Background: Ischaemic heart disease (IHD) and cerebrovascular disease are two closely inter-related clinical entities. Cardiovascular magnetic resonance (CMR) radiomics may capture subtle cardiac changes associated with these two diseases providing new insights into the brain-heart interactions.Objective: To define the CMR radiomics signatures for IHD and cerebrovascular disease and study their incremental value for disease discrimination over conventional CMR indices.Methods: We analysed CMR images of UK Biobank's subjects with pre-existing IHD, ischaemic cerebrovascular disease, myocardial infarction (MI), and ischaemic stroke (IS) . Each disease group was compared with an equal number of healthy controls. We extracted 446 shape, first-order, and texture radiomics features from three regions of interest  in end-diastole and end-systole defined from segmentation of short-axis cine images. Systematic feature selection combined with machine learning (ML) algorithms (support vector machine and random forest) and 10-fold cross-validation tests were used to build the radiomics signature for each condition. We compared the discriminatory power achieved by the radiomics signature with conventional indices for each disease group, using the area under the curve (AUC), receiver operating characteristic (ROC) analysis, and paired t-test for statistical significance. A third model combining both radiomics and conventional indices was also evaluated.Results: In all the study groups, radiomics signatures provided a significantly better disease discrimination than conventional indices, as suggested by AUC . Similar results were observed with the combined models. In IHD and MI, LV shape radiomics were dominant. However, in IS and cerebrovascular disease, the combination of shape and intensity-based features improved the disease discrimination. A notable overlap of the radiomics signatures of IHD and cerebrovascular disease was also found.Conclusions: This study demonstrates the potential value of CMR radiomics over conventional indices in detecting subtle cardiac changes associated with chronic ischaemic processes involving the brain and heart, even in the presence of more heterogeneous clinical pictures. Radiomics analysis might also improve our understanding of the complex mechanisms behind the brain-heart interactions during ischaemia. Ischaemic heart disease (IHD) and ischaemic cerebrovascular diseases are the leading causes of death and disability worldwide . AlthougMultiple interactions occur among these two disease entities, which are not fully explained by shared vascular risk factors , 4. SevePrevious studies have focused on the possible brain areas involved in the crosstalk between the two systems. They suggest that cerebral ischaemia might trigger different pathways of dysautonomia and increased inflammation, potentially resulting in cardiac dysfunction –8. The mCardiovascular magnetic resonance (CMR) radiomics analysis may provide new insights into the quantitative analysis of cardiac imaging by extracting a large number of computational quantitative metrics, including shape and texture features, which may capture a wide variety of phenotypic traits. Several studies have already demonstrated their incremental role over conventional imaging indices in identifying subtle cardiac alterations due to specific clinical conditions .Studying the morphological and myocardial tissue changes associated with ischaemic heart and brain diseases using CMR radiomics analysis may provide new insight into the relationship between these two systems and their underlying mechanisms. These additional imaging markers may also improve the early diagnosis of ischaemic events and help clinicians identify those most at risk who require more aggressive preventive strategies.In this paper, we used CMR radiomics analysis to study whether there were specific cardiac abnormalities in individuals who had previous ischaemic cerebrovascular events and cardiac events (IHD). We used machine learning (ML) methods to identify the most defining radiomics features for each condition, called “radiomics signature.” Finally, we studied whether the radiomics-based models provided incremental information to conventional approaches. To our knowledge, no previous studies have used this approach to investigate the brain-heart interactions after ischaemic processes on a large cohort of participants as it is the United Kingdom Biobank (UKB).In this work we used clinical and imaging data from UKB, a prospective cohort study which has been following the health and well-being of half a million participants aged 40–69 years-old recruited from across the UK between 2006 and 2010 . Its goaAmong all the participants from UKB who completed the CMR imaging protocol and passed the quality control check, we identified subjects with a previous diagnosis of IHD and those with cerebrovascular disease using a combination of selected ICD-10 and ICD-9 codes for diagnosis. Participants who had both conditions at the time of the CMR study were excluded from the study. The full list of ICD codes for each study group is provided in We initially identified 1,516 subjects with IHD, including angina, previous myocardial infarction (MI), or any manifestation of IHD not resulting in MI.n = 267).The ischaemic cerebrovascular disease subset, instead, included previous ischaemic stroke (IS) or transient ischaemic attack (TIA), as both clinical manifestations have a significant prognostic value , 15 (n =n = 525) and IS (n = 107) only were also considered separately as the subsets with evidence of cardiac and cerebral organ damage, respectively. Definitions for MI were consistent with those used by the UKB outcome adjudication group (Participants with MI (on group . The ideon group .n = 779). We selected this cohort because it was well-validated, and the rule-out criteria used to define the “healthy” status were robust. Subjects were thus considered healthy if they did not have any known cardiovascular diseases, traditional risk factors, or other systemic conditions that could have impacted the heart at the time of CMR study. The complete list of exclusion criteria used to define the selected healthy cohort has been described elsewhere , to obtain balanced groups, we finally selected only 779 IHD subjects to match the numbers of healthy comparators.Since there were fewer healthy participants than those with IHD (n = 779), cerebrovascular disease (n = 267), MI (n = 525), and IS (n = 107).Therefore, at the end of the selection process, we had four disease subsets each one to be compared with an equal number of healthy controls: IHD   . Among t6 . Among 16,186) . From thConventional CMR indices of cardiac structure and function were also assessed and compared to the added value of CMR radiomics. In particular, we automatically calculated: LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), RV end-diastolic volume (RVEDV), RV end-systolic volume (RVESV), LV stroke volume (LVSV), RV stroke volume (RVSV), LV ejection fraction (LVEF), RV ejection fraction (RVEF), LV mass (LVM). The CMR parameters were subsequently indexed to the subject's body surface area (BSA) and used for further analysis.From the three segmented ROIs in ED and ES we extracted radiomics shape and signal intensity-based features using the open-source packages Pyradiomics version 2.2.0 .Radiomics shape features quantify size and shape of the segmented ROIs and have the potential to capture subtle geometrical and morphological alterations of the cardiac structures beyond those described by conventional CMR indices. Shape features include conventional indices, such as cavity volume, and more advanced geometric quantifiers, such as sphericity, compactness, and elongation.Signal intensity-based radiomics features are grouped into two categories: first-order and texture features. These features describe the global distribution and pattern of voxel signal intensity (SI) and may potentially capture changes in cardiac tissue induced by disease processes.In particular, first-order radiomics describe the global SI distribution within the ROIs by plotting a histogram and without focusing on their spatial relationships. The global SIs distribution is described using simple quantifiers, such as mean, median, and standard deviation, and more advanced measures, such as skewness, uniformity, or entropy.Texture features, instead, describe the SIs patterns within the segmented ROIs considering the relationship of the voxel SIs to each other. Various mathematical processes are used to quantify the complexity, coarseness and repeatability of the SI matrix , 24. TexIt should be noted that radiomics are sensitive to intensity variations related to the image acquisition process. Therefore, to account for such variations and increase their repeatability, prior to feature extraction, intensity normalisation within the heart region was performed by means of histogram matching using as reference one of the CMR from the UKB .Radiomics shape and signal intensity-based features were extracted from the three ROIs  in ED and ES. RV first-order and RV texture radiomics features were not considered for the analysis as deemed not clinically relevant. This resulted in a total of 446 radiomics features to be included in the study.From this subset of features a highly correlated removal was applied as many of them were not independent and were expected to encapsulate redundant information. Towards this aim, we used Pearson correlation coefficient higher than 0.9, and we retained only one of the correlated features, resulting in 261, 267, 267, and 265, on average per fold, for IHD, MI, cerebrovascular disease and IS, respectively.After this data pre-processing, a ML grid search pipeline was performed, including a feature selection step. KBest algorithm based on mutual information was selected among different feature selection (FS) techniques due to its robustness and performance efficiency. Other FS techniques, such Sequential Feature Selection (SFS) were discarded due to high computational times and equal performance.Our study aimed to identify radiomics signatures that best describe the cardiac structural and tissue changes occurring in ischaemic heart and brain diseases to differentiate subjects with these conditions from healthy.For that purpose, the most informative sets of k radiomics features were selected based on the FS algorithm described in the previous section and fed to ML classifiers to discriminate between each disease vs. control group . Data from the different cohorts was properly under sampled to match equally distributed cohorts for comparison.Among different state-of-the-art ML algorithms evaluated using a simple splitting of the dataset , SVM and RF performed consistently better. Therefore, we decided to use these two algorithms to build our ML models. In this paper, we describe only the results obtained with SVM and RF in a 10-fold cross validation grid search and hyperparameter tunning, and tested in a 10-fold unseen dataset  curve analysis and area under the ROC curve (AUC) score. Group differences were evaluated using independent t-tests after assessing the normal distribution of the data. Statistical analysis was performed using Python Version 3.6.4 .Paired At the end of the selection process, the subjects with IHD, cerebrovascular disease, MI, and IS available for the analysis were 779, 267, 525, and 107, respectively.Baseline characteristics and CMR indices for each disease group and healthy controls are shown in The average age was similar across the disease groups (from 67 ± 6 to 68 ± 6 years) and it was significantly higher than the healthy controls (59 ± 7 years). The majority of participants were male, while the highest percentage of female subjects was observed in cerebrovascular disease and IS cohorts . Furthermore, the distribution of cardiovascular risk factors  was similar across the disease groups, except for hypercholesterolaemia, which percentage was significantly higher in IHD and MI.Subjects with previous MI had significantly higher LV volumes and LVM index and lower LVEF values than the healthy control. A similar pattern was observed in the more heterogeneous cohort of