Fluid intelligence is arguably the defining feature of human cognition. Yet the nature of its relationship with the brain remains a contentious topic. Influential proposals drawing primarily on functional imaging data have implicated ‘multiple demand’ frontoparietal and more widely distributed cortical networks, but extant lesion-deficit studies with greater causal power are almost all small, methodologically constrained, and inconclusive. The task demands large samples of patients, comprehensive investigation of performance, fine-grained anatomical mapping, and robust lesion-deficit inference, yet to be brought to bear on it.We assessed 165 healthy controls and 227 frontal or non-frontal patients with unilateral brain lesions on the best-established test of fluid intelligence, Raven’s Advanced Progressive Matrices, employing an array of lesion-deficit inferential models responsive to the potentially distributed nature of fluid intelligence. Non-parametric Bayesian stochastic block models were used to reveal the community structure of lesion deficit networks, disentangling functional from confounding pathological distributed effects.F = 18.491; P < 0.001; frontal worse than non-frontal and healthy participants P < 0.01, P <0.001], more marked on the right than left . Patients with non-frontal lesions were indistinguishable from controls and showed no modulation by laterality. Neither the presence nor the extent of multiple demand network involvement affected performance. Both conventional network-based statistics and non-parametric Bayesian stochastic block modelling heavily implicated the right frontal lobe. Crucially, this localization was confirmed on explicitly disentangling functional from pathology-driven effects within a layered stochastic block model, prominently highlighting a right frontal network involving middle and inferior frontal gyrus, pre- and post-central gyri, with a weak contribution from right superior parietal lobule. Similar results were obtained with standard lesion-deficit analyses.Impaired performance was confined to patients with frontal lesions [Our study represents the first large-scale investigation of the distributed neural substrates of fluid intelligence in the focally injured brain. Combining novel graph-based lesion-deficit mapping with detailed investigation of cognitive performance in a large sample of patients provides crucial information about the neural basis of intelligence. Our findings indicate that a set of predominantly right frontal regions, rather than a more widely distributed network, is critical to the high-level functions involved in fluid intelligence. Further they suggest that Raven’s Advanced Progressive Matrices is a useful clinical index of fluid intelligence and a sensitive marker of right frontal lobe dysfunction. et al. investigate fluid intelligence in focally lesioned patients using an array of lesion-deficit models. Performance on Raven’s Advanced Progressive Matrices is impaired in patients with frontal but not non-frontal lesions, with right frontal lesions associated with greater impairments than left.Cipolotti  Each problem presents an incomplete matrix of geometric figures with a multiple choice of options for the missing figure. Less commonly, verbal tests of fluid intelligence such as Part 1 of the Alice Heim 4 (AH4-1)15 are adopted. The Wechsler Adult Intelligence Scale (WAIS)16 has also been used to estimate fluid intelligence by averaging performance on a diverse range of subtests. However, several subtests (e.g. vocabulary) emphasize knowledge, disproportionately weighting measures of ‘crystallized’ intelligence,18 whilst others (e.g. picture completion) have rather low fluid intelligence correlations.19 Hence, it has been argued that tests such as the APM are the most suitable for a theoretically-based investigation of changes in fluid intelligence after brain injury.21Fluid intelligence is traditionally measured with tests of novel problem-solving with non-verbal material that minimize dependence on prior knowledge. Such tests are known to have strong fluid intelligence correlations in large-scale factor analyses.22 have argued that a network of mainly frontal and parietal areas, termed the ‘multiple-demand network’ (MD), is ‘the seat’ of fluid intelligence. The highly influential parieto-frontal integration theory (P-FIT), based largely on neuroimaging studies of healthy subjects, posits that structural symbolism and abstraction emerge from sensory inputs to parietal cortex, with hypothesis generation and problem solving arising from interactions with frontal cortex. Once the best solution is identified, the anterior cingulate is engaged in response selection and inhibition of alternatives.24 Despite its name, P-FIT also posits occipital and temporal involvement, implying widely distributed substrates of fluid intelligence.25 A modification to P-FIT proposes a closer connection between frontal than parietal, regions and fluid intelligence-related processes,27 with the frontal lobes mediating high fluid intelligence ‘domain-independent’ executive processes whilst posterior areas, including the parietal lobes, mediating low fluid intelligence ‘domain-dependent’ processing of spatial, object, or verbal information.Proposals regarding the neural substrates of fluid intelligence have suggested close links with frontal and parietal functions. For example, Duncan and colleagues28 This frontoparietal attention network29 requires expansion to account for the separate neuronal substrate underpinning visuospatial/verbal analytical reasoning.31A meta-analysis of the functional imaging literature has implicated a network of modality-independent regions involving the inferior and middle frontal and inferior parietal lobes, with additional frontal eye field activation in non-verbal tasks, and anterior cingulate and left inferior frontal activation in verbal tasks.32 For example, though neuropsychological data commonly lateralize language to the left hemisphere,33 neuroimaging activation is often bilateral.34 So, merely considering the presence or absence of activation may hide lateralized functions. Hence, lesion studies offer an advantage in furthering our understanding of the neurocognitive architecture underpinning fluid intelligence. So far, these studies have been surprisingly sparse.An important caveat of the functional imaging findings is that they do not imply causal efficacy.35–43 For example, Weinstein and Teuber43 reported that veterans with left temporo-parietal entrance wounds suffered a decline in Army General Classification Test scores. Barbey and colleagues44 investigated Veterans’ performance on three subtests from the WAIS . The authors reported that performance was associated with damage to the superior longitudinal/arcuate fasciculus. However, several of the tests adopted are not considered fluid intelligence measures,45 and the lesion characterization was rather basic and lacked modelling of the diffuse axonal injury the traumatic aetiology implies.46 In the most recent of these studies, impaired WAIS performance, not a specific test of fluid intelligence, was associated with damage to left fronto-parietal regions and white matter association tracts.47 Glascher and colleagues48 reported that the left frontal pole was associated with performance on general intelligence (g) in a large sample of patients with stroke, encephalitis, temporal lobectomy and traumatic brain injury (TBI). Similarly, Browen and colleagues49 investigated performance in general intelligence using the WAIS in a sample of patients with similar pathologies, and reported an association with white matter tracts deep to the left temporo-parietal junction, including the arcuate fasciculus.Lesion studies investigating performance on fluid intelligence tasks have mainly enrolled veterans with penetrating head injury.51 However, Tranel and colleagues52 reported no significant differences between frontal and non-frontal damage on a non-verbal subtest of the WAIS analogous to the APM (Matrix Reasoning). Preserved performance on the WAIS has been documented in frontal patients.54 In contrast, the very few studies adopting tasks loading more heavily on fluid intelligence have reported frontal deficits. Duncan and colleagues20 documented a substantial discrepancy between scores on Scale 2 of Cattell’s Culture Fair and the WAIS in three frontal but not in five non-frontal patients. However, the very small sample limited generalizability and prevented investigation of laterality effects.Studies investigating patients with lesions caused by brain tumours or stroke have generally relied on WAIS as a measure of fluid intelligence, with inconclusive results. Some studies have associated WAIS non-verbal scale performance with right posterior damage.55 Compared with healthy participants, only right frontal damage significantly impaired APM performance, and only left frontal damage impaired AH4-1 performance. The relatively small sample prevented investigation of finer anatomical effects.In a recent study we documented lateralised frontal effects on APM and AH4-1.56–61 or impairment in left hemisphere patients63 or right hemisphere patients.56–65 Villardita66 reported no difference in the performance of left or right hemisphere patients on the Coloured Progressive Matrices version of APM. However, on Set I, involving visuoperceptual factors, right performed worse than left hemisphere patients. There is similar uncertainty about the influence of aphasia, thought by some to degrade performance,67 but not by others.60–69 Large samples of patients with focal unilateral lesions, thorough investigation of performance on the APM, fine-grained anatomical mapping, and robust lesion-deficit inference are vital for definitive scientific conclusions.Lesion studies investigating the underlying behavioural and anatomical aspects of the widely used APM are old, inconclusive, and lacking in anatomical analysis. Results have variously shown no difference between right or left hemisphere patientsn = 227; 146 frontal, 81 non-frontal) and 165 healthy participants on APM. We investigated overall performance, item difficulty, and relation to MD involvement. Building upon our novel multimodal methodology,70 we employed an array of lesion-deficit models responsive to the potentially distributed nature of fluid intelligence. We focused on modelling the anatomy of neural dependence as a graph, where interactions between distributed areas are explicitly tested. This approach permits delineation of distributed substrates. It also distinguishes functionally critical areas from those the distinctive pathological structure of lesions renders spuriously correlated: a problem shown to corrupt lesion-deficit maps based on simple mass univariate methods.71 In our approach each brain locus—intact or lesioned—is conceived as a node or vertex of a graph, with the relationships between loci—functional or merely lesion-pathology driven—defining its edges. This permits us to model network-dependence explicitly, disentangling functional and pathological effects to reveal the underlying substrate.Here we assessed the largest number of patients yet reported with focal, unilateral, right or left, frontal or non-frontal lesions 73; psychiatric disorders, history of alcohol or substance abuse, or other neurological disorders; and native English language proficiency. Age at assessment, gender, and years of education were recoded.Data from 332 patients with unilateral, focal lesions who attended the Neuropsychology Department of the National Hospital for Neurology and Neurosurgery was retrospectively screened. Inclusion criteria were: presence of a stroke or tumour; ≥70% of the total lesion, segmented from MRI or CT scans obtained during routine clinical care (see ‘Neuroimaging investigations’ section), falling within either frontal or non-frontal areas; age between 18–80 years; absence of gross perceptual impairments ,P = 0.12; 74Application of these criteria yielded 227 patients, 146 frontal , and 81 non-frontal  and a significantly greater proportion of stroke patients in non-frontal than frontal . However, there were no significant differences in the proportion of tumour or stroke patients between LF and RF  or between LNF and RNF .Frontal, non-frontal and control patients were well-matched for age, gender, chronicity and years of education  = 25.319; P < 0.001; F = 21.266; P < 0.001, respectively]. Post hoc tests showed frontal performed significantly worse than non-frontal and control on S fluency  and Hayling suppression errors . Pairwise comparisons revealed that LF were significantly more impaired than RF on S fluency (P < 