Rapidly accelerated fibrosarcoma B-type (BRAF) and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors have revolutionized melanoma treatment. Approximately half of patients with melanoma harbor a BRAF gene mutation with subsequent dysregulation of the RAF-MEK-ERK signaling pathway. Targeting this pathway with BRAF and MEK blockade results in control of cell proliferation and, in most cases, disease control. These pathways also have cardioprotective effects and are necessary for normal vascular and cardiac physiology. BRAF and MEK inhibitors are associated with adverse cardiovascular effects including hypertension, left ventricular dysfunction, venous thromboembolism, atrial arrhythmia, and electrocardiographic QT interval prolongation. These effects may be underestimated in clinical trials. Baseline cardiovascular assessment and follow-up, including serial imaging and blood pressure assessment, are essential to balance optimal anti-cancer therapy while minimizing cardiovascular side effects. In this review, an overview of BRAF/MEK inhibitor–induced cardiovascular toxicity, the mechanisms underlying these, and strategies for surveillance, prevention, and treatment of these effects are provided.  •BRAF and MEK inhibitors are associated with adverse cardiovascular events.•Hypertension and LVSD are most common, and incidence is higher with combination therapy.•Understanding the incidence and mechanisms of BRAF/MEK inhibitor–associated cardiovascular toxicity will aid the refinement of strategies for cardiotoxicity prevention and treatment. Cancer outcomes have improved considerably over the past 2 decades. Approximately 50% of patients with a diagnosis of cancer in any form will now survive at least 10 years.,The prognosis for patients with metastatic cutaneous melanoma has, historically, been very poor. Immunotherapy and targeted therapies have transformed the outlook for many of these patients.In conjunction with their potent anti-cancer effects, cardiovascular toxicity associated with BRAF and MEK inhibition is increasingly recognized. These adverse cardiovascular effects include systemic hypertension, left ventricular systolic dysfunction (LVSD) and heart failure as well as venous thromboembolism, atrial fibrillation (AF), and QT interval prolongation. These effects are likely to be the consequence of the overlap between pathogenetic cancer target pathways and homeostatic pathways required for normal cardiac and vascular physiology.The most common BRAF mutation, V600E, reflects the substitution of valine to glutamine at codon 600 in exon 15, which results in constitutive activation of BRAF’s kinase function.16,While immunotherapy with T cell checkpoint inhibitors, targeting PD(L)-1 alone or combined with anti-CTLA-4 antibodies, remains first line treatment for patients with BRAF wild-type advanced (unresectable stage III or stage IV) cutaneous melanoma,,,Following the earliest demonstration of the clinical effectiveness of BRAF- and MEK-targeted therapies in patients with advanced unresectable melanoma,,V600E mutated colorectal cancer have shown that BRAF inhibition causes rapid feedback activation through the epidermal growth factor receptor (EGFR). Combining BRAF and MEK inhibitors (encorafenib and binimetinib) with the anti-EGFR antibody, cetuximab, results in higher responses and a significantly longer overall survival compared with standard therapy in patients with metastatic colorectal cancers with the V600E BRAF mutation.While the current primary role for BRAF inhibitor and MEK inhibitor is in the treatment of melanoma,•Approximately 60% of cutaneous melanomas harbor an activating BRAF gene mutation.•Combination BRAF and MEK inhibitors are used for the treatment of unresectable metastatic melanoma and as adjuvant therapy.