The incidence of breast cancer is rising worldwide. Recent advances in systemic and local treatments have significantly improved survival rates of patients having early breast cancer. In the last decade, great attention has been paid to the prevention and early detection of cardiotoxicity induced by breast cancer treatments. Systemic therapy-related cardiac toxicities have been extensively studied. Radiotherapy, an essential component of breast cancer treatment, can also increase the risk of heart diseases. Consequently, it is important to balance the expected benefits of cancer treatment with cardiovascular risk and to identify strategies to prevent cardiotoxicity and improve long-term outcomes and quality of life for these patients.This CardioTox Breast study aims to investigate the use of cardiac imaging, based on cardiac magnetic resonance and echocardiography, and to identify associated circulating biomarkers to assess early tissue changes in chemo-induced and radiation-induced cardiotoxicity in the time window of 12 months after the end of radiotherapy in patients with breast cancer.The CardioTox Breast trial is a multicenter observational prospective longitudinal study. We aim to enroll 150 women with stage I-III unilateral breast cancer, treated with breast conserving surgery, who planned to receive radiotherapy with or without systemic therapy. Baseline and follow-up data include cardiac measurements based on cardiac magnetic resonance imaging, echocardiography, and circulating biomarkers of cardiac toxicity.This study details the protocol of the CardioTox Breast trial. Recruitment started in September 2020. The results of this study will not be published until data are mature for the final analysis of the primary study end point.The CardioTox Breast study is designed to investigate the effects of systemic and radiation therapy on myocardial function and structure, thus providing additional evidence on whether cardiac magnetic resonance is the optimal screening imaging for cardiotoxicity.ClinicalTrials.gov NCT04790266; https://clinicaltrials.gov/ct2/show/NCT04790266DERR1-10.2196/31887 Incidence of breast cancer is rising worldwide. Due to developments in systemic and local therapies, median survival of early breast cancer patients has increased , resultiOur understanding of the pathophysiology and natural history of iatrogenic cardiotoxicity remains limited, and the diagnosis is carried out frequently only when cardiovascular disease presents clinically . CardiovTherefore, cardio-oncology is a rapidly developing subspecialty within cardiology, which aims to optimize the diagnosis and management of cancer treatment cardiac complications .The American Society of Echocardiography and the European Association of Cardiovascular Imaging define cardiotoxicity as a decline of LVEF ≥10% with a final LVEF <53%.Anthracyclines-based systemic therapy is considered as the prototype of type I cardiotoxic agents . It is bTrastuzumab, an anti-human epidermal growth factor receptor 2 (HER2) agent is considered a standard treatment in breast cancer overexpressing HER2. As a type II cardiotoxic agent, it induces cardiotoxicity that is usually reversible with its interruption or with HF treatment. Toxicity from type II agents is not related to cumulative dose and usually develops during treatment .The incidence of anthracycline-related cardiotoxicity is 3%-48% while it varies from 1.7% to 20.1% with trastuzumab.Due to their potential cardiotoxicity, anthracycline and trastuzumab are usually not administered concurrently .Radiotherapy (RT) can also increase the risk of several heart diseases . The relA synergistic effect on cardiac risk between left breast RT and cardiotoxic chemotherapy has been described even if its actual incidence is difficult to quantify and evaluate.Cardiotoxicity can be detected by different diagnostic methods. Circulating biomarkers could detect and predict cardiotoxicity. The 2014 American Society of Echocardiography guidelines the recommend measurement of troponin at baseline, before systemic therapy and 24 hours after, to aid in the detection of subclinical cardiotoxicity.Troponin and brain natriuretic peptide (BNP) have been investigated in many trials, but unfortunately with different results. Several studies have shown that the elevation of Troponin I may predict the development of future LVEF depression, and N-terminal pro b-type natriuretic peptide can predict the risk for radiation-induced cardiotoxicity ,8. Of noSeveral epidemiologic studies have shown a significant association between elevated plasma concentrations of high-sensitivity C-reactive protein (hs-CRP) and the prevalence of underlying atherosclerotic vascular disease, as well as the risk of recurrent cardiovascular events among patients with established disease and apparently healthy individuals -20.In 2012, Onitilo and his colleagues  publisheCardiac biomarkers could also be potential candidates to monitor cardiac damage after RT. Echocardiography (ECHO) is currently the standard method for detecting cardiotoxicity, usually by monitoring serial LVEF. A 3-dimensional modality is preferred to a 2-dimensional one because of better reproducibility . LVEF isCurrent guidelines suggest ECHO at baseline, after the end of anthracycline therapy, before the start of trastuzumab treatment, and every 3 months during trastuzumab treatment.Cardiac magnetic resonance (CMR) is the most accurate methodology for the evaluation of volumes and function of heart chambers. Additionally, it is exceptionally capable of providing myocardial tissue characterization, including the presence and extension of myocardial oedema (reflected in increased T2-weighted magnetic resonance imaging), hyperemia (assessed by an increment in early enhancement), and fibrosis  .Serial CMR imaging showed reduction in LVEF, 12 to 24 months after therapy, in women treated for breast cancer with anthracycline-based chemotherapy. Few recent studies have suggested that LVEF could start to decline earlier; however, the prognostic implications of these changes are not yet known. Recent preliminary experimental data suggest that the decline in contractile function is preceded by CMR evidence of myocardial oedema with T2 (transverse relaxation time) sequences and T2 mapping -27. FurtWhen biomarkers and cardiac imaging methods  are integrated, we could detect preclinical cardiotoxicity and prevent left ventricular dysfunction.Unfortunately, thus far, these studies have had a small sample size, and therefore we cannot draw any practice changing conclusion.In our opinion, it is important to better define high-risk patients who need intensive cardiovascular screening during and after cardiotoxic treatment. Our purpose is to detect toxicity when it is still subclinical and reversible and to prevent its deterioration with protective drugs administered to “the right patient at the right time.”This CardioTox Breast study  is a multicenter, observational, prospective, longitudinal study that includes female patients with left-breast and right-breast cancer treated with postoperative RT, with or without chemotherapy or hormonal therapy after primary breast conservative surgery. The patients will be followed for at least 1 year after RT, with cardiac imaging and circulating biomarkers (further detailed below). Three investigating centers are involved in the study: the Oncology Institute of Southern Switzerland , the North Estonia Medical Center , and Fondazione IRCCS Policlinico San Matteo . Furthermore, Cardiocentro Ticino is involved in the study as the center of analysis of CMR and echocardiography in Switzerland.We aim to enroll 150 female patients aged ≥18 years with stage I-III unilateral breast cancer treated with breast conserving surgery and planned to receive radiation therapy with or without systemic therapy.Inclusion criteria are as follows: (1) written informed consent must be obtained before any assessment is performed; (2) female, aged ≥18 years at visit 1; (3) performance status Eastern Cooperative Oncology Group (ECOG) 0-1; (4) stage I-III histology proven breast cancer ; (5) adjuvant RT and neoadjuvant anthracycline and/or trastuzumab-based therapy with or without hormonal therapy; and (6) negative pregnancy test (plasma human chorionic gonadotropin [hCG]) for all female participants of childbearing potential .Exclusion criteria are as follows: (1) known metastatic spread of any cancer; (2) known active or recurrent hepatic disorder , aspartate aminotransferase to alanine aminotransferase ratio of 2 x upper limits of normal; (3) renal function decrease (estimated glomerular filtration rate <30 ml/min); (4) known coronary artery disease; (5) angina pectoris; (6) positive or missing pregnancy test  at enrollment visit; (7) patients with baseline LVEF <53% and GLS <15%; and (8) patients with pacemaker.The patients will be recruited in participating centers. The investigators ensure that women will meet the inclusion criteria in the study and sign the written informed consent. On inclusion, patient demographics and proper medical history, including current medications and family history of cardiovascular disease will be recorded. A physical examination will be performed, including the measurement of blood pressure and pulse rate.A baseline assessment will be conducted before the start of adjuvant treatment by checking CMR, ECHO, an electrocardiogram to detect any arrhythmia, and blood sampling to analyze circulating biomarkers.CMR will be performed with Siemens Skyra 3T or a 1.5T scanner. All patients will undergo a standard protocol, including late gadolinium enhancement for estimated glomerular filtration rate >30 ml/min. For native T1 and postcontrast mapping, basal, midventricular, apical short axis, and 4-4-3 and 2 chamber apical images will be acquired by “ECG-triggered Modified Look-Locker Inversion recovery” sequence. Additionally, T2 mapping (T2-prepared True-FISP [fast imaging with steady-state free precession]) will be acquired on the same plane. The CMR images and maps will be analyzed offline. Late gadolinium enhancement will be quantified on short-axis stacks using a semiautomatic approach.Transthoracic echocardiography will be performed by using a Philips Epiq or General Electric Vivid E95. Images will be digitally stored for offline analysis on custom software. We will collect the parameters to detect myocardial dysfunction and deformation.Blood sampling will be carried out to analyze circulating biomarkers of cardiac injury. High-sensitivity cardiac troponin T, high-sensitivity cardiac troponin I, N-terminal pro-BNP, and inflammatory and anti-inflammatory mediators such as hs-CRP will be measured.patients will receive adjuvant chemotherapy in accordance with the international guidelines. Patients receiving cardiotoxic chemotherapy will be drawn blood before and, if possible, 24 hours after chemotherapy administration.Patients who receive anthracycline have an ECHO and electrocardiography after the end of this schedule.During trastuzumab, blood sample will be taken before every administration (every 3 weeks), and ECHO will be conducted after every 4 cycles (every 3 months).Patients will undergo a simulation chest computed tomography (CT) in free breathing and breath hold modality. Clinical target volume, the planning target volume, and the organs at risk will be drawn on the breath hold modality imaging if this modality improves the distance between breast and heart or left coronary artery (left anterior descending artery). An appropriate physical dosimetric study will