IHD, where significantly lower RV volumes were also observed.IS and cerebrovascular disease, instead, had the lowest indexed LVEDV and RV volumes among the disease subsets, while the cardiac function indices were similar to the healthy group.In comparison to conventional CMR indices, radiomics provided a better degree of discrimination between healthy and subjects with IHD  and cerebrovascular disease , myocardial cavity volume, and surface area to volume ratio were highly featured in both diseases.The direction of these features was also similar between the two conditions, reflecting common patterns of cardiac alterations. For instance, in both groups, there were larger cavity dimensions in end-diastole and end-systole compared to the healthy controls, as it was the volume of the LV myocardium at end-diastole. The mean value of the selected shape features for each disease group are shown in The prominence of these LV shape radiomics features indicates the tendency for the ischaemic cardiac disease to result in gross alterations of the LV geometry.Several shape, first-order, and texture radiomics were among the top-ranked features contributing to a radiomic signature in cerebrovascular diseases and IS.Skewness, kurtosis, and sphericity of the LV were the most relevant features in both conditions. Furthermore, the direction of the changes described in comparison to healthy control was similar between the two groups.For instance, the sphericity of the LV myocardium at end-diastole was greater amongst both disease groups compared with healthy individuals, indicating a less elliptical and more spherical chamber.Furthermore, in both groups, there was less skewness in the distribution of signal intensity levels and a lower number of extreme intensities (kurtosis) within the LV blood pool region than the healthy controls.The combination of all these findings indicate that ischaemic cerebrovascular diseases may be associated with subtle alterations both in the geometry and intra-cardiac haemodynamics of the LV.Finally, texture radiomics played a significant role in improving disease discrimination in both cerebrovascular diseases and IS. Among the most informative texture radiomics, there were features describing the distribution of signal intensity values , the textural heterogeneity , and the relationship between voxel intensity and neighbourhood . These features allowed a more granular tissue characterisation of the LV and myocardial tissue structure by quantifying the patterns of inter-voxel signal intensities. The analysis of texture radiomics revealed subtle differences at the tissue level between cerebrovascular disease and IS.For instance, in cerebrovascular disease, there was less homogeneity among run lengths in the myocardial structure (run-length non-uniformity) as compared to the healthy comparators.In IS, instead, there was lower variability of grey-level intensity values (grey-level non-uniformity) than healthy participants. These observations indicate that cerebrovascular disease may be associated with more textural heterogeneity of the LV myocardium than IS. These findings suggest that, despite some similarities, there may be some distinct alterations at the tissue level in the two conditions. The mean value of the selected radiomic features for each disease group are shown in By referring to the constituent features within the radiomics signature for IHD and cerebrovascular disease, we were able to consider potential common biological pathways linking the two conditions .In general, radiomics shape features appeared more important for the signatures of the primary cardiac conditions (IHD and MI), indicating that gross anatomic alterations are important characteristics of these diseases. These features, instead, were less prominent within the cerebrovascular disease signatures.There were also commonalities in the observed morphological alterations. For example, all disease categories considered showed greater sphericity and lower surface area to volume ratio of the LV myocardium compared to healthy cases, indicating a more spherical less elongated LV cavity shape.Furthermore, MI and IHD showed significantly larger least axis of the LV myocardium at end-systole compared to controls, indicating a greater thickness of the myocardial wall in these conditions compared to healthy cases. Such changes were significantly greater in MI subjects compared to those with cerebrovascular diseases.Thus, both IHD and cerebrovascular diseases had a more spherical LV shape. For IHD and MI, there was also significantly greater thickness of the LV myocardium and in general more prominence of shape alterations in the radiomics signature than with cerebrovascular disease.For both IHD and cerebrovascular disease, intensity-features appeared important components of the radiomics signature, in particular skewness and kurtosis. All the disease categories considered had significantly less variation in signal intensity levels (skewness) within the LV blood pool region compared to healthy controls. Similarly, all the disease categories also showed significantly less Kurtosis (“pointiness”) of the LV blood pool intensities compared to controls. These prominent differences in signal intensity patterns within the LV blood pool may reflect common alterations in intra-cardiac haemodynamic associated with both IHD and cerebrovascular disease.This study demonstrates that CMR radiomics can capture changes in cardiac morphology, tissue or local structure in ischaemic heart disease and cerebrovascular disease even when ischaemia has not resulted in organ damage in form of MI or stroke.Although conventional CMR indices identified some significant differences between the disease groups and the control, radiomics improved the quantification of alterations in both cardiac structure and tissue.Radiomics only and combined models provided similar incremental value over conventional indices in discriminating MI and IS from healthy. Such value remained significant, albeit to a lesser extent, in identifying changes in more heterogeneous clinical pictures, such as IHD and ischaemic cerebrovascular diseases. This finding suggests that, although the clinical presentation of cardiac and cerebral ischaemia may vary, there may be common cardiac alterations detectable on radiomic analysis.In particular, we observed that in cardiac ischaemia shape radiomics detected common changes in size and geometry of the LV and myocardium. In cerebral ischaemia, instead, the combination of shape, first-order and texture radiomics identified subtle alterations both in the geometry and tissue structure of the LV and myocardium, improving the disease discrimination significantly.Furthermore, it appeared that there was a notable overlap of the radiomics signatures of IHD and cerebrovascular disease. This finding may reflect common risk factors, such as cardiometabolic morbidities, or alternative shared biological pathways implicated in both conditions.The common cardiac alterations detected by radiomic features could represent the biological links between the brain and heart during the ischemic processes. Such alterations could also represent a valuable imaging marker for identifying individuals with previous cerebral ischaemia at risk of developing cardiac complications.Our study confirms the capacity of CMR radiomics to improve the accuracy of diagnosing important diseases over conventional image analysis.Previous studies have demonstrated the ability of radiomics to accurately diagnose myocardial infarction on non-enhanced images. For instance, Baessler et al.  showed tSimilarly, we found that radiomic analysis of cine CMR images allowed to discriminate MI from healthy comparators with significantly superior performance to conventional CMR indices.In contrast to the previous studies, in this work we analysed all three types of radiomic features. We found that in MI, shape radiomics were the most important feature in the classification models. Similar findings were observed in IHD group, which included a large spectrum of clinical conditions, that vary from stable angina to acute coronary syndrome (ACS).The analysis of shape features revealed similar changes in size, particularly in the long axis, and in the geometry of the LV myocardium, between IHD and MI.These findings might indicate that cardiac ischaemia, whether or not it results in organ damage, might lead to typical cardiac remodelling patterns that involve the LV globally.In all the clinical scenarios characterising IHD, the myocardial energy imbalance plays a central role in leading to ischaemia . We hypoTherefore, the radiomic signature for IHD may represent an additional non-invasive imaging marker of cardiac ischaemia. It might improve the diagnosis of a wide variety of conditions, including angina pectoris and silent ischaemia, without using late gadolinium enhancement (LGE) tecnique.Our study confirms also the potential of radiomics to identify cardiac changes associated with important conditions that do not affect the heart exclusively.We found that radiomic-based models provided high degrees of discrimination of ischaemic cerebrovascular disease and IS. In particular, we observed that the combination of shape, first-order and texture radiomics in the classification models led to the highest accuracy of diagnosis. Perhaps, intensity-based radiomics allowed more granular disctinction of cerebral ischaemia enhancing further the diagnostic value of the classification models.Similarly, Cetin et al.  found thIn particular, the median intensity of the myocardium and grey level non-uniformity were described as the single most discriminative radiomic to identify diabetes and current smokers, respectively.The grey level non-uniformity has been also described as the single most important feature in identifying hypertrophic cardiomyopathy (HCM) . InteresFinally, it should be noted that although some features were more representative than others, we observed that their combination significantly improved the diagnostic accuracy in each disease group. We speculate that the clinical and pathophysiological heterogeneity of the conditions examined might translate into a complex variety of subtle cardiac changes reflected in the observed features. Therefore, it was the combination of all these alterations that made a distinct signature for cardiac and cerebral ischaemia.CMR radiomics analysis uncovered common patterns of cardiac alterations in ischaemic heart and cerebrovascular diseases, which might represent the imaging markers of the biological interactions between brain and heart during the ischaemic processes.Such similarities might reflect shared cardiovascular risk factors involved in the common brain-heart disease crosstalk, probably mediated by atherosclerosis and arteriosclerosis .Furthermore, there is growing evidence suggesting that subjects who suffered cerebral ischaemic events might be highly vulnerable to cardiac complications, even in the absence of risk factors or pre-existing heart disease , 33. AltThis suggests that alternative mechanisms of brain-heart interactions, not mediated by shared risk factors, might be involved during the ischæmic processes. For instance, high circulating catecholamine level, sympathetic/parasympathetic unbalance, and stroke-related systemic inflammation mediated by cytokines, have been described as possible causes of brain damage-induced cardiac dysfunction. Other mechanisms involved in the associations include dysfunction of the hypothalamic-pituitary-adrenal axis, brain blood barrier damage, and gut microbiome dysbiosis , 35.Previous studies have suggested that endothelial inflammation, oxidative stress, and catecholamine release induced by ischaemic brain injury may lead to chronic myocardial dysfunction and remodelling, accelerating atherosclerosis, and vasoconstriction of the coronary arteries . FurtherWhether such cardiac dysfunctions are triggered by the ischaemic brain damage, are unrelated complications, or just the underlying causes is still unclear and require further investigations. Nevertheless, independently of the pathogenesis, these associated cardiac abnormalities may become the substrate of future