•BRAF and MEK inhibitors are associated with adverse cardiovascular effects.,The MAPK pathway is a key regulator of normal cell growth and proliferation. This signaling cascade is initiated by the binding of an extracellular ligand to specific membrane-bound receptor tyrosine kinases. Following the stimulation and phosphorylation of GFR adaptor protein, Src homology 2 domain containing protein becomes associated with the activated GFR with subsequent recruitment of downstream signaling proteins culminating in activation of Ras, the membrane-bound guanosine diphosphate to guanosine triphosphate (GTP) exchange protein .30,31Cen,GTP-bound Ras interacts with rapidly accelerated fibrosarcoma (RAF) kinases leading to a cascade of phosphorylation events. Of the 3 RAF serine/threonine kinases , BRAF is the most potent inducer of phosphorylation and activation of MEK1 and MEK2 dual-specificity protein kinases.ERK1 and ERK2 play important roles in cardiac development at a number of stages, reflecting their role in growth factor signaling and in the regulation of the cellular processes described previously.The Ras-RAF-MEK-ERK pathway is a key component in processes including myocyte hypertrophy, cardiac remodeling and myocardial cell death.Members of the MAPK family have cardioprotective effects, largely considered to be caused by antagonistic effects on apoptotic regulatory pathways. In vivo studies assessing loss of cardiac cRAF-1 activity revealed greater apoptosis in the resting state as well as in response to pressure overload in comparison with wild-type animals.,The Ras-RAF-MEK-ERK pathway plays a protective role in the vasculature through interaction with vascular endothelial growth factor (VEGF). In cultured endothelial cells, phosphorylation of VEGF tyrosine kinase receptor 2 activates phospholipase C with consequent activation of the RAF-MEK-ERK pathway. This results in increased endothelial cell proliferation.•The Ras-RAF-MEK-ERK pathway is a key regulator of normal cell growth and proliferation.•The Ras-RAF-MEK-ERK pathway plays a key role in myocyte hypertrophy, cardiac remodeling, and myocardial cell death.•The Ras-RAF-MEK-ERK pathway interacts with VEGF, fibroblast growth factor, and platelet-derived growth factors to stimulate endothelial cell proliferation and angiogenesis in the vasculature.Given the central role of the Ras-RAF-MEK-ERK pathway in cardiac and vascular physiology, its pharmacological manipulation might be expected to have unwanted cardiovascular effects. Indeed, BRAF inhibitor/MEK inhibitor treatment is associated with LVSD, systemic hypertension, atrial arrhythmia, QT interval prolongation, and venous thromboembolism .Figure 1,Cardiovascular adverse events (CVAEs) associated with BRAF and MEK inhibitors have been poorly captured in clinical trials. The incidence of LVSD in patients treated with BRAF inhibitor and MEK inhibitor in clinical trials, with a median follow-up of 9 to 16 months, has been reported as 2% to 12%.A higher risk of cardiotoxicity with combination BRAF inhibitor/MEK inhibitor therapy is also suggested in a subsequent meta-analysisPatient factors that may predispose to BRAF/MEK inhibitor–associated cardiotoxicity include pre-existing cardiovascular disease  as well as advancing age and other conventional cardiovascular risk factors such as hypertension, diabetes mellitus, chronic kidney disease, and cigarette smoking. These are included in a cardiovascular risk stratification proforma for patients treated with combined BRAF/MEK inhibitor published in a recent International Cardio-Oncology Society endorsed position statement from the European Society of Cardiology.Prior to treatment with BRAF inhibitor/MEK inhibitor, echocardiography is recommended to assess baseline cardiac function.An asymptomatic decline in LVEF of ≥10% to an absolute value of <50% is considered to be evidence of cardiotoxicity. A decline in LVEF by <10% from baseline and to 40% to 49% may also reflect cardiotoxicity but the diagnostic certainty of this is less clear, unless accompanied by an associated worsening in LV global longitudinal strain by >15% from baseline. We recognize that this echocardiographic measurement is not routinely performed in all centers but strongly encourage its use. Any new reduction in LVEF to <40% or the development of symptoms or signs of heart failure is considered to be “severe” cardiotoxicity. These definitions are in keeping with a recent consensus statement from the International Cardio-Oncology Society.68We propose a pathway for the management of BRAF inhibitor– and MEK inhibitor–associated LVSD . Importa,Evidence of the reversibility of LVSD following cessation of MEK inhibitor and commencement of heart failure therapies is currently limited but, similar to cardiotoxic effects of other tyrosine kinase inhibitor anti-cancer therapies,,,,,While LVSD is reported in clinical trials,,The underlying mechanisms by which LVSD occurs in association with BRAF inhibitor and MEK inhibitor has not been extensively studied. It is to be expected that disruption of the MAPK pathway could lead to a change in the physiological cardioprotective mechanisms described previously and affect apoptosis, remodeling, and hypertrophy, ultimately leading to LVSD.