be processed using treatment planning system and will be generated to achieve maximum coverage for the planning target volume region by minimizing the dose to the surrounding healthy tissues.For each contoured volume, we will analyze the minimum, maximum, and mean dose, and dose volume histogram will be evaluated for obtaining the best treatment.During follow-up, imaging (CMR and ECHO) and biomarkers will be checked 2 weeks after the end of RT and 1 year later. If a patient has symptomatic heart failure during the treatment, or if LVEF declines greater than 10% with a final LVEF <53% on ECHO, the patient will be referred to the cardiologist for a specific treatment. Adverse events will be classified according to the Common Terminology Criteria for Adverse Events. Data will be collected in a dedicated database. An accurate patient history, the type of cancer, and information on the main risk factors for a cardiac event are collected at the inclusion time. Cardiac imaging data (ECHO and CMR) and circulating biomarkers measurements are registered in the database.This study will be conducted in accordance with the Declaration of Helsinki  and in accordance with the principles of “Good Clinical Practice” and the Medical Research Involving Human Subjects Act. This study was approved by the ethics committee of the Oncology Institute of Southern Switzerland (ID 2019-01395) and by the local ethical committees of the other 2 investigating centers.The primary end point is the incidence of cardiotoxicity, as defined by consensus guidelines , measured on CMR and ECHO over the time window of 12 months from the end of radiation therapy.The primary objective is to assess the role of myocardial oedema on CMR (T2 mapping) after radiation and cardiotoxic systemic therapy in predicting the incidence of cardiotoxicity, as defined by consensus guidelines , measured on CMR and ECHO over the time window of 12 months from the end of radiation therapy.The secondary objectives are the following: (1) detect GLS decrease >15% from baseline, measured on ECHO over the time window of 12 months; (2) see if the changes in biomarkers will correlate with LVEF measurements, assessed by ECHO and CMR; (3) see if the changes in biomarkers will correlate with GLS measurements, assessed by ECHO; (4) compare the time to the biomarkers’ positivity to the time to decrease in GLS >15% or decline of LVEF ≥10% with a final LVEF of <53% measured on ECHO; (5) find out if patients with increased baseline biomarkers will develop cardiotoxicity, and identify predictors of cardiotoxicity by multivariable analysis; (6) detect major cardiovascular events  or death due cardiac problems during follow-up; (7) assess the role of fibrosis on CMR  after cardiotoxic radiation therapy or systemic therapy in predicting the incidence of cardiotoxicity; (8) detect the incidence of acute asymptomatic pericarditis after radiation therapy, measured on CMR; (9) investigate if the area of the oedema on CMR correlates with RT dose distribution; and (10) assess the incidence of myocardial oedema on CMR (T2 mapping) after radiation therapy and cardiotoxic systemic therapy, measured on CMR and ECHO over the time window of 12 months from the end of radiation therapy.Sample size of this multicenter study is evaluated based on feasibility. We hypothesize to be able to enroll 150 patients satisfying the enrollment criteria and giving consent to participate into the study. We base calculations on the primary end point.We use an alpha level of 10% one-sided test, given the lack of strong evidence in the literature (“early evidence” study). We used Stata 15 (Stata Corp) for computation.t test  and the Fisher exact test, respectively.Data at enrollment will be described as mean and standard deviation or median and 25th-75th percentiles if continuous and as counts and percent if categorical. They will be compared between groups of patients with and without oedema at the end of RT with the Student The number of patients with cardiac toxicity at 12 months will be compared between groups with the Fisher exact test. The mean difference in proportions of cardiac toxicity at 12 months and its 80% confidence interval will be reported. Logistic regression will be used to adjust for potential confounders. We do not expect losses to follow-up. A sensitivity analysis will classify them as no cardiac toxicity patients. If the mortality or losses to follow-up are above 10%, we will also compare groups using survival analysis methods to account for the different follow-ups between patients, using the same strategies.The data will be compared as described above. The time-to-event end points will be compared using survival analysis methods. The association of changes in biomarkers and changes in cardiac function will be assessed with linear regression models. Data transformation will be applied as needed. The details are provided in Multivariable analysis to identify potential predictors of cardiac toxicity will be performed, while considering a predictor-to-events ratio of 1:10 to avoid overfitting.Recruitment started in September 2020. The results of this study will not be published until data are mature for the final analysis of the primary study end point.CardioTox Breast is a multicenter prospective longitudinal study testing the role of CMR in predicting cardiotoxicity in patients with breast cancer. The study is designed to combine both cardiac imaging information regarding potential early myocardial dysfunction and anatomical coronary changes, as well as variations in circulating cardiac damage biomarkers.We will investigate the effects of systemic therapy and radiation therapy on myocardial function and structure, thus providing additional evidence on whether CMR is the optimal screening tool for cardiotoxicity. CMR is very promising for assessing the function and structure of the cardiovascular system and is starting to be investigated further in prospective studies .Cardiotoxicity can affect the quality of life of breast cancer survivors, whose numbers are increasing. It is important to distinguish high-risk patients who need intensive cardiovascular screening during and after cardiotoxic treatment.Cardiotox Breast results should improve the prediction and prevention of potential lesions to normal cardiac tissue and ultimately enhance patients’ care and quality of life.To our knowledge, this study is one of the first longitudinal studies with the primary aim of identifying any change in cardiac imaging (based on CMR and ECHO) and circulating biomarkers to predict the incidence of cardiotoxicity.


A healthy 11-year-old girl presented with exercise intolerance of unclear etiology, and her physical exam was notable for a 3/6 systolic ejection murmur at the left upper sternal border with radiation to the back. Extensive noninvasive workup consisted of ECG, transthoracic echocardiogram, and cardiac MRI/MRA, which were all nondiagnostic. She was ultimately referred for cardiac catheterization. Baseline invasive hemodynamics demonstrated a normal cardiac index and pulmonary vascular resistance but was notable for mildly elevated right and left end-diastolic pressures. A diagnosis remained elusive, so a 500 mL volume challenge was performed, which unmasked right and left ventricular waveform transformations to reveal the pathognomonic “square root sign” of restrictive cardiomyopathy with concordant RV/LV respirophasic variation. These findings and her clinical history allowed for the rare pediatric diagnosis of restrictive cardiomyopathy early in her clinical course, prior to the development of overt signs of pathologic myocardial remodeling, such as pulmonary hypertension and biatrial enlargement. An 11-year-old healthy female presented to her pediatrician for a well-child check with the new complaint of not being able to keep up with her peers during soccer due to shortness of breath and pain characterized as a shooting sensation down both legs. Physical exam was notable for a 3/6 systolic ejection murmur at the left upper sternal border with radiation to the back, mildly diminished lower extremity pulses, and normal four extremity blood pressures.z-score of -2.88) with a peak velocity of 2.1 m/s, but no discrete coarctation (2, normal PVR of 1.7 iWU, no arch gradient (An electrocardiogram was performed and demonstrated normal sinus rhythm, no atrial enlargement, no right or left ventricular hypertrophy, and no evidence of right or left ventricle strain. Transthoracic echocardiogram documented flow acceleration across the aortic arch with a peak velocity of 4 m/sec, normal systolic function with an ejection fraction of 70%, normal atrial and ventricular size, and no evidence to suggest decreased compliance. Cardiac MRI/MRA was ordered to further delineate anatomy, and it showed a crenellated aortic arch with mild hypoplasia of the proximal descending thoracic aorta (rctation . There wgradient , mildly gradient . CollectTo further investigate the significance of her elevated end-diastolic pressures, a 500 mL normal saline bolus was administered, acutely increasing the RVEDp and LVEDp to 16 and 20 mmHg, respectively. In addition to the rise in end-diastolic pressure, we observed a dramatic change in the diastolic waveform with unmasking of a “classic” square root sign and concordant RV/LV respirophasic variation . Four-chAs an outpatient at heart failure clinic, she was started on 10 mg of Lasix daily for symptom prevention. She had an unremarkable Holter monitor and exercise stress test. Genetic testing has not identified any known cardiomyopathy-associated genes to explain her restrictive phenotype.Now two years following diagnosis, she is asymptomatic on a daily diuretic. Interval hemodynamic evaluations and echocardiograms demonstrate preserved systolic function and no evidence of pulmonary hypertension. She continues to enjoy being active and participating on her soccer team at a competitive level.Restrictive cardiomyopathy is a rare diagnosis in the pediatric population with an incidence of 0.03-0.04 cases per 100,000 children . PatientThis patient presented early with exertional symptoms, and it was her nonspecific physical exam findings that led to the investigation for a cardiac etiology. Prior to cardiac catheterization, she had undergone an extensive workup with an echocardiogram and cardiac MRI/MRA, which were only significant for a mildly hypoplastic distal thoracic aortic arch—insufficient in explaining her symptoms. During her hemodynamic evaluation in the catheterization lab, her end-diastolic ventricular pressures were observed to be mildly elevated; however, the ventricular diastolic waveforms were not consistent with restrictive physiology or constrictive pericarditis. Considering the patient's NPO status and possibility that she was presenting with mild hypovolemia, a 500 mL bolus was administered to replete her volume status. Immediately, the RVEDp and LVEDp increased, the RV and LV diastolic waveforms transformed to reveal the “square root sign,” and the ventricular pressures demonstrated concordant respirophasic variation, findings consistent with restrictive cardiomyopathy –8. Thus,In conclusion, cardiac etiologies should be considered in patients with unexplained exercise intolerance, particularly in the setting of abnormal cardiovascular examination. Dehydration caused by routine fasting before cardiac catheterization may mask the characteristic hemodynamic findings of RCM. Careful fluid administration can unmask these findings, yielding a definitive diagnosis in otherwise unclear cases.


