate from the previous visit were associated with the occurrence of relapse at the subsequent visit . HoweverThere was a moderate positive correlation between change in GLS and change in heart rate between baseline and follow-up . There were no significant correlations between change in LVEF , nor was a change observed in NT-proBNP  and change in heart rate .The present study demonstrates for the first time that attained heart rate and change in heart rate from baseline are associated with relapse among patients with recovered DCM who had therapy withdrawn. This was independent of markers of disease severity and predictors of relapse at baseline. A sensitivity analysis confirmed that heart rate was not simply a proxy for beta-blocker dose. Maintaining a lower heart rate was associated with a lower risk of relapse . PatientAlthough there was overlap in heart rate profiles between patients who did and did not relapse, this was likely driven by use of a dichotomous measure to define the endpoint. This is of course imperfect because relapse represents adverse cardiac remodeling, which is a continuous phenomenon. Some patients who had therapy withdrawn and did not meet the primary relapse endpoint still had evidence of adverse remodeling associated with a rise in heart rate. Longer follow-up is likely to have identified further cases of relapse. The overlap between the 2 groups represents the spectrum of remodeling across these patients. Calculating the sensitivity and specificity of a measure to detect a dichotomized definition of relapse, therefore, has obvious limitations and is likely to underestimate its usefulness.Although the high rate of relapse in patients with recovered DCM observed in TRED-HF suggests that most patients should continue to take disease-modifying pharmacological therapy ; some paOur data suggest that changes in heart rates may be used as a non-invasive marker of relapse to guide the use of cardiac imaging and testing of natriuretic peptide. Follow-up with regular CMR, as used in this trial, is rarely feasible in clinical practice. Incorporation of a strategy informed by heart rate may facilitate the tailored and rapid reintroduction of pharmacological therapy and prevent clinical relapse. Advances in digital health care technology allow heart rate to be monitored using wearable or hand-held devices. The appearance of differences in heart rates between groups as early as 8 weeks following the start of therapy withdrawal raises the possibility of using heart-rate monitoring to predict future relapse. Altogether, until more robust evidence is available, a multiparametric approach appears advisable, with frequent assessment of heart rate and symptoms supported by less frequent assessment by imaging and biomarkers. Based on these data, a heart rate rise of >10 beats/min from baseline may act as a prompt for expedited imaging investigation. Validation of specific heart rate cutoffs is required and could be incorporated into future clinical trials investigating the management of patients with DCM and improved cardiac function.It is uncertain whether the rise in heart rate observed in this study was the cause or the consequence of worsening cardiac function. Although the withdrawal of each class of medication was associated with an overall rise in mean heart rate, the magnitude of this was greatest with beta-blockers. The rise in heart rate seen following the withdrawal of non-rate-slowing medications, suggests that it may be a consequence of decompensation and increasing myocardial workload. However, we would advise against over-interpretation of these results, given the modest number of patients taking loop diuretic agents and MRAs. It should also be borne in mind that medications were withdrawn sequentially over a relatively short period of time and that the change in heart rate observed during the withdrawal of ACE inhibitors and ARBs might have been influenced by the preceding withdrawal of beta-blockers. As demonstrated in the primary publication, those patients who relapsed had markers of more severe disease at baseline with higher concentrations of natriuretic peptides and also were older . It is aIf the rise in heart rate is an important cause for relapse, then maintaining rate-slowing medications at a dose sufficient to control heart rate may prevent relapses, allowing other medications to be reduced. Adrenergic receptor blockade may be just one means of reducing heart rate. For patients in sinus rhythm, ivabradine also improves ventricular function and clinical outcomes ,14. FurtPerspectivesCOMPETENCY IN MEDICAL KNOWLEDGE: A rise in heart rate is associated with adverse remodeling and relapse among patients with recovered dilated cardiomyopathy whose medication is withdrawn. Combining heart rate measurement with imaging and natriuretic peptide measurement may be an effective way of monitoring patients who elect to have medications withdrawn under specific circumstances. A heart rate rise of >10 beats/min may be used as a guide to prompt further investigation.TRANSLATIONAL OUTLOOK: It remains unclear whether change in heart rate is a marker or mediator of adverse remodeling in patients with recovered dilated cardiomyopathy. Whether heart rate suppression is the key to maintaining remission deserves further investigation.Among patients among patients with recovered DCM who had disease-modifying pharmacological therapy for heart failure withdrawn, attained heart rate and change in heart rate from baseline were associated with relapse. A strategy that combines frequent measurements of heart rate with less frequent imaging assessment may be a safe and effective way of monitoring treatment withdrawal or tapering, for patients where this is performed out of necessity, based on clinical circumstances or patient choice. A lower heart rate was associated with a lower risk of relapse. Whether heart rate control is a key determinant for maintaining remission of DCM deserves further investigation.The TRED-HF study was an investigator-led trial sponsored by Royal Brompton and Harefield National Health Service Trust. The study was funded by a Clinical Research Training Fellowship from the British Heart Foundation (FS/15/29/31492) awarded to Dr Halliday and Prasad. Additional support was received from the Alexander Jansons Foundation; the Cardiovascular Research Centre; and National Institute for Health Research (NIHR) Biomedical Research Unit at Royal Brompton Hospital; the NIHR Imperial College Biomedical Research Centre; and by grants from Rosetrees Trust, awarded to Dr Prasad. Dr Halliday is supported by a Clinical Lecturer Starter Grant from the Academy of Medical Sciences (SGL021∖1025). Prof John Cleland received a Centre of Research Excellence award from the British Heart Foundation (RE/18/6/34217). Prof Pennell has received research support from Siemens; and speaker fees from Chiesi and Bayer; is a consultant for ApoPharma and Chiesi; and is a director and owns stock in Cardiovascular Imaging Solutions. Prof Cowie has received personal fees from Servier and Novartis, outside the submitted work. Prof Cleland has received personal fees from Abbott, and grants and personal fees from Amgen, Bayer, Medtronic, Novartis, Pharmacosmos, Vifor, Bristol Myers Squibb, and Servier, outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.