•The incidence of BRAF inhibitor/MEK inhibitor–associated LVSD reported in clinical trials is 2% to 12%, but this may be an underestimate.•Reduction in LVEF is more common in patients treated with combination BRAF inhibitor/MEK inhibitor therapy than BRAF inhibitor monotherapy.•Echocardiography surveillance is recommended at baseline, after 4 weeks, and at 3-monthly intervals thereafter throughout treatment.•In the event of BRAF inhibitor/MEK inhibitor–associated LVSD consideration should be made to at least temporarily withholding MEK inhibitor, with or without alteration of BRAF inhibitor therapy, and commencing potentially cardioprotective therapies including ACE inhibitor and beta-blocker. Decisions should be made jointly by oncology and cardiology teams taking into account disease stage and alternative treatment options.Hypertension is the most common adverse event reported with BRAF inhibitor and MEK inhibitor, and the incidence is higher with combination therapy.In the COMBI-d trial, “all-grade” hypertension was reported in 22% of patients receiving dabrafenib and trametinib in combination (4% grade 3) versus 14% of patients receiving dabrafenib alone.In the absence of guidelines, the monitoring and management of BRAF inhibitor and MEK inhibitor–associated cardiovascular toxicity remains based on expert opinion. In a practical overview of multisystem toxic effects of BRAF inhibitor/MEK inhibitor therapy, Welsh and CorrieGiven that BRAF inhibitors and MEK inhibitors are increasingly used in the adjuvant setting, adequate monitoring and treatment of hypertension is of even greater importance to reduce the risk of developing cardiovascular disease in the longer term. We have recently published strategies to screen, monitor, and treat hypertension in the oncology population. We have made suggestions for BP targets for patients before, during, and after treatment with systemic anti-cancer therapies associated with prohypertensive effects.We recommend that regular screening for cardiovascular risk factors should continue following the completion of anti-cancer therapy. When BRAF inhibitors and MEK inhibitors are used in the setting of advanced disease, BP targets may be more lenient and balanced against the limited survival prognosis for this patient group. However, BP control remains important to avoid end-organ effects that might compromise the ability to safely deliver optimal cancer therapy. When treatment with BRAF inhibitor/MEK inhibitor is in the adjuvant setting, we would recommend strict monitoring and management to target BP levels as outlined in There is no specific evidence to suggest one class of antihypertensive agent over another in the management of BRAF inhibitor/MEK inhibitor–associated hypertension, but we suggest that ACE inhibitors or angiotensin receptor blockers should be used in patients with coexisting LVSD or proteinuria and in the absence of contraindications. Nondihydropyridine calcium-channel blockers (verapamil and diltiazem) should be avoided because of their potential to increase plasma concentrations of certain MEK inhibitors and BRAF inhibitors.Reduced bioavailability of NO may be implicated in the development of BRAF/MEK inhibitor–associated hypertension. BRAF and MEK inhibition is associated with upregulation of expression of CD47 in melanoma cells in vitro. CD47 inhibits NO/cyclic guanosine monophosphate signaling leading to a reduction in NO bioavailability with consequent vasoconstriction and hypertension. However, this potential pathophysiologic mechanism has not been tested in endothelial or vascular smooth muscle cells,•Hypertension is the most commonly reported CVAE associated with BRAF and MEK inhibitors, and the incidence is higher with combination therapy versus BRAF inhibitor monotherapy.•BP should be monitored with every cycle of treatment.