cardiovascular events, such as heart failure or CAD, and further affect patients' outcome , 38.Cardiac imaging represents a valuable diagnostic tool for identifying the aetiology of cerebrovascular disease and detecting cardiac comorbidities. The main long-term cardiac abnormalities described on conventional images are the LV systolic and diastolic dysfunction, which in conjunction with the increased burden of arrhythmia, lead to cardiac remodelling .We found that cerebral ischaemia was associated mainly with changes in the geometry and tissue structure of the LV and myocardium, the latter affecting the cardiac texture appearance in CMR images. In particular, we found that individuals with ischaemic cerebrovascular disease had less heterogeneous myocardial tissue textures than healthy comparators. We may speculate that these features represent different levels of myocardial damage in these patients. Perhaps, the toxic effect of catecholamines on the myocardium and the subsequent neurogenic hypertension are two possible mechanisms that may lead to chronic myocardial dysfunction and remodelling .Such subtle cardiac alterations, especially at the tissue level, often remain undetected to traditional CMR metrics or echocardiography. In our study, CMR radiomics provided deeper image phenotyping than conventional indices improving detection of changes in cardiac structure and tissue associated with cerebral ischaemia, thus making the diagnosis more precise.Radiomics analysis might improve our understanding of cerebral ischemia's early effects on the cardiac structure and tissues. Identifying imaging markers of adverse brain-heart disease at an early stage may enable improved clinical management and reduce mortality in patients with previous cerebral ischaemia. These markers may represent a potential intervention target to mutually protect the heart after stroke and the brain from further damage. An integrated approach based on appropriate risk stratification and early screening for cardiac dysfunction, coupled with aggressive risk factor control and early treatment, is essential in managing patients with an ischemic event.To our knowledge, this is the first study using CMR radiomics to study the cardiac changes associated with cardiac and cerebral ischaemia. We used clinical and imaging information from the UKB dataset, which has extensive data available from each participant, making it an excellent resource to address brain-heart interactions. We used a combination of ICD-10 and ICD-9 codes to select our study populations to avoid concerns about the self-reported conditions' accuracy and objectivity. However, the estimated prevalence and diagnostic accuracy of certain conditions, such as angina or TIA, may be affected by the hospital information system and the quality of the documentation recorded.Furthermore, the identification of participants with MI was only based on the clinical diagnosis. However, further information on the myocardial scar extent was not available in the UKB dataset. Therefore, in this study we could not determine whether there was a correlation between the radiomic features and the myocardial scarring extent.There were fewer subjects with cerebrovascular disease and IS than those with IHD and MI. Therefore, despite the significant discriminatory power of radiomics-based models observed in cerebral ischaemic conditions, these results must be interpreted cautiously.Radiomics are highly dependent on image acquisition factors that can greatly modify texture and histogram-based intensity values. Different centres' datasets should be evaluated to confirm validity of these machine learning algorithms in a large-scale application.Furthermore, the number of radiomics needed to achieve better performances can be considered large. Despite the automatic and fast procedure to perform this test in a real clinical scenario, reduction of these subsets must be achieved in the future, to build more interpretable and explainable tools.We did not match the healthy comparators and the disease groups on a per-patient basis. Therefore, we must acknowledge that the higher proportion of females and the younger age of the healthy controls might have partially influenced the radiomic values and thus the disease prediction. However, these limitations were mitigated by the fact that the control subjects, according to the robust definition of “health” proposed by Petersen et al. , did notFinally, we did not study the correlation between radiomics and patients' risk factors and time from the ischaemic event, as that was beyond this paper's purpose. More extensive prospective studies using external validation cohorts and accounting for confounding factors are needed to determine these models' clinical utility.This study demonstrates the potential value of CMR radiomics over conventional indices in detecting subtle cardiac changes associated with chronic ischaemic processes involving the brain and heart, even in the presence of more heterogeneous clinical pictures. Radiomics analysis might improve our understanding of the effects of cerebral ischaemia on cardiac structure and tissue contributing to shed light on the complex brain-heart interactions.http://www.ukbiobank.ac.uk/register-apply/.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: This study was reviewed and approved by the NHS National Research Ethics Service  and extended on 10th May 2016 (Ref16/NW/0274). Written informed consent was provided by participants. The patients/participants provided their written informed consent to participate in this study.ER, SP, and KL conceived the idea and designed the study. ZR-E provided support on the clinical aspect of the study. PG and CI performed the radiomics analysis and designated the machine learning methods. KL supervised radiomics analysis. NA provided cardiac measures from automated analysis pipeline. ER wrote the manuscript. CI drafted the part relative to the machine learning and radiomic analysis. All authors contributed to the articles, read, and provided critical revision of the manuscript.www.bhf.org.uk; PG/14/89/31194). SP acknowledges support from the SmartHeart EPSRC programme grant . SP and ER also acknowledge support by the London Medical Imaging and Artificial Intelligence Centre for Value Based Healthcare (AI4VBH), which is funded from the Data to Early Diagnosis and Precision Medicine strand of the government's Industrial Strategy Challenge Fund, managed and delivered by Innovate UK on behalf of UK Research and Innovation (UKRI). NA was supported by a Wellcome Trust Research Training Fellowship . NA recognises the National Institute for Health Research (NIHR) Integrated Academic Training programme which supports his Academic Clinical Lectureship post. This work was partly funded by the European Union's Horizon 2020 research and innovation programme under grant agreement no. 825903 (euCanSHare project). KL received funding from the Spanish Ministry of Science, Innovation and Universities under grant agreement RTI2018-099898-B-I00.ZR-E is supported by a British Heart Foundation Clinical Research Training Fellowship (FS/17/81/33318). SP acknowledges support from the National Institute for Health Research (NIHR) Biomedical Research Centre at Barts. SP acknowledge the British Heart Foundation for funding the manual analysis to create a cardiovascular magnetic resonance imaging reference standard for the UK Biobank imaging resource in 5,000 CMR scans (The views expressed are those of the authors and not necessarily those of the AI4VBH Consortium members, the NHS, Innovate UK, or UKRI.SP provides consultancy to and owns stock of Cardiovascular Imaging Inc, Calgary, Alberta, Canada. The remaining 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.


In Anderson–Fabry disease (AFD) the impact of left ventricular (LV) function on cardiac outcome is unknown. Noninvasive LV pressure–strain loop analysis is a new echocardiographic method to estimate myocardial work (MW). We aimed to evaluate whether LV function was associated with outcome and whether MW had a prognostic value in AFD. Ninety-six AFD patients  with normal LV ejection fraction were retrospectively evaluated. Inclusion criteria were sinus rhythm and ≥ 2-year follow-up. Standard echocardiography measurements, myocardial mechano-energetic efficiency (MEE) index, global longitudinal strain (GLS) and MW were evaluated. Adverse cardiac events were defined as composite of cardiac death, malignant ventricular tachycardia, atrial fibrillation and severe heart failure development. During a median follow-up of 63 months (interquartile range 37–85), 14 events occurred. Patient age, cardiac biomarkers, LV mass index, left atrium volume, E/Ea ratio, LV ejection fraction, MEE index, GLS and all MW indices were significantly related to adverse outcome at univariate analysis. After adjustment for clinical and echocardiographic parameters, which were significant at univariate analysis, GLS and MW resulted independent predictors of adverse events (p < 0.01). By ROC curve analysis, constructive MW ≤ 1513 mmHg% showed the highest sensitivity and specificity in predicting adverse outcome . MW did not improve the predictive value of a model including clinical data, LV diastolic function and GLS. LV function impairment (both systolic and diastolic) is associated with adverse events in AFD. MW does not provide additive information over clinical features and systolic and diastolic function. Anderson–Fabry disease (AFD) is an X-chromosome linked disorder caused by mutations in gene (GLA) coding for alpha-galactosidase-A enzyme . CardiacThe assumption that LV systolic pressure corresponds to brachial cuff systolic blood pressure (SBP) allows to noninvasively calculate indices of LV function such as myocardial work (MW) and MW efficiency. A method based on LV longitudinal strain by speckle-tracking echocardiography and noninvasive standardized LV pressure curve has been introduced as a promising tool for noninvasive measurement of MW –18. LikeIn the present study we aimed to investigate the association between cardiac involvement evaluated with different echocardiographic measurements of LV function and adverse cardiac events in AFD patients with normal ejection fraction. In particular, we sought to evaluate whether there was any predictive value of standard echocardiography parameters, including LV diastolic function indices, of GLS and of complex measurements such as MEE and longitudinal strain-based MW.This retrospective analysis included all consecutive patients with genetically proved AFD and normal LV ejection fraction referred to our institution between October 2006 and October 2016, provided that they had three available echocardiographic apical views allowing LV longitudinal strain analysis and at least 2-year clinical follow-up. Exclusion criteria were as follows: history of coronary artery disease, moderate or severe valve heart disease, permanent atrial fibrillation, diabetes mellitus, signs of overt heart failure, complete left bundle branch block, past pacemaker/defibrillator and suboptimal echocardiographic image quality.Ninety-six patients were included in the study . Data on clinical findings and adverse cardiac events were abstracted from the electronic patient record. In details, clinical data including New York Heart Association (NYHA) class, estimated glomerular filtration rate (eGFR), biomarkers values such as N-terminal brain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-TnI) obtained within 2 weeks from echocardiography were utilized for the analysis. Chronic Kidney Disease Epidemiology Collaboration equation was used to calculate eGFR from serum creatinine values . The InsThe whole study population had two-dimensional transthoracic echocardiography, including color Doppler, pulsed-wave and continuous-wave Doppler and mitral annulus tissue Doppler at the initial evaluation. Echocardiography was performed with the use of a Vivid 7 ultrasound system  equipped with M4S transducer. Apical long-axis and two- and four-chamber views obtained with the highest possible frame rates ) were utilized to evaluate LV longitudinal strain. Cuff BP values, measured immediately at the end of echocardiogram with the