Angiotensin receptor neprilysin inhibitors (ARNI), sodium-glucose cotransporter 2 inhibitors (SGLT2i), soluble guanylate cyclase stimulators (sGCs), and the traditional golden triangle standard-of-care (SOC) are effective drugs for heart failure. We aimed to assess the efficacy of 4 interventions in these patients.PubMed, The Cochrane Library, Embase, and Web of Science databases were electronically searched to collect randomized controlled trials of 3 novel drugs in the treatment of heart failure from inception to September 1st, 2021. Two reviewers independently screened literature, extracted data, and assessed the risk bias of included studies. Stata 16.0 software was used for network meta-analysis.A total of 17 randomized controlled trial involving 38,088 patients were included. The results of network meta-analysis: in terms of heart failure rehospitalization rate, 3 novel drugs lower than SOC , and SGLT2i was also lower than sGCs . In terms of all-cause mortality, ARNI was lower than SOC . In terms of cardiovascular mortality, ARNI and SGLT2i was lower than SOC . In terms of rates of cardiovascular death or heart failure rehospitalization, 3 novel drugs lower than SOC . In terms of Kansas city cardiomyopathy questionnaire score, ARNI and SGLT2i was superior to SOC . In terms of N-terminal pro-B-type natriuretic peptide outcome indexes, SGLT2i was superior to SOC . The results of Surface under the cumulative ranking sequencing: in terms of heart failure rehospitalization rate and rates of cardiovascular death or heart failure rehospitalization, the ranking was SGLT2i>ARNI>sGCs>SOC. in terms of all-cause mortality and cardiovascular mortality, the ranking was ARN>SGLT2i>sGCs>SOC. in terms of Kansas city cardiomyopathy questionnaire score and N-terminal pro-B-type natriuretic peptide outcome indexes, the ranking was SGLT2i>ARN>SOC.The available evidence suggests that all 3 novel heart failure drugs can improve the prognosis of heart failure. ARNI may be the most effective in reducing mortality, SGLT2i may be the most effective in improving quality of life, while sGCs may be inferior to ARNI and SGLT2i. In recent years, as China has entered an aging country, the prevalence of heart failure has increased, and heart failure mortality in all ages has increased more than other cardiovascular illnesses in the same period. Optimizing the treatment of heart failure is extremely important. Traditional golden triangle therapy standard-of-care (SOC) includes angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB), β-receptor antagonists, and mineralcorticoid recept antagonists (MRA). This treatment option is still widely recognized. Both the Chinese guideline of 2018 and the European and American guidelines of 2021 have recommended as the basic therapy for heart failure .–6 Various national guidelines offer angiotensin receptor neprilysin inhibitor (ARNI) as an alternative to ACEI for individuals who still have symptoms after undergoing the SOC regimen .–6 With or without diabetes mellitus, the 2021 European Society of Cardiology guideline recommends the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in addition to the SOC regimen . The Soluble guanylate cyclase stimulator (sGCs) is currently in clinical trials and has a different mechanism of action than other targeted cyclic guanosine monophosphate (cGMP) pathways.,8 It can improve heart function and inhibit myocardial remodeling. The use of sGCs in clinical research has a lot of potentials.Heart failure is the main manifestation of the advanced stage of cardiovascular disease, and its mortality and rate of rehospitalization remain high for a long time. According to data, the prevalence rate of heart failure in Europe and America is 1.5% to 2.0%,The clinical efficacy of the 3 novel heart failure drugs is statistically significant, but there is a lack of direct comparison between the efficacy of the novel heart failure treatment regimen. This study will use network meta-analysis (NMA) to evaluate the different novel heart failure treatment regimens, to provide the evidence-based basis for clinical workers in the future.http://links.lww.com/MD2/B69)Because the network meta-analysis is a secondary analysis study, it does not involve ethical approval. PubMed, The Cochrane Library, Embase, and Web of Science databases were randomized searched by computer to collect randomized controlled trials (RCTs) on the comparison of different anti-heart failure treatment regimens for patients with chronic heart failure from the establishment of the database to October 1, 2021. At the same time, reference literatures of published studies were traced back, and paper versions of relevant conferences were manually read to supplement. .The following data were recorded: publication characteristics, countries or regions of the study, patient characteristics, New York heart association functional class, left ventricular ejection fraction, sample size, interventions, duration of follow-up, blinding, intention-to -treat analysis, and efficacy outcomes. The efficacy outcomes included rate of heart failure rehospitalization, all-cause mortality, cardiovascular mortality, rates of cardiovascular death or heart failure rehospitalization, the total symptom score on the kansas city cardiomyopathy questionnaire (KCCQ),2 test and I2 value were used to determine heterogeneity. If there was significant heterogeneity between studies, the source of heterogeneity was analyzed first. The outcome indicators were odds ratio (OR) for dichotomous variables and mean difference (MD) for continuous variables, with a 95% confidence interval (CI) as the test level. If the number of included studies was greater than 10, a funnel plot was made to evaluate whether the intervention had a small sample effect and publication bias. The network plot represents the sample size and relationship of the interventions. When there was a closed loop, the node-splitting method was used to test the inconsistency. If the difference was not statistically significant, and the consistency model was used for analysis. At the same time, the node-splitting method was used to test the local inconsistency. By surface under the cumulative ranking (SUCRA), the advantages and disadvantages of therapies were quantitatively compared. The larger SUCRA was, the more likely the treatment was to become the best treatment. Then, the efficacy of different therapies could be compared comprehensively.A random-effect model was constructed based on frequency theory, and Stata16.0 software was used for direct and network meta-analysis. χ–26 including 38,088 patients . SGLT2i was lower than SOC . sGCs was lower than SOC . SGLT2i was also lower than sGCs . There was no statistical significance among other interventions . There was no statistical significance among other interventions . It is speculated that the CURRENT study is likely to use a blank control. Of course, there are other possibilities. Due to the limitation of the small number of included RCTs, random-effects model was used for analysis. Results of network meta-analysis showed that ARNI was lower than SOC , and SGLT2i was also lower than SOC . There was no statistical significance among other interventions . SGLT2i was lower than SOC . sGCs was lower than SOC . SGLT2i was also lower than sGCs . There was no statistical significance among other interventions , and SGLT2i was also superior to SOC . There was no statistical significance among other interventions . There was no statistical significance among other interventions (Table A total of 7 RCTs were included.The funnel plot was drawn for publication bias test for the outcome index of cardiovascular death or heart failure rehospitalization. The results showed that the distribution of each study point was roughly symmetrical on both sides of the funnel plot, suggesting that there was little possibility of publication bias (The funnel plot inFig.  The results of this network meta-analysis showed that among the 4 interventions, the ARNI regimen was the most effective in improving the overall prognosis of heart failure, especially in reducing all-cause mortality or cardiovascular mortality. Although the ARNI regimen could significantly improve heart function, there was no statistically significant difference from the SOC regimen in reducing the outcome indicators of NT-proBNP. It may be related to the increased levels of natriuretic peptide, bradykinin, adrenomedullin, and other endogenous vasoactive peptides in its enkephalinase inhibitors.The representative drug of ARNI is sacubitril and valsartan sodium, which has good safety and tolerability. Compared with the use of ACEI drugs, this drug does not increase the incidence of adverse reactions such as serious angioedema, renal impairment, hyperkalemia, and coughing. The effect on basal heart rate and blood creatinine is small, and the effect of blood pressure control is better.,30 The results of the network meta-analysis showed that among the 4 interventions, the SGLT2i regimen had the best effect on the KCCQ score and NT-proBNP, and might be better than the ARNI regimen in reducing the rate of heart failure rehospitalization. The SGLT2i regimen had the most significant effect in improving the symptoms of heart failure and improving the quality of life. It may be inseparable from the effect of SGLT2i drugs on blood volume. Urinary sugar excretion reduces blood sugar, while reducing volume and blood pressure through osmotic diuresis and increasing diuretic sensitivity, without the adverse effects of increased heart rate caused by decreased blood volume. SGLT2i reduces the load on the heart and kidneys and improves the quality of life.SGLT2i is not only a new type of hypoglycemic agent, but also has a high value in the treatment of cardiovascular diseases. In addition to increasing urine glucose, reducing blood sugar, diuresis, and related hemodynamic effects, SGLT2i also has effects on myocardial metabolism, iontransporters, fibrosis, adipokines, and vascular function, thereby improving the prognosis of heart failure. The results of this network meta-analysis showed that among the 4 interventions, the efficacy of the sGCs regimen was slightly inferior to ARNI and SGLT2i regimens. In terms of reducing cardiovascular death or heart failure rehospitalization rate and heart failure rehospitalization rate, the sGCs regimen was more effective than the SOC regimen, but it did not reduce the risk of death. The sGCs regimen has shown the effectiveness of the treatment of heart failure, but the mechanism of action and clinical trials of sGCs are still under study. More large-scale clinical trials are needed to verify in the future.Vericiguat is a new type of oral soluble guanylate cyclase stimulator with a dual mechanism of increasing cGMP. On the one hand, sGC can be directly stimulated by binding sites unrelated to NO, and on the other hand, sGC can be sensitive to endogenous NO by stabilizing the NO-sGC binding sites, thus having a multi-dimensional protective effect on the heart.Some limitations of this study exist. First, in the included studies, the ejection fraction classification and heart failure comorbidities were different, which might affect the results of the study. Second, no closed loop was formed between the 4 interventions, which might affect the stability of the results. Third, in the outcome indexes of KCCQ Score and NT-proBNP, the number of studies that could be included was small, and the heterogeneity between them was slightly larger. Lastly, the length of follow-up of the included studies was different, which might have a certain impact on the long-term prognosis of heart failure.Due to the influence of indirection of evidence and sample size, it is hoped that in the future there will be a direct comparison of these 3 novel drugs in randomized controlled trials to verify the relationship between their efficacy.The available evidence suggests that all 3 novel heart failure drugs can improve the prognosis of heart failure, and the efficacy of the sGCs regimen may be inferior to the ARNI and SGLT2i regimens. The ARNI regimen may have the best efficacy in improving all-cause mortality and cardiovascular mortality. The ARNI and SGLT2i regimens have similar efficacy in improving cardiovascular death or heart failure rehospitalization rate and heart failure rehospitalization rate. The SGLT2i regimen may have the best curative effect in improving the KCCQ score and NT-proBNP outcome index.Conceptualization: Kai TangData curation: Jianli Wu, Lin LuoFormal analysis: Dejin LiInvestigation: Jiuju RanMethodology: Li ZhangProject administration: Dan WangResources: Dan ZhaoSoftware: Lin Luo, Min Yu, Xu YangSupervision: Lin Luo, Xu YangValidation: Anfang Chen, Lin Luo, Xu YangVisualization: Lin LuoWriting – original draft: Lin LuoWriting – review & editing: Lin Luo