•During BRAF inhibitor/MEK inhibitor treatment antihypertensive therapy should be commenced when BP exceeds 140/90 mm Hg or 130/80 mm Hg in patients with pre-existing CV risk factors or disease, with an ideal target of <130/80 mm Hg before anticancer therapy.•BP targets should take into account disease stage and prognosis with strict monitoring and treatment to the BP target advised in the adjuvant setting.,Treatment with BRAF inhibitor and MEK inhibitor is associated with a risk of atrial arrhythmias and electrocardiographic QT interval prolongation. Systematic capture and reporting of arrhythmias are not common in clinical trials of BRAF inhibitor/MEK inhibitor; therefore, good data on this adverse effect are lacking. In the small number of studies that did report arrhythmia, the most common was AF. In the analysis of the Truven Health Analytics/IBM MarketScan database, AF was reported in 2.7% of patients,,QTc interval prolongation, defined as an increase of more than 60 ms compared with baseline or a QTc interval >500 ms,The pathophysiologic mechanisms of BRAF inhibitor– and MEK inhibitor–associated QTc prolongation and atrial arrhythmia are not known.•BRAF inhibitors are associated with a 1% to 5% incidence of QTc interval prolongation.•AF is the most commonly reported arrhythmia associated with BRAF inhibitor/MEK inhibitor with an incidence of 1% to 4%.•ECG is recommended at baseline, after 1 month of treatment, and after any dosage change.P = 0.02) compared with BRAF inhibitor monotherapy. The incidence of pulmonary embolism was 2.2% in the combination group compared with 0.4% in the BRAF inhibitor monotherapy group.As well as contributing to recurrent vasoconstriction and hypertension, BRAF inhibitor/MEK inhibitor–related reductions in NO bioavailability also lead to an imbalance between thrombotic and antithrombotic states and may result in thrombotic sequelae. Meta-analysis of 5 randomized controlled trials including 2,317 patients with melanoma concluded that combination therapy with BRAF inhibitor and MEK inhibitor was associated with a higher risk of pulmonary embolism , nivolumab and pembrolizumab (PD-1 blockade).The tumor environment in BRAF-mutated melanoma exhibits multiple acquired immunosuppressive features. These include low T cell infiltrates, increased regulatory T cells, increased myeloid-derived suppressor cells, and immature antigen presenting cells.Preclinical studies in mouse models have shown a beneficial effect on the tumor environment with combination therapy with improved tumor responses.NCT02902029), SECOMBIT , and DREAMseq  trials, and part 3 of COMBI-I trial . These trials not only inform optimal combinations and sequences of treatment, but also will contribute to the characterization of potential adverse effects of combination treatment. This is increasingly relevant, as prolonged survival results in patients continuing treatment with BRAF inhibitor and MEK inhibitor for longer periods and the long-term CVAEs are poorly characterized.Several randomized phase 3 trials examining a variety of combinations of immunotherapy plus targeted therapy are ongoing, including ImmunoCobiVem . Dr Evans has received advisory board or speaker fees from AstraZeneca, Bayer, Britsol-Myers Squibb, Clovis, Medivir, Merck Sharp & Dohme, Nucana, and Roche/Genentech; and has received research grant funding from Adaptimmune, Astellas, Bayer, Boehringer Ingelheim, Celgene, Codiak, Esai, GlaxoSmithKline, iOncture, Johnson and Johnson, Merck Sharp & Dohme, Novartis Pfizer, and Roche/Genentech. Dr Jones has received personal fees from Astellas, AstraZeneca, Bristol-Myers Squibb, Bayer, Exelixis, Janssen, Ipsen, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi Genzyme, and EUSA; and research grant funding from Astellas, AstraZeneca, Bayer, Exelixis and Roche. Dr Petrie has received research funding from Boehringer Ingelheim, Roche, SQ Innovations, AstraZeneca, Novartis, Novo Nordisk, Medtronic, Boston Scientific, Pharmacosmos, 3R LifeSciences; and served as a consultant and on clinical trials committees for Boehringer Ingelheim, Novartis, Roche, Corvia, AstraZeneca, Novo Nordisk, Medtronic, AbbVie, Bayer, Takeda, Cardiorentis, Pharmacosmos, and Siemens. Dr Lang has received speaker fees from Roche, Pfizer, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.