patient in the recumbent position, were also obtained.2.7 in women and at least 50 g/m2.7 in men, respectively [Standard echocardiography analysis was performed according to American Society of Echocardiography , as prevectively .LV end-diastolic (EDV) and end-systolic (ESV) volumes  were measured by the modified Simpson rule. Stroke volume (SV) was calculated as the difference between LVEDV and LVESV and ejection fraction was obtained as the ratio between SV and LVEDV. Stroke work (SW) was computed as echocardiographic SV times SBP, where SBP is the value of systolic BP taken by cuff sphygmomanometer immediately after echo exam . MEE, whs in 1 s .Speckle-tracking echocardiography analysis and strain-derived MW measurement were performed offline by using dedicated software . Tracking of myocardial motion was performed with the region of interest adjusted to exclude the pericardium by attentively aligning the epicardial border. The integrity of tracking was visually confirmed as well as ascertained from the credibility of the strain curves, in addition to the automated tracking detection in the software. By analyzing LV according to a 17-segment model, GLS was calculated by averaging segmental longitudinal strain measured in 2-, 3-, and 4-chamber apical views. MW and related indices were obtained through a combination of LV longitudinal strain and non-invasively estimated LV pressure curves. Peak systolic LV pressure is assumed to be equal to the peak SBP measured from brachial cuff based noninvasive method immediately at the end of the echocardiographic study. The software can construct a non-invasive LV pressure curve adjusted according to the duration of the isovolumetric and ejection phases defined by the timing of aortic and mitral valve events by echocardiography. Strain and pressure data are then synchronized using the R wave on ECG as a common time reference. Global work index (GWI) was obtained as total work within the area of the pressure–strain loop, calculated from mitral valve closure to mitral valve opening. Moreover, additional indices of MW were calculated as follows: global constructive work (GCW) as the work performed during shortening in systole adding negative work during lengthening in isovolumetric relaxation; global wasted work (GWW) as the work performed during lengthening in systole and shortening in isovolumic relaxation and was associated with energy loss; global work efficiency (GWE) as the ratio between constructive work divided by the sum of constructive and wasted work. A single principal operator performed MW analysis in the present study. To assess the intra-observer and inter-observer reproducibility, MW measurements of 16 randomly selected patients were re-evaluated after 1 month from the initial analysis by the same principal operator blinded to the previous results and by a second observer blinded to the results of the principal operator. Intra-observer and inter-observer agreements were assessed by intraclass correlation coefficient (ICC) with 95% confidence interval (CI). The ICC chosen was of single measures and absolute agreement with random effect.Composite endpoint was the occurrence of fatal and non-fatal major adverse cardiac events as follows: (1) sustained ventricular tachycardia defined as consecutive beats arising below the atrioventricular node with an RR interval of < 600 ms and lasting ≥ 30 s, requiring hospital admission or identified by Holter monitoring, which was performed every one year, by internal protocol, or (2) newly diagnosed atrial fibrillation, or (3) severe heart failure defined as the development of New York Heart Association functional class III/IV symptoms, or (4) cardiac death, classified as sudden or heart failure related death. Patients without events were censored at the time of their last clinical follow-up. Medical records and death certificates of all patients who had an event were obtained and validated by a physician unaware of echocardiography evaluations. According to selection criteria, the minimum follow-up period was 24 months. For patients who had more than 1 event, only the first was considered for the analysis.2 or t test for unpaired samples, as appropriate.Statistical analyses were performed using SPSS version 25.0  and MedCalc version 12.7 . Variables were expressed as absolute number and percentage, mean ± SD, or median (interquartile range). Comparisons were made by χUnivariate and multivariate  Cox proportional hazard analyses were performed to verify if clinical, laboratory and imaging features were associated with the occurrence of cardiovascular events.To identify the threshold level that provided the best cutoff for outcome prediction, we chose the value in which the sum of specificity and sensitivity was the highest. This value was obtained by receiver-operating characteristic (ROC) curve analysis. The C statistic was used to assess the ability to classify risk. Kaplan–Meier survival curves and the log-rank test were used for visualization of cumulative event-free survival and estimate of probability values.The incremental value of LV function as assessed by MEE index, GLS and MW indices in addition to clinical factors and standard echocardiography parameters was assessed with the use of the Cox proportional hazard model and a stepwise fashion.All statistical tests were 2-sided. For all tests, a p value < 0.05 was considered statistically significant.Clinical and imaging characteristics of the entire study population and according to sex are summarized in Table Sixteen patients (16.6%) were treated with enzyme replacement therapy (ERT) at baseline evaluation, with mean treatment duration of 6.0 ± 4.1 years, while 59 patients (61.4%) initiated ERT during follow-up. Patently, the percentage of patients receiving ERT was higher among male than female patients, either at first evaluation or during follow-up. Eighty-four patients were classified as NYHA class 1 and 12 patients as NYHA class 2.Male patients had worse LV GLS as compared to females, but similar MEE index values. Although no difference in GWW between male and female patients was observed, GCW, GWI and GWE were significantly lower in males Table . The latOf note, the intra-observer agreement between 2 repeated evaluations of MW work was excellent for all the parameters . The inter-observer agreement was also good to excellent .During a median follow-up of 63 months (interquartile range 37–85 months), 14 adverse cardiac events were detected. Two patients experienced severe heart failure and 2 patients heart failure-related death . Six patients had implanted cardioverter-defibrillator for sustained ventricular tachyarrhythmia. Of note, two of them died within the first year after implant. They were a 55 years-old man who had been under ERT over the last 12 years and a 50 years-old man who had been diagnosed with AFD at age of 40 years, respectively. Four patients developed permanent atrial fibrillation. Seven out of 14 patients experiencing adverse cardiac events had been classified as NYHA class 2.Table Figure Table By Cox regression analysis, we found that both LV mass and diastolic dysfunction showed an additive prognostic value in detecting AFD patients at risk over a model containing clinical features such as patient age, eGFR, NT-proBNP and hs-TnI levels Fig. . The modThe main results of the present study including AFD patients with normal LV ejection fraction can be summarized as follows: (1) both LV systolic function impairment and diastolic dysfunction are associated to the risk of adverse cardiac events; (2) after adjustment for clinical and standard echocardiography variables, LV GLS and MW indices are independently associated with adverse cardiac outcome; (3) any MW parameter does not improve the predictive value of a model including clinical features, LV mass assessment, LV diastolic function and GLS.According to Fabry registry data, cardiac events are the most common adverse events in AFD patients , 25, eveOur study supports LV hypertrophy as a risk factor associated with cardiovascular events , 26 and,The incremental value, albeit modest, of GLS over LV mass and diastolic function in addition to clinical risk factors, claims a role for LV systolic longitudinal function in determining cardiac prognosis of AFD patients. In principle, MW, as assessed by noninvasive LV pressure–longitudinal strain curves, is superior to myocardial strain in evaluating LV systolic function. It indeed takes in account deformation as well as afterload and strictly correlates with the equivalent invasive work measurement, as demonstrated in both experimental and clinical studies , 16. In It is conceivable that intrinsic impairment of myocardial function might impact on the prognosis of AFD patients. Our findings seem to indicate that LV longitudinal strain as well as strain-derived MW can foresee risky condition more accurately than stroke volume based functional measurements, given that MEE index, which was associated with adverse events at univariate analysis, lost any predictive value at multivariate analysis including clinical and standard echocardiography parameters. Longitudinal strain indeed reflects intrinsic myocardial function more closely than measurements based on traditional parameters as it evaluates the active component of deformation . HoweverEven with caution due to the relatively small sample size, our results indicate that the use of a cluster of factors such as patient age, cardiac biomarkers, LV mass, diastolic dysfunction and GLS strain can provide valuable criteria for identification of risky AFD patients.By exploring the additive prognostic value of MW over demographic and bio-humoral data and standard echocardiography measurements, we were able to demonstrate that MW indices can identify with high accuracy risky patients in the setting of AFD and provide information comparable to that obtained by clinical features, LV hypertrophy and diastolic function. This is an undoubtably important issue as MW assessment is not available from most vendors.Several potential limitations should be acknowledged. Given the single center nature of the study and the rarity of disease, the number of included patients can be considered small. Although comparable to other studies addressing cardiac prognosis in AFD , 41, theThe use of assumptions and composite measurements to obtain some complex echocardiographic parameters might represent another potential limit for interpretation of the results. Indeed, measurement errors may accumulate by successive approximations and assumptions. Also, MW should preferably be calculated by stress-strain loop area and not by pressure–strain loop area. Given that the risky group had increased LV wall thickness the actual MW might be lower than what is reported in our study. Furthermore, we acknowledge that results reflect a best-case scenario as we calculated optimal cut-off points and tested these in the same AFD patient cohort. It would be preferably to externally validate the calculated cut-off points in a larger independent cohort of AFD patients.A further potential limitation might arise from the fact that the potential predictive information provided by myocardial fibrosis had not been addressed, since cardiac magnetic resonance was not available for every patient included in the study. However, studies utilizing analysis of myocardial late gadolinium enhancement (LGE) in AFD patients found that more extensive LGE certainly places patients in a higher-risk category, but that the presence of LGE alone does not necessarily imply a poor outcome , 41. MorResults of the present study demonstrate that echocardiography is a risk stratification tool to assess prognosis in AFD patients with normal LV ejection fraction. Firstly, LV diastolic dysfunction in association with demographic data and cardiac biomarkers can depict an adverse risk profile for cardiac events. Secondly, GLS and MW appear to be good predictors of poor cardiac outcome. However, data need to be further explored in larger AFD populations, potentially by multicenter studies. If confirmed, they would provide clinicians useful tools in AFD management to delineate risk profile and address a patient tailored treatment.