0.01), RF were significantly more impaired than LF on Hayling suppression errors  = 18.491; P < 0.001]. Post hoc tests showed that frontal performed significantly worse than non-frontal (P < 0.01) and Control (P <0.001). There was no significant difference between non-frontal and control  = 12.237; P < 0.001]. Pairwise comparisons showed a significant difference between RF and Controls (P < 0.001) and LF and Control (P < 0.01). Importantly, RF were significantly more impaired than LF (P < 0.01). There was no significant difference between RNF and Control or LNF and Control; A one-way ANCOVA controlling for age and NART found a highly significant difference between LF, RF, LNF, RNF and Control participants  and Group . Critically, there was also a significant interaction between difficulty and group . Post hoc pairwise comparisons showed significant differences for the medium group between RF and Control (P < 0.001), LF and Control (P < 0.05), and RF and LF (P < 0.05). Thus, frontal patients were worse than Control, and RF performed the poorest. For the hardest group there were significant differences only between RF and Control (P < 0.001), and LF and Control (P < 0.001). There were no significant differences for the easy group. Thus, RF impairment on the APM appears to be driven by poor performance on the medium items. Closer inspection revealed that three specific items  were responsible for driving the RF poorer performance than LF, with an accuracy decrement of more than 20% in RF.A 3 × 3 ANCOVA, controlling for age and NART, revealed a significant main effect of difficulty . A linear regression analysis, with age, NART and extent of MD involvement entered as predictor variables, significantly predicted APM performance . However, only age and NART (both P < 0.001) were significant predictors. Extent of MD involvement did not significantly contribute (P = 0.410).A one-way ANCOVA, controlling for age and NART, showed no significant difference in overall performance between patients with versus without MD lesions , and a right-sided MD component falling within precentral and posterior medial frontal gyrus . The credibility intervals of the coefficients of other MD components all crossed zero.P < 0.0001, t-thresh >3.1) (P < 0.0001)  . The reg 0.0001) .2 0.105, coefficient mean ± SD −0.265 ± 0.068) (95% CI −0.396 to −0.129)  . The ext301579 more likely than the non-layered null.The foregoing models inevitably conflate the distributed spatial structure of the underlying neural dependence with that of the causal pathology. To disentangle the two, we need a network model capable of separating the target effects of APM performance from the incidental effects of lesion co-occurrence. This can be achieved with a layered nested stochastic block model, where adjusted APM and lesion co-occurrence weights are distributed in two distinct layers, yielding layer-specific patterns of community structure reflecting the distinct effect of each weight on the network. This model achieved substantially lower entropy—881 118.22 versus 1 182 697.66 nats—than a null model with weights randomised across the two layers , providiThe community structure was composed of blocks dominated by adjusted APM, lesion co-occurrence, or neither weight. The adjusted APM layer revealed a set of brain communities with high edge incidence linking the right middle and inferior frontal gyrus (including pars triangularis), right pre- and post-central gyri, and—weakly—the right superior parietal lobule. These communities were sharply distinct from the lesion weight  & 5.Many of the spatial constraints on the configuration of lesion patterns are imposed by the basic anatomy of the brain and will be shared across aetiologies; those that are not will arise as additional heterogeneity the stochastic block model could theoretically absorb. To determine if aetiology has a substantial structuring effect that merits explicit accounting, we reran the model with an additional, third layer identifying the aetiology of each lesion. This model exhibited far greater description length (2 133 947.48), 2.4 × that of the above for an increase of this single feature, indicating a poorer fit to the data and providing no grounds for preference over the simpler model. The anatomical pattern of APM-sensitive communities was in any event very similar .P = 0.028)  . These eOur study represents the first large-scale investigation of the distributed neural substrates of fluid intelligence in the focally injured brain. We investigated one of the most widely used fluid intelligence tests, the APM, in the largest number of patients with single, focal, unilateral, right or left, frontal or non-frontal lesions and controls. We analysed overall performance, item difficulty and the contribution of MD involvement. For the first time, non-parametric Bayesian stochastic block models were used to reveal the intricate community graph structure of lesion deficit networks, disentangling functional from confounding pathological distributed effects.21–104 and in-keeping with our previous studies70 we adopted a mixed aetiology approach. Previous comparison of a large frontal and non-frontal sample with different aetiologies on the APM and other executive tests showed that aetiology was not a strong predictor of frontal or non-frontal deficits.105 Hence, different aetiologies do not result in more severe impairments than others and combining across vascular and tumour pathologies is unlikely to significantly distort neuropsychological performance.75 Instead, focal lesions may relate more closely to the region of damage rather than aetiology. Moreover, data from multiple aetiologies will tend to attenuate distorting effects arising from pathologically driven characteristic patterns of lesion co-occurrence that are widely recognized to bedevil both network and focal lesion-deficit studies. Indeed, less spatial distortion caused by the structure of the pathology may be expected if multiple pathologies differing in their spatial properties are used.Similar to other groups55 Applying an array of lesion-deficit models to large scale data, we found APM performance to be specifically vulnerable to the integrity of the right frontal lobe, and largely resistant to damage elsewhere. The left frontal lobe appears to make a contribution to APM performance, if a more modest one. We found that the performance of the left frontal patients was significantly different from healthy controls and non-frontal patients. However, the left frontal patients performed significantly better than the right frontal patients did.Though fluid intelligence is widely thought to be dependent on the integrity of the frontal lobes, only a handful of focal lesion studies, based on modest samples, have found impairments following frontal lesions.24 We found no evidence of such non-frontal causal dependence on APM performance. It is possible that functional imaging findings merely reflect a correlation between fluid intelligence and posterior areas non-critically engaged by the necessary perceptual input.Our findings speak to the theories of non-frontal involvement in fluid intelligence. The proponents of P-FIT have argued that impairment of fluid intelligence should follow lesions of the posterior and anterior regions that putatively subserve it.et al.79 investigated 80 patients with cortical lesions with a fluid intelligence task (Cattell Culture Fair IQ test). Though the authors reported a significant correlation between MD involvement and fluid intelligence performance overall, in the 44 patients with purely frontal damage the relationship was not significant when non-MD lesion volume was taken into account. So, as far as the frontal lobes are concerned, the authors’ theoretical claim was not strongly empirically supported. In our study patients with or without MD damage did not differ significantly in performance on the APM. Moreover, the extent of MD involvement did not contribute to performance. These findings do not support the claim that MD is the seat of fluid intelligence, but neither do they exclude it: absence of evidence is not evidence of absence. In this context, we note that the Woolgar et al.79 study included 30 non-frontal patients. Of these only seven were patients with unilateral parietal lesions, whilst two patients had biparietal lesion. In contrast, our non-frontal sample includes 81 patients, of which 20 have a unilateral parietal lesion. Hence, our study has far greater coverage of non-frontal MD areas than Woolgar’s study. While we cannot rule out the possibility that lower power may be a factor relevant for our conclusion regarding weak contributions from non-frontal MD lesions, our sample is larger than that of the study, which produced the opposite conclusions. Moreover, the Woolgar et al. study reported for their parietal patients that MD lesion volume was a significant predictor for performance on fluid intelligence with and without non-MD lesion volume partialled out . We were not able to replicate this effect in our larger group .Our results are also relevant for the MD proposal. Notably, Woolgar Our findings of greater involvement of the right frontal lobe in APM performance were complemented and extended by our neuroimaging analyses. Both conventional network statistics and non-parametric Bayesian stochastic block modelling heavily implicated the right frontal lobe. Crucially, this localisation was confirmed on explicitly disentangling—uniquely in the field of lesion-deficit mapping—functional from pathology-driven effects within a layered stochastic block model, prominently highlighting a right frontal network including the middle and the inferior frontal gyrus, including pars triangularis, and pre- and post-central gyri, with a comparatively weak contribution from superior parietal lobule. The marked structuring effects of lesion co-occurrence observed highlight the importance of explicitly modelling them in lesion-deficit inference, whether in the context of network or focal analysis.Standard PLSM analyses, potentially confounded by lesion co-occurrence effects, suggested that poorer performance was associated with damage to a right frontal network including posterior middle frontal gyrus, pars opercularis, precentral gyrus, superior corona radiata and external capsule, invariantly to the degree of MD involvement. That a similar set of RF regions were implicated in Hayling suppression errors, a verbal test, suggests that function lateralization in the frontal lobes is not explained by task sensitivity to language alone.Behaviourally we found a highly significant interaction between item difficulty and frontal lesion lateralisation. The asymmetry in performance was nearly three times greater for the middle than for the highest level of difficulty, with neither population nearing the ceiling or floor. Why might that be?et al.106 identify a factor related to ‘perceiving the progression of a pattern’ (p.1301), and another to ‘the addition and/or subtraction of elements’. Lynn et al.107 offer ‘Gestalt continuation’, following Van der Ven and Ellis,108 and ‘verbal-analytic reasoning’, respectively. It is apparent that the three medium items  of the APM showing the greatest lateralisation, are all those where perceiving the progression of a pattern is an obvious approach. By contrast, the non-ceiling items with the smallest lateralization  are all those where addition or subtraction come into play. Though the limited number of items precludes firm conclusions on factorisation, these findings suggest the components of APM may lateralise in different ways. Inferences involving the perception of a progressive pattern may be especially sensitive to the integrity of the right frontal network.While complete agreement is lacking, factor analyses of progressive matrices indicate at least two material components. Dillon In conclusion, our study represents the most robust investigation of the hitherto poorly characterized fluid intelligence in patients with single, focal, unilateral lesions. Our approach of combining novel graph-based lesion-deficit mapping with detailed investigation of APM performance in a large sample of patients provides crucial information about the neural basis of fluid intelligence. We suggest that a right frontal network, rather than a wide set of regions distributed across the brain, is critical to the high-level inferences, based on perceiving pattern progression, involved in fluid intelligence. Our findings further corroborate the clinical utility of APM in evaluating fluid intelligenceand identifying right frontal lobe dysfunction.awac304_Supplementary_DataClick here for additional data file.