The purpose of this study was to explore the clinical application value of phase angle (PA) of six parts in the nutritional evaluation and construct a prediction model for diagnosing malnutrition of tumor patients.A total of 1129 patients with malignant tumors were analyzed retrospectively. The age, sex, tumor location and body mass index (BMI) of the patients were collected, and PA of six parts was measured. The Patient Subjective Global Assessment (PG-SGA) was used to evaluate the nutritional status of each patient.n = 750) of the patients were evaluated as malnourished. Patients under the age of 65 had higher PA values. The PA value of men was higher than that of women (except PA-RL). In different disease groups, the PA-RA and PA-TR values were significantly different. In our study, PA value increases with BMI and decreases with PG-SGA (except PG-SGA 0–1 group). Multivariate regression analysis indicates that the age , BMI , and PA-WB  were independent significant predictors associated with malnutrition. The AUC of the prediction model is 0.7631 (p < 0.001), indicating that the model including age, BMI, and PA-WB has certain diagnostic value for the diagnosis of malnutrition.According to the PG-SGA, 66.5% (The PA-WB is an independent prognostic factor of malnutrition. The prediction model constructed by age, BMI, and PA-WB can be used as a useful tool for nutritional evaluation of tumor patients.Clinical Trial No.: ChiCTR2100047858. Cancer patients are at high risk of malnutrition. Nutritional status is closely related to patient quality of life, tumor-related treatment results, and prognosis , 6. TherPA is considered as a good tool to assess the intracellular compartment, cell integrity, and nutritional status of cancer patients, which is derived from bioelectrical impedance analysis (BIA) . This stA retrospective analysis was performed with inpatients in the tumor center of our hospital from June 2020 to February 2021. All patients included in this study were diagnosed with malignant tumors and had able-bodied limbs. The age, sex, tumor location, and body mass index (BMI) of the patients were collected. Six parts of PA were assessed within 24 h of the patient’s hospitalization, and the following were measured separately: PA of left arm (PA-LA), PA of right arm (PA-RA), PA of left leg (PA-LL), PA of right leg (PA-RL), PA of trunk (PA-TR), and PA of whole body (PA-WB). The PG-SGA was used to evaluate the nutritional status of each patient. A total of 1176 patients were eligible, of whom 47 patients were excluded due to lack of PA data. Therefore, 1129 patients were included in this study.BMI and PA were evaluated by the Hikang H-KEY350 body composition analyzer produced by Beijing Sihai Huachen Technology Co., LTD. The test requirements were as follows: (1) strong exercise or other physical activity is not recommended within 2 h before the test; (2) it is not recommended to eat within 2 h before the test; (3) it is not recommended to bathe within 2 h before the test; (4) the indoor temperature is kept between 21 and 25℃ better; (5) it is recommended to go to the bathroom before the test, because human excrement will temporarily change body composition.The PG-SGA operation DVD recorded by the American College of Nutrition and Dietetics (AND) was used for PG-SGA evaluation.2; normal weight, 18.5 ≤ BMI < 24.0 kg/m2; overweight, 24.0 ≤ BMI < 28.0 kg/m2; and obesity group, BMI ≥ 28.0 kg/m2.BMI is the number obtained by dividing the weight (unit: kg) by the square of the height (unit: m), and BMI is often used for clinical nutritional diagnosis. According to China’s standards, BMI is divided into 4 groups: underweight, BMI < 18.5 kg/mPG-SGA was divided into four groups according to the scores recommended by the Cancer Nutrition and Supportive Treatment Professional Committee of the Chinese Anti-Cancer Association: the well-nourished group (0–1 points), the suspected malnutrition group (2–3 points), the moderate malnutrition group (4–8 points), and the severe malnutrition group (≥ 9 points).p < 0.05, which was statistically significant. The Kolmogorov–Smirnov (K-S) normality test was performed on the data. For sex and age, the Mann–Whitney U test was used to analyze differences. For the BMI, PG-SGA, and different disease groups, the Kruskal–Wallis H test was used for statistical analysis. The correlations between six parts of PA were assessed by Spearman.Statistical analysis was performed using IBM SPSS Statistics 26.0 which is produced by SPSS Inc and figures were made using GraphPad Prism 8.3.0. The median  was used to describe the PA values of the six parts. The statistical analysis used two-sided hypothesis test, t-test, rank sum test, or chi square test), and then the independent variables with statistical significance  by univariate analysis and clinically significant variables were subjected to multivariate logistic regression. Receiver operating characteristic (ROC) analysis was performed to evaluate the accuracy of model prediction.Whether the patient was