Remote ischaemic conditioning (RIC) applied to the arm by inflation and deflation of a pneumatic cuff has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention (PPCI). However, the effect of RIC on left ventricular ejection fraction (LVEF) following infarct healing remains unknown.To investigate whether RIC applied in the ambulance before PPCI can improve left ventricular (LV) function in STEMI patients 3 months following infarction.Echocardiography was performed in a total of 694 patients from the CONDI-2 study a median of 112 days (IQR 63) after the initial admission. LVEF and LV end-diastolic and end-systolic volumes were calculated using the modified Simpsons biplane method of disks. LV global longitudinal strain (GLS) was estimated using 2-dimensional cine-loops with a frame rate > 55 frames/second, measured in the three standard apical views.There was no difference in the measured echocardiographic parameters in the RIC group as compared to the control group, including LV EF, LV GLS, tricuspid annular plane systolic excursion or left ventricular volumes. In the control group, 32% had an ejection fraction < 50% compared to 37% in the RIC group (p = 0.129).In this largest to date randomized imaging study of RIC, RIC as an adjunct to PPCI was not associated with a change in echocardiographic measures of cardiac function compared to standard PPCI alone. Remote ischemic conditioning (RIC) by 5-min cycles of ischemia and reperfusion has been proposed as an adjunct to primary percutaneous coronary intervention (PPCI) in patients with ST-elevation myocardial infarction (STEMI). This was initially demonstrated in animal models , 2, thenA prospectively pre-specified sub-analysis of the CONDI-2/ERIC-PPCI trial, assessing changes in cardiovascular magnetic resonance (CMR) parameters, did not demonstrate statistically significant differences between the control and intervention groups, however an improvement in Left Ventricular Ejection Fraction (LVEF) and Microvascular Obstruction (MVO) in the RIC group was demonstrated on the acute scan when specifically assessing Left Anterior Descending (LAD) STEMI . The resAs such, conclusive evidence regarding the effects of RIC on echocardiographic variables of cardiac function following healed STEMI are required. In this pre-specified CONDI-2 echocardiographic single-center sub-study, we investigated the effect of RIC on LVEF and global longitudinal strain using echocardiography at 3 month follow-up.The CONDI-2 study received ethical approval from regional and national health service research ethics committees and was conducted in accordance with the principles of good clinical practice. All participants provided written informed consent before randomization. This echocardiographic sub-study was planned prior to commencement of the multi-centre study.In the CONDI-2 study, patients with chest pain were included if they were older than 18 years of age, had ST-segment elevation on ECG, and were eligible for PPCI . PatientRIC was administered in the ambulance before PPCI in patients randomized to the RIC group. RIC was performed using an automated cuff  on the upper arm. RIC comprised of 4 consecutive periods of inflation and deflation of the cuff from 0 mmHg and 200 mmHg, lasting two consecutive periods of 5 minutes each. Patients randomized to control received standard therapy.All patients enrolled in the CONDI-2 echocardiographic sub-study underwent echocardiographic assessment according to guidelines . A GE ViLVEF and LV end-diastolic (LV EDV) and end-systolic (LV ESV) volumes were calculated using the modified Simpsons biplane method of disks. LV global longitudinal strain (GLS) was estimated using 2-dimensional cine-loops with a frame rate > 55 frames/second, measured in the three standard apical views. The tracking algorithm automatically traced the endocardial border and was manually adjusted as appropriate. The software automatically generated a 17-segment bullseye plot, with the presented values being an average of all 17 segments. Tricuspid Annular Plane Systolic Excursion (TAPSE) was measured using M-mode in the apical 4-chamber view. All echocardiographic analysis was performed in a blinded manner by two investigators experienced in echocardiography. The first 50 analyses were performed in co-operation by the two experts in order to establish a consensus.High-sensitivity troponin T was measured at admission and 6-8 hours, 24 hours and 48-72 hours following admission, as described in the study protocol  (p = 0.129). Neither LV volumes, LV GLS or (TAPSE) differed significantly between the 2 groups.LVEF was no different in the RIC group than in the control group  . In the p = 0.14).Subgroup analysis did not show significant differences with respect to coronary territories . AlthougOur study demonstrated no difference in measured echocardiographic variables within the RIC treatment group as compared to controls. In the cardiac magnetic resonance (CMR) sub-study of 169 patients in the CONDI-2/ERIC-PPCI trial, RIC did not reduce myocardial infarct size or improve LVEF at six months when assessed as a whole cohort. However, a difference was observed when LAD STEMI patients alone were compared on the acute scans . This obWe did not find any difference in GLS between the RIC and control groups. Previous data has suggested that GLS in the RIC group improves to a greater extent than that of the control group 1 month following STEMI . HoweverInterestingly, peak high-sensitivity Troponin T was similar between groups. This supports the neutral findings of the imaging parameters.These findings further support the neutral results regarding clinical endpoints observed from the multi-centre CONDI-2/ERIC-PPCI trial, indicating that RIC may not be effective as an adjunct to standard treatment for STEMI. This echocardiographic sub-study provides a good approximation of the participants of the CONDI-2/ERIC-PPCI , as the Other applications of RIC are currently being investigated. In a recent experimental study, repetitive remote ischaemic preconditioning was shown to ameliorate anthracycline-induced cardiotoxicity resulting in significantly higher long-term LV EF and less cardiac fibrosis . This apIn conclusion, in this largest to date randomized imaging study of RIC, there were no differences in measured echocardiographic variables by RIC as an adjunct to PPCI compared to standard PPCI alone. These results further support our previous findings that RIC did not improve clinical outcomes at 12 months in patients with STEMI undergoing PPCI.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Central Jutland Regional Committee on Health Research Ethics. The patients/participants provided their written informed consent to participate in this study.HB, SP, and WK were responsible for the conception and design of the study. PJ and CF performed the data acquisition. GW, PJ, AP, and WK performed the data analysis and interpretation. GW and WK wrote the manuscript. All authors reviewed and approved the manuscript prior to submission.


We assessed its performance in simulations and in patients with non-alcoholic fatty liver disease (NAFLD) and compared outcomes with bi-exponential LSQ and NN fits and tri-exponential LSQ fits. Scanning was performed using a 3.0T free-breathing multi-slice diffusion-weighted single-shot echo-planar imaging sequence with 18 b-values. Images were analysed for visual quality, comparing the bi- and tri-exponential IVIM models for LSQ fits and NN fits using parameter-map signal-to-noise ratios (SNR) and adjusted R2. IVIM parameters were compared to histological fibrosis, disease activity and steatosis grades. Parameter map quality improved with bi- and tri-exponential NN approaches, with a significant increase in average parameter-map SNR from 3.38 to 5.59 and 2.45 to 4.01 for bi- and tri-exponential LSQ and NN models respectively. In 33 out of 36 patients, the tri-exponential model exhibited higher adjusted R2 values than the bi-exponential model. Correlating IVIM data to liver histology showed that the bi- and tri-exponential NN outperformed both LSQ models for the majority of IVIM parameters (10 out of 15 significant correlations). Overall, our results support the use of a tri-exponential IVIM model in NAFLD. We show that the IVIM3-NET can be used to improve image quality compared to a tri-exponential LSQ fit and provides promising correlations with histopathology similar to the bi-exponential neural network fit, while generating potentially complementary additional parameters.Recent literature suggests that tri-exponential models may provide additional information and fit liver intravoxel incoherent motion (IVIM) data more accurately than conventional bi-exponential models. However, voxel-wise fitting of IVIM results in noisy and unreliable parameter maps. For bi-exponential IVIM, neural networks (NN) were able to produce superior parameter maps than conventional least-squares (LSQ) generated images. Hence, to improve parameter map quality of tri-exponential IVIM, we developed an unsupervised physics-informed deep neural network (IVIM The prevalence and degree of obesity and type 2 diabetes mellitus are increasing worldwide, resulting in a concomitant increase in non-alcoholic fatty liver disease (NAFLD), which is now the most prevalent global liver disease . NAFLD i2. NAFLD has the potential to alter IVIM parameters in multiple ways. In the case of fibrosis, it can be theorized that the increased collagen depositions in the liver restrict the free movement of water molecules, leading to a reduction in the diffusion parameters, while increased hepatic resistance amongst others can lead to a reduction in hepatic perfusion. Li et al. show that while absolute values tend to vary between studies, typically a decrease in all three IVIM parameters is observed as fibrosis stage increases (IVIM assesses tissue diffusivity and perfusion reflected by random motion of water molecules in the intracellular and extracellular spaces as well as in the tissue (micro)circulation, respectively . Data acncreases . Hepaticncreases .Recent literature suggests that the bi-exponential IVIM model may be insufficient for fitting the liver’s complex structure. The marked signal decay in the IVIM signal intensity plots seen at low b-values has given rise to the hypothesis that a tri-exponential model will provide a more accurate representation of the data and improve fit accuracy . Herein, vessels . Availab vessels , seen byAlthough tri-exponential fitting more accurately describes the data, fitting of this complex model is challenging and current least-squares (LSQ) methods typically lead to noisy parameter maps, particularly in the case of pseudo-diffusion. As a result, tri-exponential fits are often done using averaged data from a region of interest (ROI), or even averaged data from multiple subjects, instead of voxel-wise fitting, reducing clinical diagnostic applicability.in-vivo MRI data (IVIM-NET)   was impl3-NET). To show our network works, we compared the performance of IVIM3-NET to LSQ fitting in simulations. We then tested the tri-exponential versus bi-exponential model in patients with various stages of NAFLD, and compared the use of IVIM-NET and IVIM3-NET to conventional bi- and tri-exponential LSQ fits.Therefore, in this work, we aim to investigate the value of a deep neural network to fit a tri-exponential model to IVIM data in NAFLD. We split up the research into two sub-questions: firstly, does the parameter map quality improve when introducing neural networks for fitting the bi- and tri-exponential models? Secondly, is there an added value of tri-exponential fitting in the non-invasive grading of NAFLD disease severity? To address these questions, we have developed a deep neural network to fit a tri-exponential model to IVIM data (IVIMPatient data were collected as part of the ongoing Amsterdam NAFLD-NASH cohort (ANCHOR) study as described in previous work . In this2 and elevated aspartate aminotransferase and/or alanine aminotransferase levels were included. The main exclusion criteria were contraindications for undergoing MRI, any condition or risk factors potentially leading to liver disease besides NAFLD , conditions or risk factors leading to bleeding disorders and decompensated liver cirrhosis or hepatocellular carcinomas. Participants were required to fast for a minimum of 4 h before diagnostic tests.36 individuals with known hepatic steatosis (confirmed on ultrasound), a BMI >25 kg/m-values were acquired: 0, 1, 2, 5, 10, 20, 30, 40, 50, 75, 100, 150, 200, 300, 400, 500, 600, and 700 s/mm2 in three orthogonal directions. The following acquisition parameters were used: repetition time 7,000 ms, echo time 45.5 ms, bandwidth 20.8 Hz/pixel in phase encoding direction, field-of-view 450 × 295 mm2 with a 3.0 × 3.0 mm2 acquisition resolution, 152 × 97 acquisition matrix, 27 slices with a 6.0 mm slice thickness and 1.0 mm slice gap, parallel