The major cause of death in the United States is heart disease. The global burden of illness and mortality from heart failure is substantial. Despite recent innovations in the treatment of heart failure, the prognosis is still poor. To identify, evaluate, and summarize the findings of all relevant studies of a drug that is equally efficacious but rather cost-effective, empagliflozin compared to the other sodium-glucose cotransporter-2 (SGLT2) inhibitors was studied. It is licensed by the Food and Drug Administration (FDA), acts by preventing the reabsorption of glucose from the kidney, and exhibits promising advantages in heart failure.We systematically explored PubMed, PubMed Central (PMC), and Medical Literature Analysis and Retrieval System Online (MEDLINE) for randomized controlled trials (RCTs) and observational studies related to cardiovascular and renal outcomes of empagliflozin in patients with heart failure with reduced ejection fraction (HFrEF). After performing scoping search and search strategy, studies were screened for quality assessment using the Cochrane risk of bias assessment tool. We screened 60 articles by titles, abstract, and exclusion and inclusion criteria, after which eight final randomized controlled trials (RCTs) with 18,659 participants treated with empagliflozin and placebo were used for the systematic review. This systematic review's objective is to investigate and explore the full range of empagliflozin's effects and advantages on cardiac structure, function, and hemodynamics and renal function in patients with heart failure with reduced ejection fraction (EF) in order to better understand the drug's effects and related mechanisms. The prevalence of heart failure in the United States from the years 2013 to 2016 was 6.2 million . It was The latest medical advances guide us to effectively manage patients with heart failure with reduced ejection fraction (HFrEF) . The treIn our systematic review, we evaluated the effects of empagliflozin in patients with heart failure with reduced ejection fraction (HFrEF) across different subgroups of associated diseases and risk factors to study the wide spectrum of benefits of the drug in these patients.MethodsThe Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines were employed for performing this systematic review .Search Source and Search StrategyWe systematically searched for the relevant articles indexed in PubMed, PubMed Central (PMC), and Medical Literature Analysis and Retrieval System Online (MEDLINE). We began by exploring the databases using two search keywords. We combined these two keywords with the Boolean "AND." For the keyword "empagliflozin," we used the concept identification words sodium-glucose cotransporter-2 (SGLT2) inhibitor and empagliflozin; these words were combined by the Boolean "OR," and a Medical Subject Heading (MeSH) search strategy was formulated. Similarly, a MeSH search strategy for the second keyword "heart failure" was formulated, and both the search strategies were combined with the Boolean "AND," which was entered in PubMed. The following MeSH strategies were employed: ("empagliflozin" {Supplementary Concept}) AND ("Sodium-Glucose Transporter 2 Inhibitors/administration and dosage" {Majr} OR "Sodium-Glucose Transporter 2 Inhibitors/adverse effects" {Majr} OR "Sodium-Glucose Transporter 2 Inhibitors/therapeutic use" {Majr} OR "Sodium-Glucose Transporter 2 Inhibitors/toxicity" {Majr}) AND ("Heart Failure/drug therapy" {Mesh} OR "Heart Failure/prevention and control" {Mesh} OR "Heart Failure/therapy" {Mesh}).The titles, abstracts, and subject headers were checked for relevance following a thorough analysis of all articles and references to verify that no publications that might be of interest were missed. The primary and secondary outcomes were determined, and the corresponding authors extracted the data. A consensus was reached to resolve any disagreements in the data extraction process.Eligibility CriteriaThe publications that are pertinent to the research issue and have been published in English throughout the previous six years, from 2017 to 2018, were included. Our study concentrated on adults (18 years and older). Prior to 2017, papers on pediatric populations and animal species that were unpublished, irrelevant, or considered "gray literature" were not included.Risk of Bias AssessmentWe used the Cochrane bias assessment tool to assess the quality of the randomized controlled trials included in our review article. Only those articles that satisfied >60% of the appraisal parameters were considered in the systematic review.ResultsStudy SelectionOur initial search employing the Medical Subject Heading (MeSH) strategy and keywords yielded sixty articles from the PubMed, PMC, and Medical Literature Analysis and Retrieval System Online (MEDLINE) databases. After performing scoping search through titles and abstracts, 34 articles were removed, and 26 articles remained. The 26 articles were reviewed for eligibility, and those that did not fit the requirements were removed, leaving eight articles. These eight articles were further subjected to quality appraisal since they included specific information relating to the research topic after reading the entire article. Since they all met more than 60% of the evaluation criteria and were randomized controlled trials, they were all employed. These articles mentioned the cardiac and renal effects of empagliflozin in patients with heart failure with reduced ejection fraction (EF). The literature screening process of the selection of eligible studies was performed employing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines as shown in the flow diagram in Figure Quality Appraisal StudiesThis systematic review includes eight randomized controlled trials, and the quality of RCTs was assessed using the Cochrane bias assessment tool. The findings are summarized in Table Characteristics of the Retrieved StudiesOur systematic review included eight randomized controlled trials with a total of 18,659 participants with heart failure with reduced ejection fraction (HFrEF). They are distributed under two sections: section 1 included four RCTs depicting the cardiac and renal effects of empagliflozin compared with a placebo in patients with HFrEF -12,17, w2 [The cardiac and renal beneficial outcomes of empagliflozin in patients with HFrEF include a significant reduction of cardiovascular death, hospitalization for heart failure, and a slowed rate of decline in estimated glomerular filtration rate (eGFR) and were observed in patients with type 2 diabetes mellitus (T2DM), and the baseline glycosylated hemoglobin (HbA1c) level did not influence the effect of the drug on the outcomes . These f2 . Another2 . These wThe beneficial outcomes on cardiac structure/function and hemodynamics include a significant reduction of left ventricular (LV) end-systolic volume index (LVESVI), left ventricular end-diastolic volume index (LVEDVI), left atrial volume index (LAVI), left ventricular mass index, left ventricular sphericity, N-terminal pro-B-type natriuretic peptide (NT-pro-BNP), and pulmonary capillary wedge pressure (PCWP) and the improvement of left ventricular ejection fraction (LVEF), peak oxygen consumption, oxygen uptake efficiency slope, six-minute walk test, and quality of life -16. ThesDiscussionEffects of Empagliflozin on Cardiovascular and Renal OutcomesOutcomes of empagliflozin across the diabetic and cardiovascular spectrum: Studies consistently show that SGLT2 inhibitors, as opposed to other antihyperglycemic medications, reduce the likelihood of heart failure hospitalizations and serious renal outcomes in diabetic patients -20. ThesIschemic cardiovascular disease manifests as a number of multifactorial disorders that worsen mostly as a result of atherothrombotic events, leading to myocardial infarction, heart failure, and death . PatientIn HFrEF Patients Across the Systolic Blood Pressure SpectrumIn addition to helping people with heart failure, SGLT2 inhibitors also lower systolic blood pressure in people with diabetes and hypertension ,24. HoweIn HFrEF Patients With Chronic Kidney Disease (CKD)2, according to Zannad et al.'s analysis of the EMPEROR-Reduced  [Heart failure patients frequently have concurrent CKD, and the likelihood of heart failure increases as kidney function declines . On dialraction) .Effects of Empagliflozin on Cardiac Structure/Function and Hemodynamics in HFrEF PatientsTo control and overcome the impaired central and peripheral metabolic situation in heart failure, a number of compensatory mechanisms are activated, including adaptive mechanisms on the cellular level and neurohormonal mechanisms  . In hearClinical outcomes in HFrEF are better when using pharmacological or biological treatments that lessen or reverse cardiac remodeling . The N-tLimitationsAlthough empagliflozin exhibited positive benefits on the cardiorenal system, its effects on patients with advanced cardiorenal disease were not considered, including those with SBP of ≤100 mmHg, patients in New York Heart Association (NYHA) class IV, and those with symptomatic hypotension. Due to their post hoc character, two of the investigations had limitations. The patients' initial characteristics showed some heterogeneity. Treatment was only administered for 36 weeks in order to analyze the left ventricular remodeling; long-term consequences were not examined. There is a need for more investigation that considers the uniformity and long-term effects of the characteristics. Additionally, more research on how empagliflozin affects people with severe renal and cardiac disease will help us learn more about its potential future applications.This systematic review demonstrated a multitude of benefits of empagliflozin in patients with heart failure with reduced ejection fraction. The favorable effects were seen on both cardiovascular and renal outcomes. There were certain anticipatory outcomes consistent with previous studies. However, these studies also displayed the need for a further extensive study to know the exact mechanism of action for its benefits. They also needed further evaluation of patients with severe cardiac and renal diseases. The studies showed a reduction in cardiovascular death and hospitalization rates for patients with heart failure. There were positive effects on cardiac structure, volumes, and hemodynamics in patients with heart failure with reduced ejection fraction (HFrEF). This results in a reversal of left ventricular cardiac remodeling, which improves morbidity and overall mortality. This systematic review also showed that the effects of empagliflozin were unaffected by the varying systolic blood pressure, cardiovascular risk, and diabetic status.There was an overall improvement in patients with chronic kidney disease, including patients on dialysis over time. This was correlated with the demonstration of the slowed decline of the estimated glomerular filtration rate (eGFR) slope. When it comes to using empagliflozin in HFrEF patients, the benefit outweighed the risk according to our study.