malnourished was taken as the dependent variable, and the relevant factors involved in the study  were taken as the independent variables. Univariate analysis was performed (n = 726) than those older than 65 years old, and more male  than female . The most frequent types of tumors were COADREAD  and STAD/EGJC  followed by NSCLC , GYNE , and ESCA , which represents a total of 81.3% (n = 918) of the sample. According to the BMI, 14.6% (n = 165) of the patients were severely malnourished (BMI < 18.5 kg/m2). The BMI of most patients ranged from 18.5 to 24.0, accounting for 54.9% (n = 620). According to the PG-SGA, 66.5% (n = 750) of the patients were moderately or severely malnourished (PG-SGA ≥ 4). The number of cases with PG-SGA score of 0–1 is very small .The characteristics of the patients are summarized in Table The PA of six parts was analyzed from the perspectives of different age, sex, disease, BMI, and PG-SGA grade Fig. . At the In order to intuitively show the concentration and dispersion of the PA of the six parts, we draw the violin diagram Fig.  and showp = 0.85, while other variables had statistical significance (p < 0.001). However, according to the results of the “p < 0.001). The increase of BMI could reduce the risk of malnutrition . The higher PA-WB, the lower the risk of malnutrition . The results showed that age, BMI, and PA-WB were independent significant predictors associated with malnutrition.Table p < 0.001). The AUC of PA-WB combined with age and BMI in the diagnosis of malnutrition was 0.7631, which was statistically significant compared with 0.5 (p < 0.001).In summary, age, BMI, and PA-WB were included to construct a prediction model of malnutrition. In order to evaluate the malnutrition diagnosis ability of PA-WB and prediction model, we drew the ROC curve Fig. . We can Z was calculated according to the AUC and SE of the two ROC curves. The formula is substituted to calculate Z = p = )p < 0.05).The statistic The first step of standardized cancer nutritional therapy is nutritional assessment. The purpose of the study was to explore the clinical application value of PA of six parts in the nutritional evaluation and construct a prediction model for diagnosing malnutrition of tumor patients. Our study analyzed 1129 patients with malignant tumors and found that PA can be used in nutritional assessment.In our study, we found that PA in six parts of the body varied according to age, sex, and disease. In addition, we found that the PA value of the trunk is very concentrated, but its correlation with other parts is poor, while the PA-WB data is relatively concentrated and has the best overall correlation with other parts, which may be the key observation of our follow-up study. We found that PA values were higher in people under the age of 65. Except PA-RL, the PA values of other parts in men were higher than those in women. Therefore, in nutritional evaluation, we should pay attention to the differences of PA values with age and sex, and there are some differences in PA values of different body parts.2 as normal weight. However, due to the differences in physiques between individuals from eastern and western countries, China has introduced another reference standard, setting the BMI index between 18.5 and 23.9 kg/m2 as the normal interval. Our study used the reference standards of China [p < 0.05). This finding may be related to the very small proportion of patients in the 0–1 group, which was only 1.77%.The World Health Organization (WHO) classifies people with a BMI in the range of 18.5–24.9 kg/mof China . AccordiZ = 2.577, p = 0.008 < 0.05. The difference of AUC was statistically significant(p < 0.05). It can be considered that the prediction model is better than PA-WB in judging malnutrition.According to the CSONSC recommends, PG-SGA ≥ 4 was used as the cut-off point for the diagnosis of malnutrition in clinical practice. Because of the relatively good data concentration and the best overall correlation with other parts, we use the PA-WB for the regression analysis. We used ROC curve to compare the diagnostic value of TR-WB and combined model in malnutrition. The AUC of both were greater than 0.5, which had a certain diagnostic value. The statistic Z was calculated according to the AUC and SE of the two ROC curves. In summary, like BMI and PG-SGA, the PA values of six parts can also be used for nutritional assessment of patients with malignant tumors, which will greatly improve the efficiency of medical staff and save labor costs. However, it should be noted that the PA reference values of different body parts for judging malnutrition are different. The prediction model constructed by age, BMI, and PA-WB can be used as a useful tool for nutritional evaluation of tumor patients.Our study focuses on the application value of PA values of six body parts for the diagnosis of malnutrition, whether nutritional intervention can significantly increase the PA value and whether increased PA can improve the clinical outcome. Further research is needed to confirm.