Stress cardiomyopathy is typically a diagnosis of exclusion after appropriate rule out of other etiologies of ventricular dysfunction. It most commonly affects the left ventricle (LV). It rarely affects the right ventricle (RV) alone. Here we present a rare clinical dilemma in the setting of cardiac arrest, which occurred in the setting of a stressful event where the final diagnosis ended up being right ventricular takotsubu cardiomyopathy. Stress cardiomyopathy usually involves the left ventricle (LV) and is typically a diagnosis of exclusion . When weA 72-year-old female with a history of asthma was admitted to the hospital after experiencing pulseless electrical activity (PEA) cardiac arrest. It all started after a stressful family fight; 30 minutes later, the patient passed out and had no pulse. Emergency medical service (EMS) arrived with the reported downtime of 10 minutes, followed by return of spontaneous circulation (ROSC).On arrival at the hospital, she was shocked, requiring norepinephrine. EKG showed non-specific ST segment and T wave changes, as shown in Figure She was started on therapeutic heparin and was off vasopressors within 48 hours. A ventilation-perfusion scan was done 24 hours later, which showed intermediate probability, so it did not prove or rule out the possibility of pulmonary embolism. Duplex venous lower extremities were negative. Repeat echocardiogram after 72 hours showed that the right ventricular dysfunction had resolved. After the AKI resolved, CT PE was done, which was negative for pulmonary embolism. This was followed by a coronary angiogram which was non-revealing.Now given reversible RV dysfunction in the setting of negative CT PE and a clean coronary angiogram, a diagnosis of RV takotsubu cardiomyopathy was presumed.Stress cardiomyopathy is transient regional systolic dysfunction with poorly understood pathophysiology . The mos1. Transient left ventricular (LV) systolic dysfunction.2. Absence of obstructive coronary disease.3. New electrocardiographic abnormalities or modest elevation in cardiac troponin.4. Absence of pheochromocytoma or myocarditis.The applicability of the mayo clinical diagnostic criteria to our case is not very practical as with isolated RV dysfunction, ruling out pulmonary embolism is critical, particularly in the setting of cardiac arrest.It is imperative to delineate that suspicion of stress cardiomyopathy should not delay managing the case as an acute coronary syndrome or pulmonary embolism as stress cardiomyopathy is typically a diagnosis of exclusion. The most common variant of takotsubu cardiomyopathy is apical left ventricular; other rare variants include mid-ventricular, basal, focal, and global variants . IsolateThe management of takotsubu cardiomyopathy is purely supportive, with particular emphasis on the pathophysiology of the shock state. For example, when stress cardiomyopathy is in the left ventricle, sometimes the mechanism of the shock is left ventricular outflow tract obstruction attributable to hypercontractile basal segments rather than related to the poor cardiac pump , while wThe case serves as the first report for cardiac arrest as a presentation for isolated RV takotsubu cardiomyopathy. Till now, isolated RV takotsubu is not identified as a separate entity or subtype of stress cardiomyopathy but instead as a concomitant to LV dysfunction in some cases. Also, CT pulmonary angiogram is not a prerequisite in the guidelines for diagnosing takotsubu cardiomyopathies. Both of the above will need to be addressed in updated guidelines to make it easier for clinicians to diagnose this condition.


Level of Difficulty: Advanced.)Cell therapy is a promising tool to prevent and treat heart failure in congenital heart disease. We report the first case of intramyocardial injection of allogeneic mesenchymal stromal cells as rescue therapy in a neonate with ischemic heart failure following arterial switch procedure for isolated transposition of the great arteries. (  Intraoperatively, the left coronary artery (LCA) was found to have a long intramural course. The patient developed acute left ventricular (LV) dysfunction after separation from cardiopulmonary bypass. Refashioning of the LCA button was attempted, supplemented by a coronary artery bypass graft . Venoarterial extracorporeal membrane oxygenation was instituted before transferring the patient to the intensive care unit and successfully discontinued on post-operative day 6.The patient had been born at 39 + 2 weeks of gestation by normal vaginal delivery and had developed oxygen desaturation (50% despite fraction of inspired oxygen of 100%) and hypotension  at 6 h of life. He had then been diagnosed with transposition of the great arteries with intact ventricular septum. Percutaneous balloon atrial septostomy had been undertaken and surgery had been planned.Acute intraoperative heart failure during the arterial switch operation is virtually always caused by myocardial ischemia related to suboptimal coronary transfer. Severe pulmonary vascular disease is an uncommon cause of right ventricular failure, which was not the case in this patient, who had isolated LV dysfunction.Coronary angiography on post-operative day 2 showed LCA and internal mammary artery occlusion. Angiography was repeated on post-operative day 50, confirming the LCA occlusion and demonstrating only modest collateral circulation from the right coronary artery . Serial Over the first 2 post-operative months, the patient developed inotrope- and ventilator-dependent LV systolic dysfunction, with failure to thrive and echocardiographic signs of anterolateral LV ischemic injury, including anterior wall akinesia, a small anterior wall LV aneurysm, and basal to mid anterior wall hyperechogenicity.The patient was deemed suitable for intramyocardial injection of allogeneic mesenchymal stromal cells (MSCs). The treatment was approved on a compassionate basis by the University Hospital Bristol and Weston NHS Foundation Trust.The Centre for Cell, Gene and Tissue Therapeutics  provided pharmaceutical-grade MSCs. The MSCs were derived from a single umbilical cord, supplied by the Anthony Nolan Cord Blood Bank from a registered volunteer cord blood donor procured under Human Tissue Authority license. Umbilical cord tissue-derived MSCs were isolated by plastic adherence, expanded, and cryopreserved until the day of administration; they were tested for purity , sterilMSC injection was undertaken on post-operative day 60. The anterolateral LV wall was accessed via a small left anterior thoracotomy. The target dose of 3 million cells/kg body weight was administered with 4 separate subepicardial injections following a technique previously used in patients with hypoplastic left heart syndrome (HLHS) . The patLV ejection fraction was 58% after extracorporeal membrane oxygenation discontinuation and had deteriorated to 23% at MSC injection despite inotropic support. After MSC injection, LV function was monitored mainly with LV fractional area change and LV global longitudinal strain. Coronary artery abnormalities remain a surgical challenge when performing the arterial switch operation, increasing surgical morbidity and mortality because of myocardial ischemic injury .Cell therapy can be delivered in different ways according to 3 main parameters. First, a cell type must be selected. To date, umbilical cord cells, peripheral blood or bone marrow–derived mononuclear cells, cardiac stem cells, and MSCs have been used clinically in congenital heart disease (CHD). MSCs can be easily isolated from different tissues and expanded in vitro, have intrinsic differentiation potential, and show marked modulatory properties that are thought to enhance the host’s regenerative processes, which is believed to be more important than the MSC expansion itself. It is known that MSCs can stimulate recovery from cardiac injury through paracrine activity, promoting reduction of fibrosis, neovascularization, immunomodulation, and stimulation of endogenous tissue regeneration .Second, the selected cells can be of autologous or allogeneic origin. The main theoretical advantage of autologous cells is their immunologic compatibility; nevertheless, there is little evidence that allogeneic MSCs, which express low levels of major histocompatibility complex class I and lack major histocompatibility complex class II antigens, induce alloantibodies. In contrast, the immediate availability of allogeneic cells renders them more feasible in an urgent setting. Moreover, the recent POSEIDON-DCM (Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis in Dilated Cardiomyopathy) randomized trial showed superiority of allogeneic MSCs over autologous MSCs in an adult cohort of patients with dilated cardiomyopathy, possibly due to better modulatory properties .Third, the route of delivery must be chosen; to date, intramyocardial and intracoronary administration have been undertaken clinically .Cell therapy has been used in preclinical models of CHD and showed initial promising results in patients with hypoplastic left heart syndrome ,7, 8, 9.MSC injection does not resolve the culprit coronary lesion, and the exact mechanism of action in this particular patient cannot be precisely demonstrated. However, we observed a correlation between MSC injection and the patient’s clinical improvement; the rationale behind this specific application is that boosts of MSCs may aid the ischemic myocardium, thanks to their acknowledged proangiogenic activity.One year after arterial switch, the patient remains on oral heart failure therapy with no clinical signs of ongoing myocardial ischemia, and he has been growing along the ninth weight centile. LV function is mildly impaired .Cell therapy is an emerging therapeutic strategy in patients with CHD. Its medium- and long-term results are not known, and further studies are needed to delineate potential candidates and outcomes in the pediatric population.This work was funded by the British Heart Foundation, the Sir Jules Thorn Award for Biomedical Research, and the Enid Linder Foundation. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.