Empagliflozin (EMPA), a sodium-glucose cotransporter 2 inhibitor (SGLT2i), is recommended for all patients with Heart failure (HF) to reduce the risk of Cardiovascular death, hospitalization, and HF exacerbation. Qualitative and quantitative evaluation was conducted by searching relevant literatures of EMPA for Heart Failure from 2013 to 2022, and visual analysis in this field was conducted.The data were from the Web of Science Core Collection database (WOSCC). The bibliometric tools, CiteSpace and VOSviewer, were used for econometric analysis to probe the evolvement of disciplines and research hotspots in the field of EMPA for Heart Failure.A total of 1461 literatures with 43861 references about EMPA for Heart Failure in the decade were extracted from WOSCC, and the number of manuscripts were on a rise. In the terms of co-authorship, USA leads the field in research maturity and exerts a crucial role in the field of EMPA for Heart Failure. Multidisciplinary research is conducive to future development. With regards to literatures, we obtained 9 hot paper, 93 highly cited literatures, and 10 co-cited references. The current research focuses on the following three aspects: EMPA improves left ventricular remodeling, exert renal protection, and increases heart rate variability.Based on methods such as bibliometrics, citation analysis and knowledge graph, this study analyzed the current situation and trend of EMPA for Heart Failure, sorted out the knowledge context in this field, and provided reference for current and future prevention and scientific research. Empagliflozin (EMPA), a sodium-glucose cotransporter 2 inhibitor (SGLT2i), is recommended for all patients with Heart failure (HF) who have been treated with ACE-I/ARNI, β-blockers, and MRA, regardless of diabetes, to reduce the risk of Cardiovascular (CV) death, hospitalization, and HF exacerbation in HF patients –4. The E+/H+ exchanger (NHE) and reducing intracellular Na+ and Ca2+ . In ClinicalTrials.gov1, a database of privately and publicly funded clinical studies conducted around the world, we performed a combination search of “Empagliflozin” and “Heart Failure” for clinical trials focused on intervention therapy. Then the retrieval results were analyzed comprehensively according to the stage of the experiment.The following category was used to retrieve literature from WOSCC: (Topic = Empagliflozin and Heart Failure). There were no language, publication date, and document type restrictions in the selection of the articles. To avoid data bias, the plain text files containing full record and cited references were exported in the text as download_VOSviewer (Version 1.6.17) was utilized for the analysis of countries, organizations, and authors. Based on network visualization, VOSviewer divides countries, organizations, or authors into diverse clusters and colors them in the light of the temporal progression of their occurrence, superimposing time on the network of co-occurrence countries, organizations, or authors. The data about country cooperation was converted into GML format by VOSviewer and imported into Scimago Graphica Beta software (Version 1.0.18) to demonstrate geographical distribution and country cluster.The software CiteSpace (Version 5.8.R3 64-bit) was used for the analysis of co-cited reference and keywords. In the co-occurrence graph, the circle size represents the number of co-citations, and the centrality and burstiness was strikingly marked by the purple and red in the outer ring of the node, respectively. Key points in CiteSpace are nodes with a centrality of more than 0.1. Long-likelihood ration algorithm was used for keywords cluster analysis based on co-occurrence. In the cluster map, the ones surrounded by boxed represent the same cluster. Cluster names are displayed based on the cluster scale.It can be seen from ClinicalTrials.gov Identifier: NCT03152552) and outbreak involvement , and 1 has unknown information . Of the 21 completed trials, 10 submitted final findings and all of them had positive effects, as detailed in To date, EMPA has 42 clinical trials for HF worldwide and the exact distribution is shown in A series of clinical trials have demonstrated that EMPA improves hemodynamics in patients with HF, rapidly reducing pulmonary artery pressure that is amplified over time and appears to be independent of loop diuresis management –23. In tCirculation is the most published journal with 86 articles, with IF of 39.918 and JCR of Q1, followed by Cardiovascular Diabetology , European Journal Of Heart Failure , Diabetes Obesity Metabolism , European Heart Journal , Journal Of The American College Of Cardiology , Esc Heart Failure , Diabetologia , Heart Failure Reviews  and New England Journal Of Medicine   .In terms of publication numbers, USA is the country with the highest number of publications, accounting for 37 percent of the total, followed by the Germany , Canada , England , Japan , China , Italy , Greece , France , and Netherlands  . Figure The three institutions with the largest number of publications were from University of Toronto, Boehringer Ingelheim and Saint Michaels Hospital Toronto, accounting for 11.567, 10.678, and 8.966% of the total reports respectively, will in With regards to authors, Butler J from the University of Mississippi was the most prolific, followed by Anker SD from Charite Universitatsmedizin Berlin and Inzucchi SE from Yale University. Of the top 15 authors, eight are from the USA and Germany, evenly split. Inzucchi SE from Yale University have the most citations of 1,0007 and the highest h-index of 26 on the field of EMPA for HF . Figure New England Journal of Medicine . The above nine hot papers included two meta-analyses, and the results showed that SGLT2 inhibitors were associated with a reduced risk of major adverse CV events and renal outcomes  and Ca2+([Ca2+]c) concentrations and decreased mitochondrial Ca2+([Ca2+]m) concentrations are driving factors for HF and cardiac death  in 2015, is the first study to provide evidence that antidiabetic agents reduce CV events (P = 0.001). The separation of Kaplan–Meier curves for CV mortality and HF hospitalization observed during the first 3 months of the trial suggests that the treatment mechanism for EMPA has an early and profound effect on the risk of death or HF  in 2016, highlighting the strength 13.9, also reported these findings from the same randomized controlled trial .The first article named “Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes,” which written by Zinman B and published in the V events . In the V events  and BlooV events , CV deatth or HF . AnotherOur analysis of the co-occurrence diagram was used to see which were the main directions and hotspots of EMPA for HF research, as well as to understand how its themes and topics developed and changed over time. The keyword co-occurrence diagram of 386 nodes and 768 links was obtained by running CiteSpace . The nodQ = 0.7799, the closer Q value was to 1, the better the clustering result of the network was, and Q value > 0.3 indicated that the clustering structure was significant. Silhouette S = 0.91, which measured network homogeneity. When Silhouette was more closely to 1, the more homogenous the Silhouette would be. An S value > 0.5 was considered reasonable and an S value > 0.7 was considered convincing .Acute or chronic myocardial injury results in metabolic disorders followed by cardiomyocyte death. The remaining viable myocardium copes with cell loss through the development of cardiomyocyte hypertrophy and fibrosis in the interstitial space , 49. A rVentricular remodeling, first described in animal models of LV stress and injury, occurs progressively after large myocardial infarction and in patients with dilated cardiomyopathy. Ventricular remodeling refers to changes in ventricular structure, associated with increased volume and changes in ventricular structure, which are driven by pathological cardiomyocyte hypertrophy, cardiomyocyte apoptosis, myofibroblast proliferation, and interstitial fibrosis at the histological level –58. LVEF2 in the EMPA group and 0.01 g/m2 in the placebo group (P = 0.01), with a significant reduction in the EMPA group, which is presumed to have a positive effect on CV outcomes.EMPATROPISM trial, a pioneer trial to be published first, demonstrated a reduction in LV volumes, regression in LV mass, improvement in LVEF, amelioration in LV sphericity . MoreoveThe results were verified in animal experiments. Researchers used LAD ligation to establish a model of HF after MI in female Yorkshire pigs and randomly assigned them to either EMPA or placebo for 2 months. Myocardial injury was subsequently detected using cardiac magnetic resonance and three-dimensional (3D) Echocardiography. The LV end-systolic and end-diastolic diameters of EMPA treated pigs were significantly reduced, indicating a significant mitigation in LV dilatation. LV mass was significantly reduced in EMPA treated pigs and the degree of sphericity of the heart was lower than in control pigs, as indicated by the lower 3D-LV sphericity index, thus indicating reduced structural changes in the treated arm. Further CMR results showed that the improvement of LV remodeling in the EMPA group was associated with an increase in LVEF 2 months after treatment . Santos-In the EMPEROR-Reduced Trial, EMPA slowed the progression of eGFR reduction compared with placebo , 70. EMPIns2+/Akita mice was significantly higher than in control groups, reflecting glomerular hyperfiltration, which was ameliorated in EMPA treatment , and this process is defined as type 4 cardiorenal syndrome. Trials have shown that SGLT2i treatment significantly improves the outcome of HF, reducing the length of hospitalization for this complication in CKD patients by 30–40% . Indeed,Juni et al.  provide Arterial stiffness, a surrogate marker of renal and CV clinical outcomes, is influenced by activation of the renin angiotensin aldosterone system (RAAS) and sympathetic nervous system (SNS) and inhibition of NO , 88, incP < 0.01), SDANN , and RMSSD  were significantly higher after 24 weeks of EMPA versus baseline.Heart rate variability is a non-invasive ECG parameter that assesses sympathetic vagal balance at the sinoatrial level, but its physiological interpretation is still under discussion –106. In There are some limitations in this paper. We analyze all the articles on EMPA for HF from the WOSCC database, but due to differences in text quality, the credibility of the analysis may be low. With the continuous updating of WOSCC literature, the number of literatures obtained is different from the actual number of literatures, and the cited times and H-index will also change accordingly.The research progress, hotspots, and frontier in this field in the decade were elucidated by us through information visualization technology. The publications of manuscripts were on a rise. With regards to country, USA leads the field in research maturity. The scholars, institutions, and representative literature that play an important role in this area have been identified. The current research focuses on the following three aspects: EMPA improves LV remodeling, exert renal protection, and increases HRV.The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.XZ and YZ designed the study and co-wrote the manuscript. XZ re-examined and analyzed the data. YH reviewed and revised the manuscript. All authors contributed to the article, approved the submitted version, and agreed to be held responsible for all aspects of the work.