imaging factor (SENSE) 1.3, partial averaging factor 0.6, spectral attenuated inversion recovery (SPAIR) fat suppression and three saturation slabs to suppress signal from the anterior abdominal wall. The total acquisition time was 8.1 min.MRI scanning was performed using a 3.0T MRI scanner  with a 16-channel phased-array anterior coil and 10-channel phase-arrayed posterior coil. IVIM data were acquired using a free-breathing multi-slice diffusion-weighted single-shot echo-planar imaging sequence. Eighteen unique bliver). Four different models were used to fit the ROIliver, all implemented in Python (version 3.6.12). These consisted of our newly developed IVIM3-NET tri-exponential fit, the IVIM-NET bi-exponential fit, and the LSQ bi- and tri-exponential fits. Data were normalized to the S(b = 0 s/mm2) for all fitting methods. For the deep learning approaches, we used PyTorch (1.8.1) whereas the least-squares fitting was done with scipy’s (1.5.2) optimize. curve_fit function. All fitting methods can be found on https://github.com/oliverchampion/IVIMNET (commit 751f272 on 14 Dec 2021).Images were analysed by a single observer (M.T.) with 4 years of experience in hepatic MRI. The entire liver was manually segmented using reconstructed b-value = 0 images, avoiding liver edges and any areas or slices containing (motion) artefacts . Fitting was done in a parallel routine, using eight cores from an Intel(R) Xeon(R) Gold 6132 CPU at 2.60 GHz and fitting times were recorded.To determine goodness of fit, the bi- and tri-exponential LSQ models were also separately fit in a ROI-wise manner using the ROI–5.IVIM-NET bi and tri-exponential fits were also performed voxel-wise. The IVIM-NET bi-exponential fit was performed following previously published work, using a fully-connected network per IVIM parameter  in a side-by-side fashion. Image preference was recorded per slice per patient based on subjective image quality analysis.3-NET tri-exponential approach, we ran simulations and determined the root mean square error between the predicted parameters and the ground truth parameters used to simulate the data. To train the network, 5,000,000 signal curves were simulated at the same b-values acquired in vivo, using randomly selected IVIM parameters ranging from 0.5 × 10−3 mm2/s > D > 3 × 10−3 mm2/s, 0.05 > f > 0.3, 10 10–3 mm2/s mm2/s > D1>50 × 10−3 mm2/s, 0.05 > f2>0.3 and 0.2 mm2/s > D2>4 mm2/s. These boundaries were representative for values found in vivo. Random Gaussian noise was added with SNR exponentially distributed between 10 and 100. From preliminary results, we found there were two local minima for training, and three out of 10 networks ended up in a poorly performing local minima, with loss substantially higher than the other 7. Therefore, training was repeated 10-fold and the network with the lowest unsupervised training loss was used for further analysis. Four new datasets were created for testing, each consisting of 300,000 randomly generated tri-exponential IVIM curves from similarly distributed parameter values. Each dataset had a different SNR, namely, 15, 20, 30 and 50. Both the trained IVIM3-NET and LSQ fit were performed on these new datasets and the root-mean-square errors (RMSE) between their predicted values and the ground truth values were taken as measures for performance.Simulations run in previous work for the bi-exponential IVIM-NET showed that the neural network approach resulted in a smaller error compared to other methods, particularly when compared to the LSQ fit . To confPercutaneous ultrasound-guided liver biopsies acquired after MRI scanning were assessed by an experienced liver pathologist (J.V.). Biopsy length and biopsy quality assessment discerning poor quality, suboptimal quality and good quality were recorded for each sample. Histology specimens were scored according to the steatosis, activity and fibrosis score . SteatosThe statistical analysis was performed using R version 3.6.3 .SNR) was selected in the right liver lobe in homogenous liver tissue, avoiding liver edges, (motion) artefacts and visible vessels. For each individual, the SNR was defined as the ratio of the mean parameter value within ROISNR and the standard deviation from this same ROISNR. Differences between means and SNRs of the bi- and tri-exponential models were assessed using Wilcoxon signed-rank tests. A p-value < 0.05 was considered statistically significant.The SNR of the parameter maps within homogeneous liver tissue was used to determine whether the NN fitting approach was less noisy than the LSQ approach. A separate ROI  included in the ANCHOR study were analysed in this work. The average liver biopsy length was 1.81 cm (SD = 0.55). 20 biopsy specimens were classified as good quality, 11 as suboptimal quality and two poor quality. Quality assessment was not available for three patients included. Liver fibrosis was found on biopsy in all but two patients (F0). Seven patients were classified as F1, nineteen as F2, seven as F3 and one as F4. All patients showed a steatosis level ≥1 on biopsy, of which 20 patients had S1, twelve S2 and four S3. Three patients had a disease activity grade of A0, twelve A1, fifteen A2, five A3 and one A4.3-NET was able to provide smoother parameter maps with less extreme outliers than the LSQ fit . For the tri-exponential approach, the network took a median of 12.2 min to train, with a range of 3.4–16.2 min, and 52 s to inference (1.5 × 10−5 s per voxel). The least-squares fits took substantially longer, with 85 min (150 × 10−5 s per voxel) for bi-exponential fitting and 166 min (300 × 10−5 s per voxel) for tri-exponential fitting. Training took a median of 91 epochs before converging.For the bi-exponential approach, the network took a median of 8.7 min to train, with a range of 6.5–12.8 min, and 40 s to inference , with a higher adjusted R2 for the tri-exponential model in 33 out of 36 patients. The bi-exponential and tri-exponential R2 values of each individual along with example fits of the best and worst performing tri-exponential fit compared to bi-exponential fit can be found in The average adjusted 3-NET showed a significant decrease in s = -0.43, p = 0.0097), s = -0.47, p = 0.0036), s = -0.55, p < 0.001) and s = -0.59, p < 0.001) with increasing fibrosis stage. s = 0.36, p = 0.033). Significant differences in medians between fibrosis stages were seen for 2 = 11.18, p = 0.025, df = 4), 2 = 11.00, p = 0.027, df = 4) and 2 = 14.43, p = 0.0060), while post-hoc analysis only showed a significant difference between fibrosis stage 0–3 for IVIMd f1+2 .3-NET parameters except s = -0.35, p = 0.040 s = 0.42, p = 0.011; s = -0.36, p = 0.029; s = -0.49, p = 0.0024; s = -0.48, p = 0.0029) was observed, with 2 = 9.77, p = 0.044, df = 4; χ2 = 9.97, p = 0.041, df = 4 respectively). Post-hoc analysis, however, did not provide significant differences between individual disease activity grades (A significant correlation was observed between disease activity grade and all IVIMy grades .3-NET parameter and no significant differences between group medians were found (Steatosis grade did not correlate with any IVIMre found .3-NET is the first neural network able to provide high-quality tri-exponential IVIM parameter maps and IVIM3-NET is shared on our GitHub. We had four main findings: first, IVIM3-NET provides substantially more precise parameter estimates. This was confirmed in simulations, where the RMSE was considerably lower for the IVIM3-NET than LSQ fits for all parameters and at all SNRs. The better estimates resulted in improved parameter map quality, as both neural networks provided a less noisy fit than the LSQ fits. Second, the neural network was substantially faster and produced parameter maps in times that would allow for immediate on-console evaluation. Third, the majority of patients with NAFLD displayed a significantly higher adjusted R2 for the tri-exponential model compared to the bi-exponential model, suggesting that the data behaves in a tri-exponential manner and hence should be fitted by a tri-exponential model. However, we did not find a clear clinical advantage of the tri-exponential model parameters compared to the bi-exponential model parameters in our cohort. Fourth, correlating IVIM data to liver histology results from patients with varying levels of NAFLD severity showed that both the IVIM3-NET and IVIM-NET showed similar diagnostic performance, while generally outperforming both the bi- and tri-exponential least-squares models.Our IVIMR2 in the majority of subjects.Multiple studies in healthy volunteers support the use of a tri-exponential model for assessing IVIM scans of the liver. For example, The clinical added value of the extra compartment is less clear in our cohort, as both the bi- and tri-exponential models showed comparable correlations with histopathology. However, NAFLD is known to cause vascular changes , thus pa vessels . We (visfibrosis , which cWhile our cohort contained the full spectrum of NAFLD disease severity, only a single patient had fibrosis stage 4 and two with fibrosis grade 0. Similarly, for disease activity, only a single patient exhibited grade A4. This is a large limitation of the current study and future studies with larger cohorts with more patients in the higher and lower ranges of disease severity will be required to confirm the results and potentially improve disease severity stratification.3-NET than LSQ fit, in particular at lower SNRs, confirming the results seen for the bi-exponential IVIM-NET (3-NET parameters as a non-invasive biomarker in NAFLD. Moreover, with the improved image quality, additional information may be available. Improved image quality allows for the analysis of images in a voxel-wise manner and may be able to provide more insights into disease pathophysiology. The visual decrease of areas with high signal intensity on The use of a neural network for the generation of IVIM parameter maps resulted in higher quality images when compared to a least-squares fit, and in a fraction of the time. Simulated data shows a smaller error for the IVIMIVIM-NET . A highe–3 mm2/s which is in line with what we found with the IVIM3-NET and higher than our tri-exponential LSQ fit as seen in –3 mm2/s. The largest variation was found in the –3 mm2/s. The 3-NET values were at the high end of the range. The 3-NET only.For healthy volunteers, an overview of average tri-exponential IVIM-values was published in a recent review . Values Discrepancies between values found in this study and previous studies could in part be explained by intrinsic effects caused by NAFLD. We would expect the values in the literature derived from healthy volunteers to be most comparable to patients exhibiting a lesser NAFLD severity, i.e. low levels of fibrosis and disease activity. From 2. Despite this, our IVIM3-NET showed 3-NET is relatively uninfluenced by the presence of noise compared to the LSQ fit. Comparison of other optimisation techniques such as free-breathing acquisitions versus respiratory or navigator triggering, as well as motion correction methods are not yet available for tri-exponential fitting and are likely to influence absolute parameter values. In future work these effects will need to be further assessed to optimise and standardize scan protocols.The wide spread in ncreased . The b-vBayesian fitting techniques resulted in comparable parameter map quality to the IVIM-NET for bi-exponential fitting, however, are impractical for tri-exponential fitting due to long calculation times . SettingIn this study, we adapted the IVIM-NET physics-informed deep neural network to include tri-exponential fitting. We chose a physics informed loss function as it allows for training on patient data without inputting any ground-truth answers. Conventional loss functions are also available , but the3-NET can be used to produce high quality IVIM parameter maps, displaying less noise than a tri-exponential LSQ fit and providing strong correlations with liver histopathology scores, the current gold standard to diagnose and grade NAFLD.In conclusion, the use of a tri-exponential IVIM model can be applied in patients with NAFLD and the IVIM