Cancer therapy-related cardiac dysfunction (CTRCD) is a relevant clinical problem and needs early prediction. This study aimed to analyze myocardial injury using serial laboratory and cardiac magnetic resonance imaging (CMR) parameters after epirubicin-based chemotherapy compared with left-sided radiotherapy and to study their value for early prediction of CTRCD.n = 39 with epirubicin-based chemotherapy and n = 27 with left-sided radiotherapy were prospectively studied by 3 T CMR including left ventricular (LV) mass and volumes for ejection fraction (LVEF), as well as feature-tracking with global longitudinal strain (GLS) and T1/T2 mapping. CMR was performed at baseline, at therapy completion , and after 13 ± 2 months (FU2). CTRCD was defined as LVEF decline of at least 10% to < 55% or a > 15% GLS change at FU2.Sixty-six consecutive women (53 ± 13 years) including p = 0.005) with excellent sensitivity , but low specificity . Combined use of increased T1 and LVEF ≤ 60% at FU1 improved AUC to 0.810 (0.695–0.896) resulting in good sensitivity  and specificity .T1 and T2 increased at FU1 after epirubicin-based chemotherapy, but not after left-sided radiotherapy. CTRCD occurred in 20% of patients after epirubicin-based chemotherapy and in 4% after left-sided radiotherapy. T1 at FU1 was the best single parameter to predict CTRCD with an area under the curve (AUC) of 0.712  occurred in 20% of patients after epirubicin-based chemotherapy and in 4% after left-sided radiotherapy.• Combined use of increased T1 and reduced LVEF had an AUC of 0.810 (0.695–0.896) to predict CTRCD with good sensitivity  and specificity .• The online version contains supplementary material available at 10.1007/s00330-021-08260-7. The standard of care in early breast cancer, which has not spread beyond the breast or the axillary lymph nodes, includes systemic anthracycline-based chemotherapy and/or radiotherapy , 2. A tyCardiac magnetic resonance imaging (CMR) allows accurate detection of myocardial injury using novel T1 and T2 mapping techniques, which detect myocardial edema related to acute injury , 7. A reThe aims to prospectively analyze myocardial injury using serial T1/T2 mapping CMR and laboratory parameters after epirubicin-based chemotherapy compared with left-sided radiotherapy and to study the value of these parameters for early prediction of CTRCD.2) combined with cyclophosphamide (600 mg/m2) and 12 cycles of paclitaxel (80 mg/m2) according to current guidelines [n = 15, 38%) or after chemotherapy . FU2 CMR was acquired in group 1 at 13 ± 2 months after BL CMR.The local ethics committee approved the study PV5292) and all women gave their written informed consent. Women with breast cancer were prospectively recruited between October 2016 and October 2017  with left-sided breast cancer, who were treated with initial surgery followed by left-sided radiotherapy lasting for 1.2 ± 0.4 months . The CMR protocol included a cine short-axis stack for LV volumes, mass, and function assessment using a standard steady-state free-precession (SSFP) sequence. T2 mapping was performed using a free-breathing navigator-gated black-blood prepared gradient and spin-echo (GraSE) hybrid sequence in three short-axis slices  . T1 mapp 5500 ms . Ten min 5500 ms . DetailsTwo investigators (M.A. and S.S.) independently and blindly analyzed each CMR in random order using CVi42 software (Circle Cardiovascular Imaging Inc). Parameters were indexed to the body surface area (BSA). Evaluation of LV and right ventricular (RV) volumes and LV mass was performed in standard fashion . To measMyocardial strain was analyzed on cine CMR images using Segment feature-tracking software version 2.1.R.6108 (Medviso) . In shorPresence of cancer therapy–related cardiac dysfunction (CTRCD) was defined as a decline in LVEF of at least 10 to < 55% or a > 15% GLS change at FU2 CMR , 15.p < 0.05.Statistical analysis was performed using MedCalc for Windows, version 13.3.3.0 , and SPSS for Windows, version 21.0 (IBM SPSS Statistics). All CMR data are given as the mean of two observers. Continuous data are presented as mean ± SD and categorical data are presented as absolute numbers and percentages. A mixed model was applied to analyze changes in the obtained parameters with time and pairwise comparison. A receiver-operating characteristic (ROC) analysis was performed to evaluate the performance of the obtained values at FU1 to predict the occurrence of CTRCD at FU2 by calculating areas under the curve (AUC) and optimal cut-off values from the ROC curves using the Youden-index. Statistical significance was defined as Patients with epirubicin-based chemotherapy had higher weight, body mass index (BMI), and body surface area (BSA) compared to patients with left-sided radiotherapy Table . Cancer p = 0.04) and remained increased at FU2 with 8 ± 11 pg/ml (Table p < 0.001) and 45 ± 3 ms (p < 0.001) respectively, indicating the presence of myocardial edema  and FU2 (p = 0.01 for both) with less negative strain values of − 17 ± 2% and − 17 ± 3% compared to baseline with − 18 ± 2% and − 18 ± 2%, respectively (Table p = 0.52), excluding diffuse myocardial fibrosis. There was no indication that trastuzumab had additional cardiotoxic effects (Table n = 34) and with trastuzumab treatment (n = 5) were similar at all times.High sensitive troponin T increased after epirubicin-based chemotherapy from 5 ± 4 to 8 ± 4 pg/ml (ts Table . Laboratp < 0.04) and normalized at FU2 (Table High sensitive troponin T slightly increased after left-sided radiotherapy to 6 ± 3 pg/ml at FU1 (CTRCD occurred at FU2 in 8 of 39 patients (20%) after epirubicin-based chemotherapy and in one of 27 patients 4%) after left-sided radiotherapy, resulting in a total number of 9 of 66 patients (14%) with CTRCD. High sensitive troponin T and T1 and T2 increased in both groups at FU1 and normalized at FU2 (Table % after lp = 0.005) and 0.712 (p = 0.07), respectively  T1 and T2 relaxation times increased after epirubicin-based chemotherapy, but not after left-sided radiotherapy. (2) CTRCD occurred at FU2 in 20% of patients after epirubicin-based chemotherapy, but only in 4% after left-sided radiotherapy. (3) Myocardial T1 after therapy completion was the best single parameter to predict CTRCD with an AUC of 0.712 and excellent sensitivity of 100% (66–100%), but low specificity of 44% (31–58%). (4) The combined use of T1 and reduced LVEF ≤ 60% at FU1 improved the AUC to 0.810 resulting in good sensitivity of 78% (44–95%) and improved specificity of 84% (72 − 92%).Galán-Arriola et al recently showed in an animal study that increased T2 is the earliest imaging marker of doxorubicin-related cardiotoxicity . T2 incrOur study in humans confirms and extends the knowledge about the value of T2 and T1 to detect chemotherapy-related myocardial injury. Interestingly, we found a more pronounced increase in T1 compared to T2 in our patients with chemotherapy. This finding is most likely related to the fact that we performed the first follow-up CMR 2 weeks after chemotherapy completion, which was given for 5 months, whereas Galán-Arriola et al performed weekly CMR . We presThe CTRCD frequency of 20% after chemotherapy is well in line with a recent meta-analysis, which reported a cardiotoxicity frequency of 17% with the highest risk in the high-dose chemotherapy subgroup with 19.6% . The occOur study showed that T1 and GCS at FU1 were the best single parameters to predict CTRCD at FU2 with good AUCs of 0.712. T1 was characterized by excellent sensitivity of 100%, but low specificity of 44%. Conversely, GCS resulted in a balanced sensitivity of 67% and specificity of 75%. Interestingly, blood parameters of myocardial injury such as high sensitive troponin T and NT-proBNP had lower AUCs compared to T1 and GCS, indicating that the increase of these laboratory parameters is an epiphenomenon of chemotherapy and radiation, but they have limited value to identify CTRCD. This is in line with a recent meta-analysis on the use of troponins and NT-proBNP for cardiotoxicity prediction after chemotherapy reporting similar sensitivity of 69%, but higher specificity of 87% for troponins and limited predictive value of NT-proBNP . InteresHowever, the combined use of increased T1 and reduced cardiac function by LVEF ≤ 60% at FU1 increased the diagnostic accuracy and AUC was 0.810. The combination of T1 and LVEF ≤ 60% resulted in balanced sensitivity (78%), specificity (84%), and accuracy (83%).The sample size is relatively small. However, this prospective and consecutive study adds to the body of evidence on cardiotoxic effects of cancer therapy in humans and evaluates the predictive value of CMR. Second, our findings are confined to the chemotherapy and radiotherapy applied in this study.This prospective CMR study revealed that myocardial T1 and T2 relaxation times increase after epirubicin-based chemotherapy in breast cancer patients, but not after left-sided radiotherapy, indicating the presence of chemotherapy-induced myocardial toxicity. Follow-up 2 CMR at 13 months revealed that 20% of chemotherapy patients developed CTRCD supporting the notion that the observed myocardial injury was associated with LV dysfunction. Conversely, left-sided radiotherapy did not result in increased T1 or T2 and only a small fraction of patients (4%) developed CTRCD later on. ROC analysis revealed that myocardial T1 obtained after therapy completion was the best single parameter to predict CTRCD with an AUC of 0.712 and excellent sensitivity (100%), but low specificity (44%). The combined use of T1 and reduced LVEF ≤ 60% at FU1 improved the AUC to 0.810 resulting in balanced sensitivity (78%), specificity (84%), and accuracy (83%). Therefore, functional and mapping analysis by CMR enables monitoring of chemotherapy-related cardiotoxicity and CTRCD prediction.Supplementary file1 (DOCX 58 KB)Below is the link to the electronic supplementary material.