Many endocrine diseases, such as neuroblastoma (NB), can be linked with acquired cardiomyopathy and heart failure. Neuroblastoma’s cardiovascular manifestations are typically hypertension, electrocardiogram (ECG) changes, and conduction disturbances.A 5-year-old 8-month-old girl was admitted to the hospital with ventricular hypertrophy and hypertension (HT) and heart failure. She had no previous history of HT. On color doppler echocardiography, the left atrium and left ventricle were enlarged. The left ventricular ejection fraction (EF) was as low as 40%, and the ventricular septum and left ventricular free wall were thickened. The internal diameters of both coronary arteries were widened. Abdominal computed tomography scan (CT) demonstrated an 8.7 cm × 7.1 cm × 9.5 cm tumor behind the left peritoneum. In urine catecholamines analysis, free-norepinephrine (f-NE), free-dopamine (f-DA), free-normetanephrine (f-NMN), free-3-methoxytyramine (f-3MT), vanillylmandelic acid (VMA), and homovanillic acid (HVA) levels were all greater than the normal range for 24 h except free-metanephrine (f-MN) and free-epinephrine (f-E). Based on these findings, we diagnosed her as NB complicated by catecholamine cardiomyopathy manifested by hypertrophic cardiomyopathy (HCM). Oral metoprolol, spironolactone, captopril and amlodipine furosemide, and intravenously injected sodium nitroprusside and phentolamine were employed for treating HT. After the tumor resection, the blood pressure (BP) and urinary catecholamine levels were all restored. After a follow-up of 7 months, echocardiography indicated normalization of ventricular hypertrophy and function.This is a rare report showing catecholamine cardiomyopathy in NB children. Tumor resection leads to a return to normal of the catecholamine cardiomyopathy manifested as HCM. Catecholamine-induced cardiomyopathy (CICMP), a rare, devastating, and difficult-to-treat complication of phaeochromocytoma-paraganglioma (PPGL), is common in pheochromocytoma , but uncNB is one of the most common solid tumors in early childhood accounting for approximately 8% to 10% of all childhood malignancies . The preHere, we present a case of catecholamine cardiomyopathy manifested with HCM in NB, explain the differential diagnosis, and clinical outcome.A girl aged 5 years and 8 months was admitted to our hospital with ventricular hypertrophy. The child gained and lost weight gradually for more than a year. Five months ago, a heart murmur was discovered during a health check, and her transthoracic echocardiography revealed left ventricular hypertrophy without affecting the left heart’s systolic function. Thus, she was diagnosed with nonobstructive hypertrophic cardiomyopathy (HCM), and began treatment with nutritional therapy. About 3 days before admission, she developed shortness of breath, decreased activity tolerance, and an increased heart rate, with no symptoms of cyanosis, dizziness, headache, nausea, or vomiting. She also had no family history of tumor, diabetes, HT, dyslipidemia, or endocrine disorders. The child gained and lost weight gradually for more than a year.2, respectively. Blood pressure (BP), pulse rate, respiratory frequency, and temperature were 170/135 mmHg, 130 beats/min, 47 beats/min, and 36.1°C. She had tachypnea and a dilated suprasternal fossa. Auscultation reveals attenuated bronchovesicular lung sounds in the right lung’s basal region. A Class III/6 systolic murmur was heard in the 2–4 intercostal space at the left sternal margin. The abdomen was slightly distended, and a mass was felt in the upper abdomen’s middle and left side, 10 cm below the xiphoid process and 2 cm below the left rib.Her height, weight, and body mass index were 98 cm, 14 kg and 14.6 kg/mIn myocardial markers, creatine kinase isoenzymes (CK-MB), high-sensitive cardiac troponin T (hs-cTnT), and brain natriuretic peptide (BNP) levels were elevated . The ECGHer maximum systolic blood pressure (SBP) surpassed 160 mmHg and her maximum diastolic blood pressure (DBP) surpassed 100mmHg for up to 10 days after admission . In releFollowing the abnormal physical examination of her abdomen, we further performed an abdominal CT examination, which indicated an 8.7 cm × 7.1 cm × 9.5 cm mass shadow with low density behind the left peritoneum . And herα blocker phentolamine for 10 days. During this period, SBP was up to 266 mmHg and DBP was up to 159 mmHg. Amlodipine, in combination with sodium nitroprusside and phentolamine, was used to stabilize BP before tumor resection, followed by captopril and sodium nitroprusside. On the 27th day, we stopped the sodium nitroprusside, and switched to furosemide, spironolactone, metoprolol tartrate, captopril, and amlodipine tablets for 15 days. Then BP was sustained at 110–130/70–100 mmHg, and the values of catecholamines in urine were all returned to normal  with heart failure –23, but  failure . Numerou failure .Catecholamine excess status has been linked to the pathogenesis of multiple cardiomyopathies, including tachycardia-associated cardiomyopathy, HCM, DCM, and Takotsubo cardiomyopathy (TCM) ,  28–30.DCM and HCM are treated differently. Angiotensin converting enzyme inhibitors (ACEI), diuretics, digoxin, and nutritional agents have been used in all reported cases of DCM. However, as the loss of left ventricular volume may exacerbate the development of ventricular gradient, diuretics and digoxin should be avoided in HCM. Beta blockers and calcium antagonists, for example, are drugs that promote left ventricular filling. Metoprolol used in this case also controlled catecholamine-induced tachyarrhythmia . ACEI, sα receptors mediating contraction, whereas small coronary arteries are almost entirely equipped with β receptors (β1 subclass) mediating relaxation (β1 adrenergic receptor, leading to increased cardiac oxygen demand and hypoxia in specific areas, which may contribute to coronary artery vasospasm (The child in this case developed coronary dilatation, but certain previous research showed that the coronary usually had no major disease , 35, 36.laxation . Acute easospasm , 39. ThuCatecholamine cardiomyopathy in NB is rare, thus early recognition of the complication is important for diagnosis and treatment. Cardiomyopathy may also occur in the absence of HT due to the direct effect of catecholamine on the myocardium. Therefore, throughout the course of treatment, BP monitoring and cardiovascular assessment should be actively improved, with a focus on cardiac problems connected to NB.This case remains limited. First, while urine catecholamine metabolites were found, plasma catecholamine metabolites were not. Second, the mechanism of catecholamine cardiomyopathy complicated by coronary artery dilatation requires further investigation. Third, we did not conduct a genetic test on this patient, and it will be refined during a later follow-up to provide more insight into the pathogenesis of catecholamine cardiomyopathy.We experienced a case of catecholamine cardiomyopathy in NB manifested with HCM. After tumor resection, catecholamine cardiomyopathy normalized. This case extremely important for clinicians in the early detection and treatment of special cardiomyopathy.


Insights in Cardiovascular Imaging: 2021.”Imaging plays an increasingly important role in the diagnosis of cardiovascular disease and the understanding of cardiovascular physiology, driven by technological advancements, integration into clinical practice, and increasing evidence of clinical effectiveness. Here we highlight a few of the many important studies that were published under the topic “Enabling diagnosis of cardiac conditions with widespread availability and minimal side effects, echocardiography is often the primary cardiac imaging modality. There has been remarkable advancement recently in long-established features of echocardiography such as tissue Doppler imaging, contrast echocardiography, myocardial speckle tracking, and real-time 3-D echocardiography.The right atrium (RA) has an important role in the function of the right heart, with its triple function as a reservoir receiving blood from the venae cavae during ventricular systole, a conduit transferring blood to the right ventricle during early diastole, and with its active contractile function pushing blood into the right ventricle during late diastole. For a long time, the right atrium has received little notice, but has recently been the focus of numerous studies.Lagrangian strain (ε) is the change in myocardial fiber length from diastole to systole, as a percentage of the diastolic length, and strain rate is the change of strain per unit time . Strain Hosseinsabet et al. provides new insights into normal RA phasic function. Data from 15 studies involving 2,469 healthy subjects were combined to derive normal ranges for RA strain during the reservoir, conduit and contraction phases. The authors commented on sources of inter-study heterogeneity, including technical factors such as the software used for speckle tracking and the method used to derive a global value, and biological factors such as the body mass indices and body surface areas of the participants. This study provides important information to contextualize future measurements of RA function in different disease states, and highlights the importance of working to standardize RA strain measurement.The systematic review and meta-analysis by Richter et al., throws light on RA function in 56 patients being treated for pulmonary arterial hypertension (PAH). PAH is known to be associated with impaired RA reservoir and conduit function, making it important to understand how these parameters vary with treatment (p = 0.022) and poor prognosis as compared to those with stable or improved RA PLS (log-rank p = 0.012).Another study by reatment . Change Computed tomographic coronary angiography (CTCA) is a well-established non-invasive imaging modality, which allows assessment of plaque composition and burden, including plaque characteristics associated with increased vulnerability. In addition, CTCA-based coronary artery reconstruction enables the assessment of local hemodynamic forces, which in turn regulate plaque formation and allow the prediction of lesions that are prone to progress and cause events.Yamaura et al.). 375 patients with suspected stable angina but no previous history of MI, PCI or CABG were included. At a mean follow-up of 2.2 years, the primary endpoint of death, non-fatal MI or urgent revascularization was observed in 15 patients (4%), of whom 65% were from the fourth quartile of LAP volume. LAP volume independently predicted the occurrence of the primary outcome after adjustment for CAD-RADS score (a grading system based on the maximum severity of obstruction in any coronary artery), coronary artery calcium score (CACS) > 100, and Suita score (a cardiovascular risk prediction score used in Japan). CACS and epicardial adipose tissue volume were associated with LAP volume. This study emphasizes the importance of factors other than stenosis severity in determining and predicting the risk of future events, and should encourage prospective research in larger samples to clarify the role of LAP volume in clinical practice.Quantifying high-risk plaque burden assists in the prevention of future coronary events . Low attZhou et al.). It is promising further insight into the potential role of CTCA as a screening tool in outpatient settings and may throw light on the plaque pathophysiology in patients with mild to moderate coronary disease, as most cardiovascular events occur in this group of patients.CTCA reliably identifies coronary artery plaque with high-risk features such as low attenuation, napkin-ring-associated lesions, or positive remodeling . AbnormaCardiac magnetic resonance imaging (CMR) has become an increasingly important tool for both functional assessment and tissue characterization. For functional analysis, identifying sub-clinical stages of LV systolic dysfunction is a promising role for CMR.Mandry et al. studied 118 participants free from established cardiovascular disease, but with a high prevalence of risk factors (26% had hypertension and 52% were obese). Subjects underwent ejection fraction (EF) assessment using CMR, with phase-contrast sequences to determine aortic flow and therefore cardiac output, at baseline and median follow-up of 5.2 years. Change in EF between baseline and follow-up was inversely related to change in mean systolic  and diastolic blood pressure  and to a greater extent to change in SVR , indicating that LV afterload affects EF. The findings of this study highlight the importance of recording the conditions under which EF is measured, and the potential role of this confounder when assessing serial changes in EF.Fischer et al. provided insight into how coronary autoregulation copes with changes in blood pressure in the intra or perioperative state. They used vasoactive drugs to manipulate the mean arterial blood pressure (MAP) in 10 anesthetized pigs, in steps of 10–15 mmHg from 29 mmHg to 196 mmHg, inside an MRI scanner. Oxygen-sensitive cine images were acquired in each hemodynamic state, and LV and RV circumferential systolic and diastolic strain were measured using CMR feature tracking software. Coronary blood flow was measured using a surgically implanted Doppler ultrasound probe, and the “autoregulatory zone,” the range of MAP in which coronary blood flow remains relatively constant, was calculated for each animal. LV and RV peak strain were compromised when MAP was both below and above the autoregulatory zone. Time to peak strain was higher, and strain rate was lower, when MAP was above the autoregulatory zone. LV peak strain was linearly and inversely related to myocardial oxygenation, determined using oxygen-sensitive CMR images, when MAP was below the autoregulation zone.In a similar vein, Mass immunization has helped mitigate the burden of the COVID-19 pandemic on healthcare systems across the world. Myocarditis has been reported as a consequence of both COVID-19 infection and vaccination . Jahnke Laohabut et al. investigated myocardial extracellular volume (ECV) by CMR T1 mapping in 739 patients with and without type II diabetes mellitus (T2DM) who were undergoing investigation for known or suspected ischemic heart disease. Compared to patients without T2DM, those with T2DM had higher ECV and were more likely to have late gadolinium enhancement, but there was no difference in ejection fraction. ECV was independently associated with increased hazard of adverse cardiovascular outcomes  and provided improved prognostic performance when added to a model including typical cardiovascular risk factors, diagnosis of T2DM, and LV ejection fraction.Chamling et al. report the CMR findings in two patients with suspected cardiac involvement in AA amyloidosis that was subsequently confirmed by endomyocardial biopsy. Both patients were found to have markedly elevated native T1 and ECV, similar to other forms of cardiac amyloidosis, but without the typical presence of late gadolinium enhancement. This study provides valuable insight into the CMR findings in cardiac AA amyloidosis, and will be of value to clinicians presented with this rare condition.Amyloid A (AA) amyloidosis is a rare condition characterized by the deposition of fibrils of the acute phase protein serum amyloid A in tissue. In contrast to transthyretin and light chain (AL) amyloidosis, cardiac involvement is uncommon and not well characterized. Rauseo et al. published a paper where they compared manually contoured datasets of short axis cine CMR images by expert analysts with automated contours derived using an ML algorithm. The results showed that automated contours scored better than the manual contours  when presented to blinded experts.Machine learning (ML) algorithms incorporated into imaging technologies promise to further improve time efficiency and reproducibility of CMR. Chen et al. to improve the tedious and time consuming manual myocardial segmentation of MRI sequences. The team proposed a two-stage segmentation framework in which conventional neural networks and recurrent neural networks were combined, incorporating temporal information which demonstrated a 2% improvement in the Dice coefficient on the automated cardiac diagnosis.Numerous algorithms have been developed to automatically segment the myocardium by defining endo- and epicardial contours, with the goal of saving clinicians time and improving accuracy and reproducibility. Similarly, automatic myocardial segmentation using a machine learning technique has been explored by In summary, these advancements in cardiovascular imaging hold promising new perspectives for echocardiography, computed tomography and cardiac magnetic resonance imaging. They further support the paradigm shift toward non-invasive assessment for patients with established or suspected cardiovascular disease. Further research is needed to fully assess their true value in everyday clinical practice.CB, SP, and SK contributed to conception and design of the editorial. RP, KW, and RT drafted and revised the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.