Current knowledge about the relationship between physical activity (PA) and cardiac remodeling is mainly derived from cross-sectional studies of athletes, and there is a knowledge gap of this association in the general adult and elderly population. Therefore, we aimed to explore the longitudinal association between cumulative PA and change in cardiac structure and function in a general adult and elderly population.This longitudinal study includes 594 participants from the sixth  and seventh  survey of the Tromsø Study. Cardiac structure and function were assessed by echocardiography at two time points, and PA was self-reported by questionnaire at both time points. PA volume was expressed as cumulative PA  and the association with left atrial (LA) and left ventricular (LV) structure and function was assessed using ANCOVA.2, 95% CI 0.01–0.15, p = 0.020) from Tromsø6 to Tromsø7. When stratified by sex or age, higher levels of cumulative PA were associated with increased LADi in males and in participants <65 years only. Indexed LV mass (LVMi) increased significantly more in Moderate than in Low PA . When stratified by sex or age, these changes in LVMi and indexed LV diameter (LVDi) were only significant in females. No significant associations were observed between cumulative PA and change in relative wall thickness, E/e' ratio, e' velocity, LV ejection fraction, and LADi/LVDi ratio.Overall, LA diameter index (LADi) increased significantly more in Hard compared to Moderate PA (+0.08 cm/mHigher levels of cumulative PA were associated with increased LADi in males and participants <65 years, and with increased LVMi and LVDi in females. Despite cardiac chamber enlargement, the pump function of the heart did not change with higher levels of PA, and the atrioventricular ratio was unchanged. Our results indicate that cardiac chamber enlargement is a physiological response to PA. Changes in cardiac structure and function can occur as a result of physiological remodeling from exercise or pathological remodeling . WhereasExercise-induced cardiac remodeling is generally considered a benign physiological adaption of exercise, and is characterized by enlarged cardiac chambers and increased LV wall thickness . ParadoxCurrent knowledge about the relationship between physical activity (PA) and cardiac remodeling is mainly derived from cross-sectional studies of athletes , and theThe Tromsø Study is a single-center population-based cohort study with seven repeated health surveys of the population of the Tromsø municipality, Norway . This stn = 21). Furthermore, eight participants were excluded due to missing data on the covariate hypertension. Finally, our analytical sample consisted of 594 participants free from valvular heart disease, and with valid data on PA, echocardiography, and covariates at baseline  ultrasound scanner and for Tromsø 7 collected from August 2015 to October 2016 using a GE Vivid E9  ultrasound scanner. The echocardiographic assessments were performed with the use of standard imaging planes in the left lateral decubitus position according to the joint American and European guidelines . In Trom2  / . LV myocardial mass was calculated according to the cube formula .Blood pressure was recorded three times with 1 min intervals after 2 min seated rest with an automatic device , the average from reading two and three was used in our analyses. Blood pressure was classified into hypertension groups : (a) NorData on atrial fibrillation was derived from the diagnosis registry of the University Hospital of North Norway, the only hospital in the region, by linking the hospitals records of atrial fibrillation to the participants' unique Norwegian national 11-digit identification number . Blood sn). The associations between cumulative PA and cardiac structure and function were evaluated by one-way analysis of covariance with Bonferroni adjusted post hoc comparisons. Data are presented as adjusted means with standard error (SE), and effects with 95% confidence intervals (CI) unless otherwise stated. Model 1 is unadjusted, model 2 is adjusted for age, sex, body mass index, and hypertension groups.Descriptive characteristics of the study population are presented as means with standard deviations (SD) or percentages with number of observations (*PA was a significant interaction term in the association between PA and change in LA diameter (p = 0.024), body mass index*PA was a significant interaction term between PA and change in E/e' ratio (p = 0.028), and hypertension (normotensive/hypertensive)*PA was a significant interaction term between PA and change in average e' (p = 0.040).SexTo test the robustness of the fully adjusted model 2, we performed sensitivity analyses excluding participants with known cardiac pathologies  stepwise. Moreover, we performed sensitivity analysis adjusted for additional covariates  stepwise added to the model.For sensitivity analyses of the PA assessments, we compared the mean PA score in Tromsø6 with the mean PA score in Tromsø7, stratified by level of cumulative PA , to asseAll statistical analyses were performed using SPSS version 28 , with a two-sided alpha ≤ 0.05 considered statistically significant.In total, 266 males (61.1 ± 8.9 years) and 328 females (58.9 ± 9.9 years), ranging from 37 to 76 years, were included in our study. Descriptive baseline characteristics of the analytical sample, stratified by PA, is given in p = 0.018) and LVMi (p = 0.037) between groups of cumulative PA in multivariate adjusted analyses  (p = 0.128) and Moderate and Low PA (p = 1.000).Overall, from Tromsø6 to Tromsø7, LADi increased significantly more in Hard compared to Moderate PA, with a mean group difference in LADi enlargement of 0.08 cm/m= 0.020) . No sign2, SE 0.03) than in Moderate  and Low PA , with a mean group difference of 0.12 cm/m2  between Hard and Low, and a mean group difference of 0.16 cm/m2  between Hard and Moderate PA. No statistical difference between Moderate and Low PA was observed (p = 1.000). In females, no differences were observed (p = 0.852).In sex-stratified adjusted analysis , LADi in2, SE 0.03) PA, with a mean group difference of 0.10 cm/m2 . No statistical difference between Hard and Low PA (p = 0.474), or between Moderate and Low PA (p = 1.000) was observed. No statistical differences in LADi between groups were observed for participants ≥65 years (p = 0.262).In age-stratified adjusted analysis , LADi inAssociations between cumulative PA and cross-sectional LADi in Tromsø7 are presented in 2.7  (p = 0.172) and Hard and Moderate PA (p = 1.000).Overall, from Tromsø6 to Tromsø7, LVMi increased significantly more in Moderate compared to Low PA, with a mean group difference in LVMi enlargement of 3.9 g/m= 0.037) . No sign2.7 , and in Moderate than Hard PA, with a mean difference in LVMi enlargement of 4.1 g/m2.7 . No significant difference between Hard and Low PA (p=1.000) was observed. In males, no significant differences were observed (p = 0.224). In age-stratified adjusted analysis (p ≥ 0.182).In sex-stratified adjusted analysis , LVMi inanalysis , no sign2 ± SE 0.03) than in Low PA , with a mean group difference of 0.13 cm/m2 . However, no significant differences in LVDi change were observed between Hard and Low PA (p = 0.087) and Hard and Moderate PA (p = 1.000).In analysis of the association between cumulative PA and change in LVDi, significant associations were observed in females only . LVDi inAssociations between cumulative PA and cross-sectional LVMi in Tromsø7 are presented in p = 0.075), stratified by sex (p ≥ 0.065), or stratified by age (p ≥ 0.083) was non-significant (p = 0.903), stratified by sex (p ≥ 0.529), stratified by age (p ≥ 0.749), or stratified by hypertension (p ≥ 0.196) (p = 0.253), stratified by sex (p ≥ 0.286), stratified by age (p ≥ 0.213), or stratified by body mass index (p ≥ 0.180) (p = 0.970), stratified by sex (p ≥ 0.652), or stratified by age (p ≥ 0.556)  . No sign≥ 0.180) . No sign≥ 0.556) .p = 0.068).When we stepwise, or jointly, excluded participants with known cardiac pathologies, we observed rather similar associations between cumulative PA and change in echocardiography measurements as in the fully adjusted model 2 . FurtherExercise-induced cardiac remodeling is well documented in athletes. Our longitudinal study adds to this knowledge by showing that more moderate levels of habitual PA over time is associated with cardiac remodeling also in a general adult and elderly population. The main finding from our study is that higher levels of cumulative PA was associated with increased LA size in males and in participants <65 years, and that moderate level of cumulative PA was associated with increased LV size in females.Despite the association between cumulative PA and increased LA and LV sizes, indices of cardiac pump function and atrioventricular remodeling did not differ significantly between groups of cumulative PA. This may indicate that cardiac chamber enlargement is a physiological response to PA.In our study of the general population, we observed that Hard cumulative PA was associated with a larger increase in LADi than lower PA levels; although when stratified by sex or age, increased LADi was only observed in males and in participants <65 years. Furthermore, Moderate cumulative PA was associated with increased LVMi and LVDi, but only in females when stratified by sex or age.Our observations are at large consistent with previous studies of athletes. Several meta-analyses have reported that LA and LV sizes are larger in endurance trained athletes compared to non-athletes or sedentary controls , 30–32. Furthermore, the relationship between endurance training and enlarged LA volume and LV volume has been confirmed in middle-aged sedentary males and females after 10 months high-intensity endurance training ; both LAThe findings from the previously discussed studies demonstrate that extensive LA and LV remodeling requires high amounts of endurance training stimuli over a long time. Similarly, our results indicate that the left atrium adapts faster to exercise than the left ventricle, and that sufficient and potentially higher stimulus from exercise intensity and volume is required for the left ventricle to remodel. The faster LA remodeling may be explained by the fact that the LA walls are thinner than the LV walls , and theIt is well documented that the prevalence of cardiovascular risk factors such as hypertension increase progressively with age, with a prevalence of 60% in participants ≥60 years . UntreatThe observed sex differences in the association between cumulative PA and LA size may be explained by physiological and morphological differences between males and females . FemalesDespite the association between cumulative PA and increased LA and LV sizes, no significant differences in mitral annular e' velocity, E/e' ratio, LV EF, or LADi/LVDi ratio were observed between groups of cumulative PA. Thus, our results demonstrate that changes in indices of LV diastolic and systolic function, and atrioventricular chamber ratio, do not differ between groups of cumulative PA. The observed cardiac chamber enlargement with higher levels of cumulative PA in our study seems to be a physiological adaptation to exercise.Our observations are consistent with previous reports of preserved cardiac function in athletes with exercise-induced cardiac remodeling. Studies of endurance athletes and elite soccer players have observed that LV diastolic function, as measured by Mitral valve and/or Tissue Doppler imaging, is preserved or even supranormal in athletes with cardiac chamber enlargement , 38, 44.In contrast, Lakatos and colleagues observed normal, but lower LV systolic function, as measured by LV EF and/or LV global longitudinal strain, in elite endurance athletes compared to non-athletes . SimilarOur observations of a balanced LADi/LVDi ratio, despite increased LA and LV sizes, is consistent with studies observing symmetrical enlargement of all four chambers , and thaIn contrast to preserved pump function and balanced remodeling in the athlete's heart, increased risk of atrial fibrillation is seen in both adult and elderly endurance athletes , 49. It The main strength of our study is the longitudinal design with repeated measurements of PA and echocardiographic structural and functional data, which enables evaluation of the direction of the associations as well as change from baseline. Moreover, the broad diversity of covariates allowed us to adjust for multiple potential confounders.r = 0.42), and between LADi and LA volume index (r = 0.45). Furthermore, LVDi correlated strongly with LV volume index (r = 0.87). Third, our study lacks assessment of LA function which may distinguish between pathological and physiological remodeling  , which strengthens our external validity to other Northern-European Caucasian adult populations.Our study has several limitations that should be addressed. First, due to the observational nature of this study, causation cannot be established. Second, LADi, LVDi, and LV EF were assessed by linear measurements, which are less accurate and have more geometrically assumptions than the recommended biplane volume calculated parameters . Howeverex r = 0.7. Third,modeling , and mis< 0.001) . Moreove< 0.001) . This is< 0.001) . Fifth, In conclusion, higher levels of cumulative PA were associated with increased LADi in males and participants <65 years, and with increased LVMi and LVDi in females. Despite the association between cumulative PA and cardiac chamber enlargement, the function of the heart did not change with higher levels of PA, and the atrioventricular ratio was unchanged. This indicate that cardiac chamber enlargement is a physiological response to PA.The datasets presented in this article are not readily available because the legal restriction on data availability is set by the Tromsø Study Data and Publication Committee to control for data sharing, including publication of datasets with the potential of reverse identification of deidentified sensitive participant information. The data can however be made available from the Tromsø Study upon application to the Tromsø Study Data and Publication Committee. Requests to access the datasets should be directed to the Tromsø Study, Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway; e-mail: tromsous@uit.no.The studies involving human participants were reviewed and approved by Regional Committee for Medical and Health Research Ethics, Tromsø, Norway (20828/REK Nord). The participants provided their written informed consent to participate in this study.KH, BW, and BM contributed to conception or design of the work. KH drafted the manuscript. All authors contributed to acquisition or analysis of the data. All authors contributed to interpretation of the data, critically revised the manuscript, gave final approval, and agree to be accountable for all aspects of work ensuring integrity and accuracy.KH was supported by the Northern Norway Regional Health Authority (Grant Number HNF1406-18).