O treinamento de caminhada (TC) melhora a capacidade de caminhar e reduz a pressão arterial (PA) clínica em pacientes com doença arterial periférica (DAP), mas seus efeitos na PA ambulatorial permanecem desconhecidos.Investigar o efeito de 12 semanas de TC na PA ambulatorial e sua variabilidade em pacientes com DAP.24), o desvio-padrão ponderado de vigília e sono (DPvs) e a variabilidade real média de 24 horas (VRM24). Os dados foram analisados por ANOVAs mistas de dois fatores, considerando significativo P<0,05.Trinta e cinco pacientes do sexo masculino com DAP e sintomas de claudicação foram alocados aleatoriamente em dois grupos: controle  e TC . Antes e depois de 12 semanas, a PA ambulatorial de 24 horas foi avaliada. Os índices de variabilidade da PA ambulatorial avaliados em ambos os momentos incluíram o desvio-padrão de 24 horas . Nenhum dos grupos apresentou mudanças significantesnos índices de variabilidade da PA diastólica após 12 semanas.Após 12 semanas, nenhum dos grupos apresentou alterações na PA de 24 horas, vigília e sono. O TC diminuiu as variabilidades da PA sistólica e média :898-905) A claudicação intermitente, o sintoma mais prevalente da doença arterial periférica (DAP), prejudica a capacidade de locomoção, afetando os níveis de atividade físicaDentre as doenças cardiovasculares, a hipertensão arterial é uma comorbidade frequente, afetando mais de 80% dos pacientes com DAP,Recentemente, demonstramos que o treinamento de caminhada (TC) supervisionado melhora a capacidade de caminhada e reduz a PA clínica de pacientes com DAP sintomática,,2; (e) PA sistólica em repouso <160 mmHg e PA diastólica <105 mmHg; (f) não estar tomando β-bloqueadores ou bloqueadores dos canais de cálcio não diidropiridínicos; (g) ausência de neuropatia autonômica cardiovascular nos pacientes diabéticos;Este é um dado complementar de um estudo anterior.O diagnóstico de DAP foi feito com base no histórico clínico e na medida do ITB em repouso e após teste máximo em esteira.O desenho experimental está descrito na Para todas as avaliações, as recomendações prévias incluíam a não realização de exercício vigoroso nas 48 horas anteriores, realização de uma refeição leve 2 horas antes, a não ingestão de alimentos com propriedades estimulantes como cafeína, bebida alcoólica ou o consumo de tabaco nas 12 horas anteriores. As avaliações clínicas foram realizadas pela manhã em um laboratório com temperatura controlada (20-22 °C).A monitorização ambulatorial da PA foi realizada com um aparelho oscilométrico não invasivo  posicionado no braço não dominante e programado para realizar medidas a cada 15 minutos durante 24 horas. A precisão do dispositivo foi confirmada por um esfigmomanômetro de mercúrio antes do uso.24); desvio-padrão ponderado em vigília e durante o sono (DPVS) e a variabilidade real média de 24 horas (VRM24). Esses índices foram calculados conforme relatado anteriormente.24 foi calculado pelo desvio-padrão (DP) ao longo de 24 horas ponderado pelo intervalo de tempo entre as medidas. DPvs foi calculado pela média de DP de vigília e sono corrigido para o número de horas de cada um desses períodos  / horas de vigília + horas de sono]. A VRM24 foi calculada pela média das diferenças absolutas entre as medições consecutivas, contabilizando a ordem de medição pela seguinte fórmula:Para a análise, os níveis ambulatoriais de PA sistólica, diastólica e média foram calculados pela média de todas as medidas realizadas por 24 horas, bem como durante os períodos de vigília e sono relatados pelo paciente. Além disso, a variabilidade da PA ambulatorial foi calculada para a PA sistólica, diastólica e média usando três índices diferentes:Onde k varia de 1 a N−1, PA o valor da pressão arterial e w é o intervalo de tempo entre PAk e PAk+1. N é o número de registros válidos da PA.Detalhes das intervenções foram relatados anteriormente.Conforme descrito anteriormente,A normalidade da distribuição dos dados e a homogeneidade da variância foram avaliadas pelos testes de Shapiro-Wilk e Levene, respectivamente. Distribuições que não atenderam aos critérios de normalidade foram normalizadas usando transformações logarítmicas. No início do estudo, as diferenças entre os grupos foram identificadas por meio do teste qui-quadrado  ou teste t de Student não pareado (variáveis contínuas). Os efeitos das intervenções foram avaliados pela ANOVA mista de dois fatores , tendo como fatores grupo (GC e GTC) e fase do estudo (início e 12 semanas). Teste post-hoc de Newman-Keuls foi usado quando necessário. O valor de p<0,05 foi considerado significante e os dados foram apresentados em média ± DP.O fluxograma de pacientes está representado na Esses grupos tinham características iniciais semelhantes quanto à idade, grau de obesidade, níveis clínicos de PA, limitações da doença, comorbidades e uso de medicamentos .Os níveis de PA ambulatorial foram semelhantes entre os grupos no início do estudo, e nenhum deles apresentou qualquer mudança significante na PA de 24 horas, vigília e sono após as 12 semanas de intervenção .24, DPvs e VRM24 da PA sistólica e média apenas no GTC , mostrando redução do DPs no GTC . Nenhum O principal achado deste estudo foi que 12 semanas de TC diminuíram os índices de variabilidade da PA sistólica e média, sem alterar os níveis de PA ambulatorial.No presente estudo, 12 semanas de TC não alteraram a PA ambulatorial em pacientes com DAP, o que contrasta com estudos realizados com indivíduos normotensos e hipertensos24, DPvs e VRM24. Esses resultados estão de acordo com estudo anterior com treinamento resistido em pacientes sintomáticos com DAP.,Apesar da ausência de alteração nos níveis de PA ambulatorial, foram observadas reduções nas variabilidades sistólica e média da PA ambulatorial para todos os índices de variabilidade: DPMesmo sem quaisquer alterações nos níveis de PA ambulatorial, a diminuição da variabilidade da PA ambulatorial obtida com o TC pode ter implicações clínicas relevantes. A variabilidade da PA tem sido associada à presença e progressão de lesões de órgãos alvo, bem como à incidência de eventos cardiovasculares,,Este estudo apresenta algumas limitações que devem ser reconhecidas. Foi realizado apenas com homens e as adaptações induzidas pelo treinamento podem diferir entre os sexos.Em conclusão, 12 semanas de TC diminui a variabilidade ambulatorial da PA em homens com DAP sintomática. Intermittent claudication, the most prevalent symptom of peripheral artery disease (PAD), impairs walking capacity, impacting on patient’s physical activity levelsAmong cardiovascular diseases, arterial hypertension is a common comorbidity that affects more than 80% of the patients with PAD,We have recently demonstrated that supervised walking training (WT) improves walking capacity in addition to reducing clinic BP in patients with symptomatic PAD,,2; (e) resting systolic BP ≤ 160 mmHg and diastolic BP ≤ 105 mmHg; (f) not taking β-blockers or non-dihydropyridine calcium channel blockers; (g) absence of cardiovascular autonomic neuropathy for diabetic patients;This is a complementary data from a previous study.Diagnosis of PAD was made based on clinical history and ABI measurement at rest and after a treadmill maximal test.The experimental protocol is shown in For all the assessments, recommendations included no vigorous exercise in the previous 48 hours, a light meal 2 hours before, no ingestion of food with stimulant properties such as caffeine, no alcoholic beverages or smoking in the previous 12 hours. Clinic assessments were conducted in the morning in a temperature-controlled laboratory (20-22°C).Ambulatory BP monitoring was performed with a noninvasive oscillometric device  placed on the non-dominant arm and programmed to perform measurements every 15 minutes for 24 hours. The accuracy of the device was confirmed by a mercury sphygmomanometer prior to use.24); the awake and asleep weighted standard deviation (SDdn), and the 24-hour average real variability (ARV24). These indices were calculated as previously reported. Briefly, SD24 was calculated by the standard deviation (SD) over 24 hours weighted for the time interval between measures. SDdn was calculated by the mean of awake and asleep SD corrected for the number of hours of each of these periods [i.e SDdn = [(awake SD x awake hours) + (asleep SD x asleep hours)]/(wake + asleep hours)]. ARV24 was calculated by the average of absolute differences between consecutive measurements accounting for the order of measurement using following formula:For the analysis, ambulatory systolic, diastolic and mean BP levels were calculated by the average of all BP measurements taken during the 24 hours as well as during the awake and asleep periods reported by the patient. In addition, ambulatory BP variability was calculated for systolic, diastolic and mean BP using three different indices:where k ranges from 1 to N−1, BP is the blood pressure and w is the time interval between BPk and BPk+1. N is the number of blood pressure readings.Details of the interventions have been previously reported.As previously described,Normality of data distribution and homogeneity of variance were evaluated using the Shapiro-Wilk and Levene tests, respectively. Skewed distributions were normalized using logarithmic transformations. At baseline, group differences were identified via chi-square test  or unpaired Student’s t-test (continuous variables). The effects of the interventions were assessed using a mixed two-way ANOVA , the groups being the between factor, and the study phase (baseline and 12 weeks) being the within factor. Newman-Keuls post-hoc tests were used when necessary. P<0.05 was considered significant, and data were presented as mean ± SD.Patients flowchart is shown in These groups had similar initial characteristics regarding age, obesity level, clinic BP levels, disease limitations, comorbidities, and medication use .Ambulatory BP levels were similar between WTG and CG at baseline, and neither group presented any significant change in 24-hour, awake and asleep BPs after the 12 weeks of intervention .24, SDdn, and AVR24 of systolic and mean BP in the WTG , showing a reduction in SD the WTG . NeitherThe main finding of this study was that 12 weeks of WT decreased systolic and mean BP variability indices without changing ambulatory BP levels.In the present study, 12 weeks of WT did not alter ambulatory BP in patients with PAD, which contrasts with studies with normotensive subjects and hypertensive patients24, SDdn and ARV24. These results are in accordance with a previous study with resistance training in symptomatic PAD patients.,Despite the absence of change in ambulatory BP levels, reductions in ambulatory systolic and mean BP variabilities were observed for all variability indices: SDEven without any changes in ambulatory BP levels, the decrease in ambulatory BP variability obtained with WT may have relevant clinical implications. BP variability has been associated with the presence and progression of subclinical organ damage as well as the incidence of hard endpoints such as cardiovascular events,This study has some limitations that should be acknowledged. It was conducted only with men, and training-induced adaptations may differ between genders.In conclusion, 12 weeks of WT decreases ambulatory BP variability in men with symptomatic PAD.