Type 2 diabetes mellitus (T2DM) increases the risk of worse long-term outcomes in patients with non-ischemic dilated cardiomyopathy (NIDCM). However, the additive effects of T2DM on left ventricular (LV) function in NIDCM remain unclear. Accordingly, we aimed to investigate the impact of comorbid T2DM on LV deformation in NIDCM individuals.Three hundred forty-two NIDCM patients without T2DM [NIDCM (T2DM−)], 93 with T2DM [NIDCM (T2DM+)] and 80 age- and sex-matched normal controls who underwent cardiac magnetic resonance scanning were included. LV geometry, function, and LV global strains, including peak strain (PS), peak systolic strain rate (PSSR) and peak diastolic strain rate (PDSR) in the radial, circumferential and longitudinal directions, were measured. NIDCM (T2DM+) patients were divided into two subgroups based on the HbA1c level (< 7.0% and ≥ 7.0%). The determinants of reduced LV myocardial strain for all NIDCM individuals and NIDCM (T2DM+) patients were assessed using multivariable linear regression analyses.Compared with normal controls, both NIDCM (T2DM −) and NIDCM (T2DM+) patients exhibited increased LV end-diastolic and end-systolic volume index and decreased LV ejection fraction. LV global strains progressively declined from the normal controls to the NIDCM (T2DM−) group to the NIDCM (T2DM+) group , except for radial PDSR and PSSR. Subgroup analysis showed that LV global radial PS and longitudinal PS, PSSR-L and PDSR-L were worse in NIDCM patients with poor glycemic control than in those with good glycemic control (p < 0.017). T2DM was an independent determinant of reduced LV global circumferential PS and longitudinal PS in patients with NIDCM (both p < 0.05). An increased HbA1c level was independently associated with a decreased global radial PS  and longitudinal PS  in NIDCM (T2DM+) patients.T2DM has an additive deleterious effect on LV systolic and diastolic function in NIDCM patients. Among NIDCM patients with T2DM, HbA1c was found to be associated with reduced LV myocardial strain. Type 2 diabetes mellitus (T2DM) is associated with heart failure (HF) and is an independent risk factor for cardiovascular morbidity and mortality. In T2DM, subclinical cardiac structural and functional abnormalities, including left ventricular (LV) hypertrophy, myocardial fibrosis and stiffness , and redCardiac magnetic resonance (CMR) is the most accurate technique for assessing cardiac structure and function without the known limitations introduced by echocardiography  , 9. CMR  The study protocol was approved by the Biomedical Research Ethics Committee of our hospital and complied with the Declaration of Helsinki (2013 edition). Informed consent was waived due to the retrospective nature of the research.Initially, we retrospectively enrolled 541 patients with NIDCM who underwent CMR examinations in our hospital from October 2014 to November 2021. The diagnosis of NIDCM was based on the criteria from the World Health Organization/International Society and Federation of Cardiology definition . The inc2, matrix size = 208 × 174/192 × 162 pixels, flip angle = 40°/50°. A dose of 0.2 ml/kg gadobenate dimeglumine  was intravenously injected at an injection rate of 2.5–3.0 mL/s, followed by a 20 mL saline flush. Late gadolinium enhancement (LGE) images were acquired by a phase-sensitive inversion recovery sequence at 10–15 min after contrast administration .All enrolled subjects underwent CMR on a 3.0T whole-body Siemens MAGNETOM Trio Tim system or a MAGNETOM Skyra system . A standard ECG-triggering device and breath-hold technique were used to monitor dynamic changes. Cine images such as a stack of short-axis views from the base to apical level and long-axis views , were acquired by applying an electrocardiogram-gated balanced steady-state free precession (SSFP) sequence. Typical acquisition parameters were as follows: temporal time = 39.34/40.35 ms, echo time = 1.22/1.20 ms, slice thickness = 8 mm, field of view = 240 × 300/288 × 360 mmAll image analyses were performed by two experienced radiologists (more than three years of experience with CMR) using CVI42 software . The optimal endocardial and epicardial contours of LV were delineated manually at the end-diastole and end-systole phases from the stack of short-axis cine images. Papillary muscles and moderator bands were diligently excluded. The global cardiac geometry and function parameters, including LV end-diastolic volume (LVEDV), end-systolic volume (LVESV), stroke volume (LVSV), LVEF, and cardiac mass (LV mass), were obtained. Volume and mass measurements were indexed by body surface area (BSA). Additionally, the LV remodelling index was calculated as LV mass divided by LVEDV.The LV global strain parameters were quantified on short-axis cine images and long-axis cine images (2-chamber and 4-chamber) using a feature-tracking module. The end-diastolic phase was chosen as a reference phase. To ensure the accuracy of the automated tracking in the subsequent phases, the observer reviewed the tracking performance and performed manual adjustments when needed. Subsequently, three-dimensional feature tracking parameters were obtained: LV global radial peak strain (GRPS), global circumferential peak strain (GCPS), and global longitudinal peak strain (GLPS) and their corresponding peak systolic strain rate (PSSR) and peak diastolic strain rate (PDSR) in the three directions . The intraobserver variability for the strain parameters was measured twice by the same observer (MTS) at an interval of 2 weeks. The interobserver variability was assessed using measurements from the same population by a second independent observer (YL) after 1 week.All data were analyzed with SPSS statistical software , R  with RStudio , and GraphPad Prism . Categorical variables are presented as numbers (percentages) and were compared using Fisher’s exact test or the chi-square test, as appropriate. The Shapiro–Wilk test was performed to check for normality of continuous variables. Continuous data are expressed as the mean ± SD for variables with a normal distribution and the median  for those with a nonnormal distribution. Parameters among the NIDCM (T2DM−), NIDCM (T2DM+) and normal control groups were compared by one-way analysis of variance (one-way ANOVA) followed by Bonferroni’s post hoc test  or the Kruskal–Wallis rank test (nonparametric variables), as appropriate. The same methods were also utilized for comparison among NIDCM (T2DM+) patients with good and poor glycemic control and the normal control groups. Correlations between LV strains and clinical indices was assessed using Spearman’s analysis. Furthermore, variables with a probability value of less than 0.1 in univariable analysis and an absence of collinearity were included in stepwise multivariable linear regression analysis to identify the independent determinants of LV strain parameters. The intraclass correlation coefficient (ICC) was calculated to evaluate both intra- and interobserver variability. A two-tailed test and a p value of < 0.05 were considered significant.Overall, 515 participants (435 NIDCM and 80 controls) were included in the present study. Of the 435 NIDCM patients, 93 patients (21%) were identified as having T2DM, and the remaining 342 patients (79%) were classified as non-T2DM patients. The main clinical characteristics of the study cohort are summarized in Table The CMR findings for the observed groups are presented in Table Regarding the LV myocardial strains, almost all of the LV global strains progressively decreased from normal controls to the NIDCM (T2DM−) group to the NIDCM (T2DM+) group , whereas the PSSR and PDSR in the radial direction showed no significant difference between NIDCM patients with and without T2DM .2 vs. 172.86  mL/m2; LVESVi: 125.45  mL/m2 vs. 140.43  mL/m2; LVSVi: 38.03  mL/m2 vs. 32.43  mL/m2; LVEF: 24.69%  vs. 20.28% ; all p < 0.017).According to the status of glycemic control, NIDCM (T2DM+) patients were divided into two subgroups: good glycemic control  and poor glycemic control . The CMR-derived LV global strain parameters for the observed groups are shown in Fig. Univariable and multivariable linear regression analyses were performed to evaluate the independent effect of T2DM on LV peak strains in NIDCM patients Table . After aThe univariable analysis of NIDCM (T2DM+) patients showed that HbA1c level, together with log-transformed NT-proBNP level, was negatively associated with GRPS , and positively associated with GCPS  and GLPS  , and GLPS . Moreover, the log- transformed NT-proBNP level was found to be an independent determinant of global peak strain in all three directions   NIDCM patients displayed reduced LV deformation, and comorbid T2DM further deteriorated LV strains; (2) after adjustment for confounding factors, T2DM was found to be an independent determinant of reduced LV global circumferential and longitudinal peak strain in NIDCM patients; (3) LV global peak strains declined progressively with the increase in HbA1c in NIDCM patients with T2DM; in addition, HbA1c was an independent determinant of decreased LV global radial and longitudinal peak strains. These findings indicated the deleterious effect of T2DM on LV deformation in patients with NIDCM and emphasized the importance of the glycemic control in NIDCM patients with T2DM.T2DM is a growing health concern and is associated with HF and increased cardiovascular mortality . The preThe potential causes for cardiac alterations in NIDCM patients with T2DM are complex. Indeed, DCM is characterized by alterations in myocardial metabolism , which mHbA1c, a biomarker of long-term blood glucose concentrations that represents the average blood glucose levels over the previous 8–12 weeks, is widely used to assess the status of glycemic control for patients with diabetes. Jia et al. found that elevated blood glucose levels were significantly associated with incident HF events . Each 1%Additionally, our data found that male sex was an independent determinant of LV strains in patients with NIDCM. A previous study suggested that male sex is an important risk factor for HF among DCM patients. Men with DCM had higher apoptosis-related protein expression than women, and the incidence of myocardial fibrosis was higher in men than women , 35. MeaThe current study had several limitations. First, this was a retrospective single-centre study, so there may be some selection bias in the results. Second, the influence of medication on NIDCM patients was not assessed. Third, this study was a cross-sectional study, and long-term outcomes and follow-up examinations evaluating the evolution of LV function were not available, so further studies are needed in this regard. Finally, although the presence of LGE was assessed in the present study, the extent and pattern of LGE were not evaluated; we aim to accomplish this in our future research.In patients with NIDCM, T2DM had an additive deleterious effect on LV myocardial strain. In addition, the HbA1c level was associated with decreased LV function in NIDCM patients with T2DM, which emphasizes the importance of glycemic control in NIDCM patients.