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Objective: This study aimed to evaluate the intervention effect of curcumin in myocardial infarction rodent models.Methods: A systematic retrieval of relevant studies on curcumin intervention in rats or mice myocardial infarction models was conducted, and the data were extracted. The outcome indicators included biochemical blood indicators, such as creatine kinase (CK), creatine kinase isoenzyme (CK-MB), malondialdehyde (MDA), lactate dehydrogenase (LDH) and superoxide dismutase (SOD), as well as cardiac tissue structure indicators, such as left ventricular weight to body weight ratio (LVW/BW), apoptosis index, left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic diameter (LVESD), and myocardial infarction area, and hemodynamic indexes, such as systolic blood pressure (SBP), diastolic blood pressure (DBP), left ventricular end-diastolic pressure (LVEDP), left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), maximum rate of left ventricular pressure rise (+dp/dtmax), and maximum rate of left ventricular pressure decline (–dp/dtmax). These results were then analyzed by meta-analysis. Studies were evaluated for methodological quality using the syrcle’s bias risk tool.Results: A total of 24 studies were included in the meta-analysis. The quality assessment of included studies revealed that the evidence was low quality and none of studies was judged as having a low risk of bias across all domains. The results revealed that curcumin could reduce CK-MB, CK, LDH, and MDA levels. They also revealed that it could lower SBP, DBP, LVEDP, LVW/BW, apoptosis index, LVEDD, LVESD, and myocardial infarction area and increase LVEF, LVFS, +dp/dtmax, and–dp/dtmax. However, it had no significant impact on the heart rate and the levels of SOD in the models.Conclusion: Curcumin alleviates myocardial injury and oxidative stress in myocardial infarction rodent models in terms of blood biochemistry indicators, improves the diastolic and systolic capacity of the ventricle in terms of hemodynamic indexes, and reduces the necrosis and apoptosis of cardiomyocytes in terms of tissue structure. The methodological quality of the studies was low and additional research is warranted. Myocardial infarction refers to the necrosis of any size of myocardial cells caused by myocardial ischemia . MyocardCurcumin is a phenolic compound extracted from the roots of plants in the Zingiberaceae family . In receRelated studies were retrieved from PubMed, Embase, Cochrane Library, Web of Science, CNKI, VIP, and Wanfang. The time range was from the establishment of the databases to 9 June 2022. The keywords used for retrieval included three parts: 1) curcumin, 2) myocardial infarction, 3) rats or mice, and the three parts were connected by “and.”1) Research subject: a rat or mouse myocardial infarction model; the preparation method of the model had to be recognized.2) Intervention measures: The drugs used had to be curcumin or curcumin preparations. The experimental group could not additionally use other drugs that may affect the heart; the control group did not use any drugs, or only used a placebo.3) Outcome indicators: The indicators for evaluating drug effects had to be in digital form to ensure that the key indicators could be extracted or calculated directly or indirectly, including their mean and standard deviation.The inclusion criteria for the studies were as follows:1) The data for evaluation indicators was incomplete.2) Information regarding meta-analysis, systematic evaluation, and correspondence was incomplete.3) The experimental group or the control group involved the use of other drugs.4) The study involved animals other than a rat or mouse.The exclusion criteria were as follows:Two authors extracted data independently. Any differences were resolved through discussion until a consensus was reached, or a third author was consulted to add a decisive input. The following pieces of information were extracted from qualifying studies: author, year of publication, drugs used, modeling method, number of models, mode of administration, dosage, detection indexes, detection index unit, and detection results . FinallyTo assess the quality of the included studies, we used the SYstematic Review Center for Laboratory Animal Experimentation bias risk tool (syrcle’s bias risk tool) for animal studies . Syrle’s2 test were used to evaluate the existence and severity of heterogeneity were. When both p < 0.1 and I2 > 50%, it was considered that there was heterogeneity, and the random-effects model was used for meta-analysis; otherwise, the fixed-effects model was used.Meta-analysis was conducted using RevMan 5.1 software. Quantitative data were expressed as mean ± standard deviation (±SD). Cochran’s Q test and the IThe literature review flow chart is shown in n = 3) described the random sequence generation method like completely random design, Simple random sampling method and random block method (n = 6) reported random outcome assessments , creatine kinase isoenzyme (CK-MB), malondialdehyde (MDA), and biochemical blood indicators, such as lactate dehydrogenase (LDH) and superoxide dismutase (SOD). The hemodynamic indexes measured included systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), left ventricular end-diastolic pressure (LVEDP), left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), maximum rate of left ventricular pressure rise (+dp/dtmax), and maximum rate of left ventricular pressure decline (–dp/dtmax). The cardiac tissue structure examined included the left ventricular weight to body weight ratio (LVW/BW), apoptosis index , left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic diameter (LVESD), and myocardial infarction area.The present study sorted and merged related studies on the effects of curcumin on CK, CK-MB, MDA, and LDH levels in rats or mouse models of myocardial infarction. The results showed that curcumin could reduce CK, CK-MB, MDA, and LDH levels in myocardial infarction models but had no significant impact on SOD levels in myocardial infarction models.p = 0.04), CK by 116.31 U/L (p = 0.004), LDH by 601.77 U/L (p < 0.00001), and MDA by 4.93 nmol/L (p = 0.008) in rats or mice with myocardial infarction. The forest map is presented in The results also found that the use of curcumin can reduce the levels of CK-MB by 1,831.77 U/L (p < 0.00001) and DBP by 5.4 mmHg (p = 0.008). It was also found to increase LVEF by 13.56% (p < 0.00001), LVFS by 7.66% (p = 0.0006), LVEDP by 6.99 mmHg (p < 0.00001), +dp/dtmax by 1551.38 mmHg/s (p = 0.0008), and–dp/dtmax by 1184.05 mmHg/s (p = 0.0007). It had no significant impact on the heart rate in rats or mice models of myocardial infarction. The forest map is presented in In rat or mouse myocardial infarction models, curcumin was found to reduce SBP by 10.05 mmHg (p = 0.003), the apoptosis index by 18.35% (p = 0.03), LVEDD by 0.65 mm (p = 0.0002), LVESD by 1.04 mm (p < 0.00001), and myocardial infarction area by 11.05% (p = 0.02). The forest map is presented in Curcumin was found to reduce the LVW/BW by 0.2 , the apoptosis index by 24.29% (p = 0.005) in rats or mice with myocardial infarction. It had no significant impact on the heart rate in rats’ models of myocardial infarction. These results are not very different from those before the removal of mice.Among the included research literatures on LDH, one is about the mouse myocardial infarction model, and the heart rate and apoptosis index are the same. We removed this study to observe the impact on the research results, as shown in p = 0.006) in rats with myocardial infarction, LVEDD by 0.53 mm (p = 0.05) in mice with myocardial infarction. Curcumin was found to increase LVEF by 16.06% (p < 0.00001) in rats with myocardial infarction, LVEF by 11.37% (p = 0.004) in mice with myocardial infarction. Curcumin was found to increase LVFS by 6.80% (p = 0.02) in rats with myocardial infarction, LVFS by 7.66% (p = 0.0006) in mice with myocardial infarction.In our relevant research literature, rats and mice were included in the literature of LVEDD, LVEF and LVFS. We classified the rats and mice, as shown in In this meta-analysis, we found that curcumin could reduce CK-MB, CK, LDH, and MDA levels. Also, it could lower SBP, DBP, LVEDP, LVW/BW, apoptosis index, LVEDD, LVESD, and myocardial infarction area and increase LVEF, LVFS, +dp/dtmax, and–dp/dtmax. However, it had no significant impact on the heart rate and the levels of SOD in the models.The levels of CK, CK-MB, and LDH are commonly used markers of myocardial injury, as their changes can reflect the degree of myocardial injury. In myocardial infarction models, curcumin reduces CK, CK-MB, and LDH levels and alleviates myocardial injury. Inflammatory reaction and oxidative stress are the initiating and promoting factors of myocardial infarction, existing throughout the process of myocardial infarction. A by-product of lipid peroxidation in oxidative stress is MDA, changes in which can reflect the degree of oxidative stress. Curcumin reduces the MDA concentration in myocardial infarction models, indirectly confirming the antioxidant effect of curcumin.Curcumin has also been found to reduce SBP, DBP, and LVEDP. Blood pressure has an important impact on the prognosis of acute myocardial infarction. However, in human epidemiological studies, there has been debate about the reasonable control range of blood pressure. An international cohort study observing data from 22,672 patients with coronary atherosclerotic heart disease demonstrated that when SBP was controlled between 120 and 140 mmHg (1 mmHg = 0.1333 kPa), the incidence of cardiovascular events was the lowest. However, an SBP <120 mmHg was associated with an increased risk of cardiovascular death and all-cause death, and a mean follow-up of 5 years revealed that an SBP ≥140 mmHg or <120 mmHg and a DBP ≥80 mmHg or <70 mmHg were associated with an increased risk of cardiovascular events and showed a J-curve relationship .Curcumin reduces indicator numbers of cardiac structure, including LVW/BW, LVEDD, and LVESD, reduces left ventricular dilatation, alleviates myocardial hypertrophy and remodeling, increases cardiac systolic function indicators, including LVFS, LVEF, +dp/dtmax, and–dp/dtmax, and improves the diastolic and systolic capacity of the ventricle.Myocardial apoptosis is the main form of myocardial cell loss in the early stages of myocardial ischemia . During In some of the included studies, the dosage of curcumin was divided into several levels. The results of almost all such articles showed that the dosage of curcumin showed a dose effect with different dosage, and the effect of curcumin increased with the increase of dosage. In our study, the research results of the maximum dosage included in the study were selected. Because the dose distribution of the included studies was quite different, it was not possible to classify the doses for the time being.Curcumin alleviates myocardial injury and oxidative stress in myocardial infarction rodent models in terms of blood biochemistry indicators, improves the diastolic and systolic capacity of the ventricle in terms of hemodynamics, and reduces the necrosis and apoptosis of cardiomyocytes in terms of tissue structure. These results show the valuable effects of curcumin on myocardial infarction in the clinic. However, the methodological quality of the studies was low. Additional research is warranted focusing on rigour of assessment, intensity of interventions delivered and methodological limitations.