Hypertrophic cardiomyopathy (HCM) and primary restrictive cardiomyopathy (RCM) have a similar genetic background as they are both caused mainly by variants in sarcomeric genes. These “sarcomeric cardiomyopathies” also share diastolic dysfunction as the prevalent pathophysiological mechanism. Starting from the observation that patients with HCM and primary RCM may coexist in the same family, a characteristic pathophysiological profile of HCM with restrictive physiology has been recently described and supports the hypothesis that familiar forms of primary RCM may represent a part of the phenotypic spectrum of HCM rather than a different genetic cardiomyopathy. To further complicate this scenario some infiltrative (amyloidosis) and storage diseases (Fabry disease and glycogen storage diseases) may show either a hypertrophic or restrictive phenotype according to left ventricular wall thickness and filling pattern. Establishing a correct etiological diagnosis among HCM, primary RCM, and hypertrophic or restrictive phenocopies is of paramount importance for cascade family screening and therapy. Cardiomyopathies are a heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction, due to a variety of causes that are frequently genetic . They caMYH7, MYBPC3 , TNNT2, and TNNI3. The majority of patients reveal increased wall thickness by early adulthood . Sp. SpMYH7 reported . Probabl(TNNI3) variant [TNNT2), alpha cardiac actin (ACTC), myosin-binding protein C (MYBPC3), tropomyosin 1 (TPM1), and myosin light chain 2 (MYL2) and 3 (MYL3) [TNNI3, MYH7, and MYL2 variants were reported as responsible for some familial cases of HCM with “restrictive phenotype” (phenotypes diagnostic of RCM) [Primary RCM is a rare myocardial disease characterized by normal or decreased volume of both ventricles associated with biatrial enlargement, normal left ventricular wall thickness, impaired ventricular filling with restrictive physiology, and normal or near-normal systolic function . Since t variant , primary variant ,38,39,40 variant ,42,43,443 (MYL3) ,46,47,48 of RCM) . The coe of RCM) ,49. The phenotypic expression of other cardiomyopathies  may mimic primary RCM ,50,51. HThe key aspect of primary RCM is the impairment of the ventricular filling dynamics that ultimately lead to the increase of ventricular end-diastolic pressures and atrial dilation. Such diastolic impairment is responsible for the development of progressive heart failure symptoms . Cardiac catheterization shows increased ventricular filling pressures with the typical dip-and-plateau or square-root sign; left ventricular diastolic pressure is usually 5 mmHg higher compared to the right one due to imbalanced involvement and compliance of the two chambers . EqualizAs happened for all the other principal cardiomyopathies, before the understanding of molecular genetics of the disease primary RCM was referred to as “idiopathic” RCM . The larSome infiltrative and storage diseases may present as phenocopies of either HCM or primary RCM, according to the degree of hypertrophy observed and left ventricular filling pattern . If maxiHerein we describe the cardiomyopathies that can show either a hypertrophic or a restrictive phenotype. TTR gene that increase the likelihood of the TTR tetramer to dissociate into monomers and form amyloid fibrils. In the absence of TTR pathogenic variants, spontaneous dissociation of TTR tetramers may occur , determining ATTRwt amyloidosis (senile amyloidosis). AL amyloidosis is rare and has an estimated prevalence of 8 to 12 per million [TTR gene causing ATTRm amyloidosis are relatively rare but are endemic in some geographic regions  [Amyloidosis is a systemic syndrome that represents the archetype of the infiltrative form of RCM. Extracellular deposition of insoluble amyloid fibrils involves a variety of organs including the heart, leading to cardiomyocyte separation, cellular toxicity, and apoptosis. Overall, these morphological changes increase myocardial stiffness causing diastolic disfunction and heart failure. The three most common types of amyloidosis affecting the heart (“cardiac amyloidosis”) are AL, ATTRwt, and mutant transthyretin (ATTRm) amyloidosis. AL amyloidosis is a rare hematological disorder, in which there is an increased production of monoclonal kappa or lambda light chains that tend to misfold favoring tissue deposition. Transthyretin is a protein with tetrameric configuration, produced mainly in the liver; its monomers have amyloidogenic properties. ATTRm amyloidosis is a heritable autosomal disorder caused by variants in the  million ,60,61, a million . Variant Sweden) .n = 63) showed a mean left ventricular wall thickness  of ≤15 mm (range 11.5–15 mm), and the other two thirds >15 mm [Clinical presentation is useful, per se, in the differential diagnosis with sarcomeric cardiomyopathies, as patients with amyloidosis show variable extracardiac organ involvement. Peripheral and autonomic neuropathy, carpal tunnel syndrome, macroglossia, nephropathy, and hepatopathy are red flags for amyloidosis and should be sought in all patients . At the s >15 mm . A restrs >15 mm . Early ss >15 mm ,70. CMR s >15 mm ,72,73. Bs >15 mm . In the s >15 mm . Howevers >15 mm ,76.The treatment of amyloidosis goes beyond the purpose of the present review, but novel specific therapies improving cardiac and neurological outcomes have been recently approved and its recognition is therefore of paramount importance ,78. GLA gene, that determine an absent or deficient activity of lysosomal alpha galactosidase A. As a result, globotriaosylceramide accumulate within virtually all cell types’ lysosomes, leading to cellular death, inflammation, oxidative stress, and fibrosis; cardiomyocyte hypertrophy results from increased concentrations of sphingolipid and vascular smooth muscle cell proliferation [Fabry disease is a lysosomal storage disease with an X-linked recessive inheritance caused by variants in the feration . The preferation ,81. Indeferation . First sferation . In adulferation . Patientferation . Left veferation . Other dferation ,85. Arrhferation .GLA gene. In addition, endomyocardial biopsy can identify histological alterations by showing the accumulation of the degradation product of globotriaosylceramide in the sarcoplasm of myocytes, forming concentric lamellar bodies [The electrocardiogram often displays increased QRS voltages as the result of the deposition within the cardiomyocytes rather than in the interstitium as it occurs in infiltrative disease  characterized on the contrary by low QRS voltages. Other ECG changes that can be seen in Fabry disease patients include a short PR interval, sinus bradycardia, atrioventricular conduction disturbances, bundle branch blocks, pathologic Q waves, negative T waves, and atrial fibrillation ,83,87,88r bodies ,97. Althr bodies ,100,101.Glycogen storage diseases are a group of inherited genetic disorders that cause glycogen to be improperly accumulated in the body. Although they are listed as cardiomyopathies that can also have a restrictive phenotype ,51, patiPRKAG2 syndrome is another type of glycogen storage disease, whose presentation includes skeletal myopathy, marked cardiac hypertrophy, arrhythmias, and conduction defects . Left veThe heart is also part of the clinical spectrum of Pompe disease  . This diHCM and primary RCM have a similar genetic background as they are both sarcomeric cardiomyopathies, and significant phenotypic overlap can exist between them. Patients with HCM and primary RCM may coexist in the same family and a new category of HCM with restrictive physiology has been recently described. One hypothesis is that familiar forms of primary RCM may represent a part of the phenotypic spectrum of HCM rather than a different genetic cardiomyopathy. To further complicate this delicate scenario some infiltrative and storage diseases may show either a hypertrophic or restrictive phenotype (HCM and primary RCM phenocopies) according to left ventricular wall thickness and filling pattern. Establishing a correct diagnosis is of paramount importance for cascade family screening and therapy.