Physical inactivity is a global health pandemic. Allied healthcare providers, including chiropractors, are well placed to integrate individual physical activity (PA) promotion into routine care. A previous systematic review identified that approximately 90% of chiropractors held a positive opinion towards healthier patient lifestyles; however, the extent to which chiropractors promote PA to their patients within routine care is unclear. This systematic review aimed to describe chiropractors' attitudes towards and current practice in advising, counselling, discussing, supporting, or recommending PA to patients.Five databases were searched from inception to December 2021 for cross-sectional surveys that explored PA promotion by chiropractors in practice. We assessed the risk of bias of the included studies with the ‘Risk of Bias in Cross-Sectional Surveys of Attitudes and Practices’ tool. Descriptive data were extracted, grouping similar survey questions and responses into emerging categories. Chiropractors’ views regarding the perceived importance and/or their preparedness to counsel and provide PA or exercise information are reported.From 661 studies, 15 met the selection criteria. Surveys included 7999 chiropractors primarily from the USA, UK, Australia, and Sweden. All studies were rated as moderate-to-high risk of bias, with methodological weaknesses characterised by inconsistent reporting of missing data, non-representative samples, low response rates , and unknown validity of survey instruments. Chiropractors frequently recognised the importance of PA promotion, as demonstrated by the proportion of respondents reporting that they: (1) support the importance of providing PA or exercise information and counselling (64% to 100%); (2) are prepared to provide PA or exercise information and/or counselling to patients ; (3) frequently obtain PA or exercise information from patients ; 4) frequently discuss PA or exercise and/or provide PA or exercise information to patients (68% to 99%); and 5) frequently provide PA counselling to patients (50% to 81%.).A large majority of practising chiropractors actively engage with PA promotion. However, the results should be interpreted with caution owing to the moderate-to-high risk of bias of the included studies. Forthcoming research initiatives should explore unbiased surveys, further PA education and training as well as capitalising on chiropractors’ own PA participation.The online version contains supplementary material available at 10.1186/s12998-022-00467-9. Physical activity (PA), including structured exercise, is widely recognised as an important behaviour for reducing the risk of all-cause mortality, and chronic diseases, including (but not limited to) cardiovascular diseases, type 2 diabetes and various forms of cancer . FurtherIn light of recent global estimates showing that one in four 28%) adults are not meeting PA recommendations , the WHO% adults Allied health care providers (AHPs) such as chiropractors, may be well positioned to deliver PA promotion within the healthcare sector. Worldwide, the median 12-month utilisation of chiropractic services has been estimated to be approximately 9%, primarily for musculoskeletal conditions . Yet, thWhile the chiropractic literature regarding PA promotion is relatively sparse, among other AHPs such as physiotherapists, PA data exist to both inform clinical practice and highlight where evidence-based practices are not being implemented . For insWe present a systematic review of available cross-sectional surveys of chiropractic clinicians on PA promotion. Specifically, we aimed to describe chiropractors' attitudes towards and current practice in advising, counselling, discussing, supporting, or recommending PA to patients. This knowledge will inform further research and opportunities to strengthen future practice delivery.A systematic review of published literature to establish and describe current chiropractic practice in PA promotion. This systematic review was pre-registered with PROSPERO (CRD42022297430) and conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 statement .We developed a structured search strategy comprising text and MeSH terms  independently screened titles and abstracts for eligibility. Studies considered potentially eligible by at least one reviewer were obtained in full text. All potentially relevant full text studies were checked against the selection criteria by two independent reviewers (MF and AY). Disagreements were resolved by discussion, engaging a third reviewer if needed (JH).The quality assessment of each study was performed by two independent reviewers (MF and AY) using the ‘Risk of Bias in Cross-Sectional Surveys of Attitudes and Practices’ tool . Risk ofRelevant data were extracted from the included studies  by two independent reviewers (MF and AY) using a standardised form. The main results of each study  were also extracted. Disagreements were resolved by discussion with a third reviewer if needed (JH).Two independent reviewers (MF and AY) independently synthesised descriptive and analytic data by grouping similar survey questions and subsequent responses into emerging categories. These categories were developed to closely resemble the original material based on the common PA questions asked within the different surveys. To understand current PA promotion practices in chiropractic, we extracted data based on the percentage of chiropractors who answered relevant survey questions via Likert scale response options. Only the percentage of participants who responded favourably to the provided statement or question on PA were extracted. For example, for the statement ‘chiropractic care should include PA recommendations’, favourable responses included ‘strongly agree’ or ‘agree’. Similar responses were categorised and subsequently organised into tables reflecting five main themes: (1) the importance of counselling and providing PA or exercise information; (2) readiness to counsel and/or provide PA or exercise information; (3) obtaining PA or exercise information from patients; (4) discussing PA or exercise and/or providing PA or exercise information; and (5) counselling. Considering the descriptive and analytical nature of the included studies, we performed a narrative synthesis of the results. We provide the prevalence point estimates for each included study in a tabular format (using the Wilson score method) and the proportion of respondents from the arising categories in the text. Any disagreements between authors were resolved through discussion with a third reviewer if needed (JH).Our search strategy identified 661 studies, 15 of which met the inclusion criteria, representing a collective sample of 7999 registered chiropractic clinicians  the importance of counselling and providing PA or exercise information; (2) readiness to counsel and/or provide PA or exercise information; 3) obtaining PA or exercise information from patients; (4) discussing and/or providing PA or exercise recommendations, including information or resources; and (5) PA counselling. The proportion of reported practice and the factors identified within each theme that influenced PA delivery in chiropractic services are described below and summarised in Table  obtainin2.Readiness to counsel and/or provide PA or exercise informationNine studies examined the frequency in which clinicians (n = 3211) considered it important to counsel on PA and provide PA or exercise for fitness information , 34, 35.3.Obtaining PA or exercise information from patientsThree studies examined the frequency in which clinicians (n = 883) felt ready to counsel and/or provide PA or exercise for fitness information , 23, 34.4.Discussing and/or providing PA or exercise recommendations, including information or resourcesFive studies sought to examine the frequency in which clinicians (n = 1788) gather information on PA participation from patients , 28, 35.5.PA counsellingEight studies sought to examine the frequency in which clinicians (n = 4862) discussed PA or exercise with their patients , 33, 36,Three studies examined the frequency in which clinicians (n = 2188) counselled patients on PA. Proportions ranged from 50 to 81% for this category. One study reported that more than 80% of clinicians counselled patients at a frequency of once-to-several times per day, with respect to physical fitness and exercise promotion . The twoThis systematic review of surveys aimed to explore the attitudes and practice of chiropractors with respect to PA promotion within their clinics. To the best of our knowledge, this is the most up to date and comprehensive review of chiropractic PA promotion in practice.We found a high proportion of chiropractors recognise the importance and are prepared to routinely discuss and/or counsel patients with respect to PA promotion. Our findings are consistent with a previous review, which reported that approximately 90% of chiropractors prescribed or advised on PA ; howeverOur findings suggest that a high percentage of chiropractors gather information on PA participation from patients. For the most part, the specific nature of data collected in relation to PA is undefined. Thus, it is not clear whether chiropractors are conducting formal PA assessments as part of their routine information gathering. Other AHPs report often or always asking or screening their patients about PA . This isOur review is limited by the methodological weaknesses of the included studies, with all studies rated as moderate-to-high risk of bias. Therefore, proportions reported in our review should be interpreted with caution. All but one of the included studies were vulnerable due to ‘missing data’ for primary outcomes, which in relation to extracting data can further reduce confidence in the proportions reported in our review. Eighty-seven percent of included studies used surveys that were not formally validated, creating some uncertainty with respect to instrument quality and comparisons with prior established studies. Eighty-seven percent of studies did not achieve an ‘adequacy of response rate’, hence the low response rates in our included studies could lead to biased prevalence estimates. Eighty-seven percent of studies were not considered to include a representative population sample of a professional body or a defined geographical area, while 67% of studies conducted pilot testing, thus maximising greater survey user acceptability. A sensitivity analysis comprising only moderate risk of bias studies continued to show high a proportion of respondents, with discussing and providing PA ranging from 68 to 98%, while the importance of PA counselling and obtaining PA information from patients ranged from 64 to 99%. A universally accepted definition of discussing, counselling, and providing information with respect to PA, exercise and/or fitness promotion in chiropractic was not available in our studies. While this was anticipated, future standardisation of these and related PA outcome measurements would aid cross-study comparability.There are several strengths and limitations of this review, which should be acknowledged. We did not take trials or qualitative studies into account, although we plan to analyse known clinician barriers such as a perceived lack of time and lack of reimbursement, which has previously been reported among AHPs , 48. OthThe research survey output reporting PA promotional practice in chiropractic has increased slightly over the last 10 years, with a high proportion of respondents for PA promotion remaining constant over the last 30 years. This is consistent with the increased recognition of PA by the WHO and their more recent ‘whole systems approach’, in response to the complex physical inactivity public health challenge globally . DespitePast reviews have explored HCPs own personal PA level, with some evidence suggesting higher participation in one’s own PA could translate into higher PA promotion in practice , 42, 50.Although further enquiry is needed, chiropractors (like other AHPs) are well positioned to promote PA to their patients in practice. The nature of chiropractic practice is one of multiple patient-clinician interactions, where chiropractors build rapport and trust with their patients, creating a therapeutic alliance and the likelihood for important follow up consultations . PA inteOur systematic review of cross-sectional surveys describes current attitudes and practices of chiropractors discussing, counselling, assessing, and providing information in relation to PA promotion. A high proportion of chiropractors surveyed are engaged in PA promotion, however methodological limitations within studies suggest caution be taken when interpreting results. Nevertheless, with the health benefits of PA well established, there is scope for chiropractors to be more involved in PA promotion in routine practice. Apart from the need for future unbiased surveys, forthcoming research initiatives should explore further PA education and training as well as capitalising on chiropractors’ own PA participation. This can further communicate the positive effects of PA on health-related quality of life by way of discussion, counselling or performing PA assessments.Additional file 1. Search strategy Medline, Mantis, AMED, EMBASE and Index to Chiropractic literature.Additional file 2. PRISMA flowchart describing the process of study selection.Additional file 3. Reasons for study exclusion.