Acute myocardial infarction (AMI) is a critical cardiovascular disease (CVD). Laminin (LN) is involved in the process of myocardial fibrosis and ventricular remodeling observed in AMI; however, there are currently no studies on the correlation between LN and AMI prognosis.To explore the predictive value of serum LN levels for major adverse cardiovascular events (MACE) in patients, 6 months after an acute myocardial infarction.A total of 202 AMI patients who were hospitalized in the Department of Cardiology of the Second Affiliated Hospital of Nantong University between December 2019 and December 2020 were included. The observation endpoint was the occurrence of MACE. Univariate and multivariate logistic analyses were used to evaluate the relationships between the variables and endpoint. The predictive value of LN for MACE in AMI patients was assessed using receiver operating characteristic (ROC) analysis.p < 0.05). Multivariate logistic analysis showed that LN was an independent predictor of MACE . According to the ROC curve, LN can be used as an effective predictor of MACE . According to the cutoff value, LN>58.80 ng/ml  or LN>74.15 ng/ml  indicate a poor prognosis for AMI. Different cut-off values are selected according to the need for higher sensitivity or specificity in clinical applications.A total of 47 patients developed MACE. Univariate logistic analysis showed that smoking, emergency percutaneous coronary intervention (EPCI), age, cardiac troponin I (c-TNI) levels, N-terminal prohormone brain natriuretic peptide (NT-proBNP) levels, and LN levels were associated with the occurrence of MACE (LN may be a predictor of MACE following AMI in patients and could be utilized as a novel substitute marker for the prevention and treatment of AMI. Acute myocardial infarction (AMI) is one of the most common causes of death worldwide . Over thWe enrolled 202 patients (152 men and 50 women) with acute myocardial infarction who were admitted to the Department of Cardiology of the Second Affiliated Hospital of Nantong University from December 2019 to December 2020. All included cases were treated with standardized treatment. The patients were followed up for 6 months and then divided into an event group and a non-event group according to the occurrence of MACE. The study complied with the Declaration of Helsinki and was approved by the hospital ethics committee. Informed consent was obtained from all patients. The inclusion criteria were the diagnostic criteria for acute myocardial infarction: patients with troponin I levels above the 99th percentile of the upper limit of the reference value and at least one of the following: chest pain lasting >20 min or diagnostic serial ECG changes, including new pathological Q waves or ST segments and T wave changes (Somking and EPCI (emergency percutaneous coronary intervention) will be included as factors in the analysis; According to the regulations of the World Healteh Organization, smoking is defined as those who have smoked continuously or accumulatively for 6 months or more since birth. EPCI refers to emergency percutaneous coronary intervention therapy, that is, coronary catheterization technique implemented within 24 h after the occurrence of acute myocardial infarction to dredge coronary stenosis or even occlusion of coronary vessel lumen, so as to improve myocardial blood perfusion.For patients diagnosed with acute myocardial infarction, 3 ml of venous blood was collected in the morning after 12 h of fasting. The serum was separated and stored at −20°C for future testing. The concentration of LN was detected by chemiluminescence immunosandwich method. One monoclonal antibody against LN was labeled ABEI and the other monoclonal antibody was labeled FITC. Samples, calibration, ABEI labeling monoclonal antibodies, FITC labeled monoclonal antibodies and Magnetic microspheres coated with goat anti-FITC antibody formed immunocomplex. Apply a magnetic field for precipitation, remove the supernatant, wash the precipitated complex with washing solution 3 times, and enter the sample measurement chamber. The instrument  was automatically pumped into the automatic immunoassay system with substrates 1 and 2, and the relative light intensity (RLU) emitted within 3 sec was automatically monitored. LN concentration was proportional to RLU, and the detection instrument automatically fitted and calculated LN concentration. The kits were provided by New Industry Biomedical Engineering Co., LTD .The primary endpoint was MACE, which mainly included composite death, recurrent myocardial infarction, and heart failure hospitalization within 6 months. Endpoint data were obtained from the hospital database and telephone follow-ups, which were validated by reviewing medical records. We completed 100% of the follow-up visits.T-test was used for statistical analysis. Data that did not conform to the normal distribution were described using the M-estimator  and the non-parametric test  for statistical analysis. The Chi-square test was used for categorical variables. Independent predictors of myocardial infarction prognosis were screened using logistic regression analysis. Finally, the receiver operating characteristic (ROC) curve was used to judge the predictive value of LN for the occurrence of MACE. All statistical analyses were performed using SPSS version 23 .The measurement data that conformed to the normal distribution are described in the form of mean ± standard deviation, and the independent sample p > 0.05). Smoking (%), age, N-terminal prohormone brain natriuretic peptide (NT-proBNP), cardiac troponin I (c-TNI), and LN were significantly higher in the MACE group than in the non-MACE group (p < 0.05). Conversely, emergency percutaneous coronary intervention (%) was significantly lower in the MACE group than in the non-MACE group (p < 0.05)  .p < 0.001]. In addition, age  and EPCI  were independently associated with MACE after 6 months  as independent variables in univariate analysis, a multivariate logistic regression analysis was performed. Multivariate regression analysis demonstrated that the level of LN was an independent predictor of MACE 6 months after a myocardial infarction , and a cut-off value of 58.80 ng/ml  or 74.15 ng/ml  indicate a poor prognosis for AMI . Compared with c-TNI , LN, elastin, and proteoglycans. In response to ischemic injury, neurohormonal activation, or changes in hemodynamic load, the ECM undergoes structural remodeling, involving collagen degeneration, production of new collagen, changes in the ratio of collagen phenotypes, and changes in the amount of collagen cross-linking . StudiesAt present, numerous studies have found that many markers of liver fibrosis, such as N-terminal propeptide of procollagen III (PIIINP), 7S domain of the collagen type IV N-terminal propeptide, (P4NP7S) , hyaluroLaminin is a non-collagen glycoprotein first discovered by Timple et al. . LamininThus far, studies on changes in parameters reflecting the integrity of the basement membrane in patients with acute myocardial infarction have not been sufficient. We can prove that the increase in LN levels after AMI can predict the occurrence of short-term MACE , which may be a substitute marker for the early activation of extracellular myocardial matrix metabolism. In the early stages of AMI, this rapid activation of LN may represent non-specific repair because it is independent of other clinical variables.The increase in serum LN levels in the early stages of myocardial infarction can be explained by the biological function of the LN family. Laminin is a major structural component of the basement membrane and plays a role in cell proliferation, adhesion, differentiation and migration .Elevated serum LN antigen concentrations have been reported in patients with liver fibrosis and cirrhosis, regardless of the source of the disease  –22. FurtIn this study, we noted that laminin levels were significantly higher in patients with AMI who had MACE than in those without MACE. We speculate that laminin reflects early extracellular matrix remodeling and is involved in tissue repair after ischemia. As an indicator of liver fibrosis, laminin could also suggest the occurrence of myocardial fibrosis. More importantly, laminin may be of greater value in the future treatment of AMI patients to improve prognosis.Our study has some limitations. The progression of remodeling is influenced by many different factors, such as metalloproteinase (MMP) and metalloproteinase tissue inhibitor (TIMP) systems, cytokines, and neuroendocrine activation . In addiIn conclusion, our findings suggest that the development of short-term MACE due to early cardiac remodeling after ischemic injury is reflected by an increase in serum LN levels. Therefore, LN may be a predictor of MACE following AMI. It is also necessary to expand the sample size and extend the follow-up time to further demonstrate the correlation between LN level and AMI prognosis.The original contributions presented in the study are included in the article/Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.L-YX: conceptualization, methodology, formal analysis, data curation, resources, writing—original draft, writing—review and editing, project administration, and funding acquisition. LX: investigation, validation, formal analysis, data curation, writing, and original draft. JW: formal analysis and investigation. H-XC: formal analysis and data curation. H-LC: formal analysis and validation. L-JT and QZ: resources, writing—review and editing, supervision, project administration, and funding acquisition. All authors contributed to the article and approved the submitted version.This work was supported by the Scientific Research Project of Nantong Municipal Health Commission (grant MB2021010), Kangda College of Nanjing Medical University (grant KD2021KYJJZD012), and Nantong Science and Technology Bureau Plan Project (grant JC2020054).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.