Endothelial dysfunction and no-reflow share microcirculatory obstruction as a common pathophysiological mechanism. This study evaluated the relationship between systemic peripheral endothelial dysfunction assessed by flow-mediated dilatation (FMD) of the brachial artery and no-reflow in patients with ST-segment elevation myocardial infarction (STEMI) who received successful fibrinolysis.p = 0.006), and lower FMD . Also, they showed more endothelial dysfunction; however, this difference was statistically nonsignificant . One hundred and thirty-six patients (90.7%) had endothelial dysfunction. They were older , more smokers . Patients with normal endothelial function had a more myocardial blush grade (MBG) 3  in comparison with more MBG 2 in those with endothelial dysfunction . Endothelial dysfunction patients had nonsignificant more no-reflow . There was a significant weak positive correlation between thrombolysis in myocardial infarction (TIMI) flow and FMD  and a significant moderate positive correlation between MBG and FMD . Patients with TIMI I flow had significantly lower FMD compared with patients with TIMI II and TIMI III flow post-PCI. FMD ≤ 6% could predict post-procedural TIMI I flow.This study included 150 patients managed by the percutaneous coronary intervention (PCI) after successful fibrinolysis. Patients were divided according to coronary angiographic success into normal flow versus no-reflow groups. According to FMD measured through brachial artery ultrasound, patients were divided based on their endothelial function into endothelial dysfunction versus normal endothelial function. No-reflow occurred in 44 patients (29.3%). No-reflow patients had longer pain to door time (6.52 ± 1.82 vs 5.19 ± 1.85 h), more Killip class II . FMD ≤ 6% could predict TIMI I flow. Normal endothelium regulates vascular motor tone through the release of nitric oxide. Also, it regulates vascular hemostasis and maintains blood flow by preventing platelet adhesion, leukocyte activation, and uncontrolled coagulation. On the other hand, dysfunctional endothelium plays a pivotal role in the development and progression of atherosclerosis. Also, it increases the vulnerability of atherosclerotic plaques and the risk of myocardial infarction –4. RuptuNo-reflow is related to increased cardiovascular morbidity and mortality. The pathophysiological mechanism of no-reflow is complex and multifactorial . It inclThis study evaluated the relationship between systemic peripheral endothelial dysfunction assessed by flow-mediated dilatation (FMD) of the brachial artery and no-reflow in patients with STEMI who received successful fibrinolysis.This prospective observational study was carried out in our institution in the period between September 2019 until August 2021. It included patients presented with STEMI within 12 h from chest pain who received successful fibrinolysis as the reperfusion modality when primary PCI is not available within 120 min; they were scheduled for invasive coronary angiography within 24 h from fibrinolysis according to European society of cardiology (ESC) guidelines . The stuCoronary angiography was done through femoral or radial access using a 6F arterial sheath under local anesthesia, and intravenous pre-medications were given as needed. Infarct-related artery (IRA) was identified (left anterior descending artery (LAD), left circumflex artery (LCX), or right coronary artery (RCA)), then thrombolysis in myocardial infarction (TIMI) thrombus grade  and pre-Assessment of endothelial function was done by measuring FMD before coronary angiography. Brachial artery duplex was performed using a General Electric (GE) vivid S5 machine using 8L-RS linear array transducer (4–13 MHz) with clear anterior and posterior intimal surfaces. Patients were lying in a supine position with their hands at the level of the heart, blood pressure cuff was placed over the antecubital fossa. Then the ultrasound probe was placed at a level just above the antecubital fossa and a baseline resting trans-sectional image of the brachial artery was obtained to measure its baseline diameter. After that, a blood pressure cuff was inflated to 40 mm Hg above systolic pressure for a standardized time (5 min), then the cuff was rapidly deflated to allow reactive hyperemia. Brachial artery diameter was recorded during the first minute after the pressure release to detect the maximal reactive hyperemia at the same point of the baseline diameter measurement. FMD is the percent change in diameter from baseline and was calculated by dividing the difference between hyperemic diameter and baseline diameter by the baseline diameter and then multiplying by 100. FMD% = (D2 − D1)/D1 × 100, Where D1 is baseline brachial artery diameter and D2 is hyperemic brachial artery diameter, and FMD% less than 10% was used to diagnose endothelial dysfunction . The intt-test, and nonparametric variables were analyzed by Mann–Whitney U test. Using receiver operating characteristic curves (ROC), we determined the prediction utility of brachial artery FMD% for no-reflow. The margin of error accepted was set to 5% by setting the confidence interval to 95%, so the p-value was considered significant if p < 0.05.Data were collected, coded, and entered into IBM Statistical Package for Social Science (SPSS) version 23. Parametric numerical data were described by mean and standard deviation, while nonparametric numerical data was described by median and interquartile range (IQR). Non-numerical variables were presented as frequency and percentage. Analyses of qualitative variables were performed by chi-square. Parametric variables were analyzed by independent p = 0.006), higher CK-MB (136 (78.5–230.5) vs 69.5 (54–96) IU, p < 0.001), and lower ejection fraction (EF) . On comparing the findings of brachial artery ultrasound, the no-reflow group had significantly lower FMD . Also, they showed more endothelial dysfunction; however, this difference was statistically nonsignificant .The study flowchart is represented in Fig. p value ≤ 0.001), more smokers , and had a significantly higher incidence of family history of premature coronary artery disease . On comparing angiographic findings between both groups, there was no significant difference in baseline coronary TIMI flow and thrombus burden before PCI or post-PCI TIMI flow. However, on comparing MBG between both groups, patients without endothelial dysfunction had a higher incidence of MBG 3 (78.6% vs 26.5%) in comparison with a higher incidence of MBG 2 in those with endothelial dysfunction (41.9% vs 14.3%). However, on comparing the success of myocardial perfusion, endothelial dysfunction patients showed more no-reflow; however, this was not statistically significant .Patients were divided according to FMD into one-hundred and thirty-six patients (90.7%) with endothelial dysfunction, while 14 patients (9.3%) had a normal endothelial function with Table r = − 0.101, p = 0.217) or pain to door , while there was significant weak positive correlation between post-procedural TIMI flow and FMD   . Also, FMD ≤ 6% could be able to predict TIMI I flow.In the current study, the assessment of systemic endothelial function was done by measuring brachial arterial FMD which correlates with coronary endothelial function . EndotheIn comparison with the current study, Levi et al.  study diThe clinical importance of the findings of the current study may be summarized in two points. First, although endothelial dysfunction is not the only determinant of no-reflow, it is correlating with post-procedural angiographic success. So, measures taken to improve endothelial function may have a beneficial effect on angiographic success in the setting of acute myocardial infarction. Many studies evaluated the effect of different drugs on improving endothelial function , 21–23. One of the limitations of the study is that STEMI patients mostly have endothelial dysfunction. In the current study, nearly 10% only showed normal endothelial dysfunction. This small number of patients could explain that despite more no-reflow in those with endothelial dysfunction, this finding was statistically non-significant. The limitations of endothelial dysfunction assessment using this technique include the need for standardized protocols by trained personnel to maintain reproducibility, accuracy, and reliability , 26.In STEMI patients who underwent PCI within 24 h after successful fibrinolysis, those who had no-reflow showed worse peripheral systemic endothelial function as they had lower brachial artery FMD. Also, FMD showed a significant positive correlation with the post-procedural angiographic flow (TIMI flow and MBG). FMD ≤ 6% could predict TIMI I flow on PCI to IRA.These findings emphasize the relationship between endothelial dysfunction and no-reflow. Also, they may point to a potential reduction of no-reflow through improving endothelial dysfunction.