Natural history of atrial and ventricular secondary mitral regurgitation (SMR) is poorly understood. We compared the impact of the degree of SMR on survival between atrial and ventricular dysfunction.We conducted a retrospective cohort study of patients who underwent echocardiography in a healthcare network between 2013–2018. We compared the survival of patients with atrial and ventricular dysfunction, using propensity scores developed from differences in patient demographics and comorbidities within SMR severity strata . We fitted Cox proportional hazards models to estimate the risk-adjusted hazards of death across different severities of SMR between patients with atrial and ventricular dysfunction.Of 11,987 patients included , 6,254 (52%) had isolated atrial dysfunction, and 5,733 (48%) had ventricular dysfunction. 3,522 patients were matched from each arm using coarsened exact matching. Hazard of death in atrial dysfunction without SMR was comparable to ventricular dysfunction without SMR . Using ventricular dysfunction without SMR as reference, hazards of death remained higher in ventricular dysfunction than in atrial dysfunction across increasing severities of SMR: mild SMR  and moderate/severe SMR .SMR across all severities were associated with better survival in atrial dysfunction than in ventricular dysfunction, though the magnitude of the diminishing survival were similar between atrial and ventricular dysfunction in increasing severity of SMRs. Atrial functional mitral regurgitation (AFMR) is a form of secondary mitral regurgitation (SMR) increasingly gaining recognition . AFMR isAlthough the etiology of SMR in patients with isolated atrial dysfunction differs from SMR resulting from ventricular dysfunction, current guidelines do not clearly distinguish management . In AFMRLeveraging a large echocardiogram database of a health care system, we aimed to compare the impact of different severities of SMR on survival between those with atrial and ventricular dysfunctions.This retrospective cohort study was conducted at Yale-New Haven Health, a large healthcare network in the United States, encompassing 5 acute care hospitals in academic and community settings and over 120 outpatient clinics at satellite locations throughout Connecticut . The sys2) [Structured data fields on echocardiographic parameters and full text of the cardiology attendings’ echocardiogram reads were extracted. We identified patients with isolated atrial dysfunction or ventricular dysfunction using the following definitions: isolated atrial dysfunction was defined as enlarged left atrium (LA dimension index >34 mm/m2)  with LVE2) . Ventric2) . LVEF waWe restricted the cohort to those without significant concomitant valvular pathologies and MR of primary etiologies by the following exclusion criteria: those with primary MR of any severity , mitral stenosis of any severity, greater-than-mild aortic stenosis or aortic regurgitation, those with findings of vegetation or intracardiac mass or thrombus. Patients with prosthetic valves were also excluded . AdditioThe Institutional Review Board at Yale University approved this study, and individual consent was waived for the minimal risk nature of the study.The outcome of the study was cumulative survival since the time of echocardiogram. Patient data were linked to the Connecticut Vital Statistics data curated by the Connecticut State Department of Public Health to ascertain the date of death. The state’s vital statistics record captures deaths of all Connecticut residents, whether the death occurred in or out of the state. The last date of follow-up available via the vital statistics data was October 15, 2019.International Classification of Diseases 10threvision, Clinical Modification (ICD-10-CM) codes [Demographic variables extracted from the medical records system were age at the time of echocardiogram, sex, and race. Comorbidities were selected based on prior studies and identified via the patient’s past medical history that were grouped based on the corresponding M) codes . The extM) codes . In addiWe linked the echocardiogram database with the institutional Society of Thoracic Surgeons Adult Cardiac Surgery Database and the list of cardiovascular procedures that the patient underwent within our health system since the time of the index echocardiogram and October 15, 2019. Mitral valve surgery  or mitral valve intervention  was treated as the time-varying covariate in the Cox proportional hazard models. Similarly, catheter-based ablations performed for atrial fibrillation or flutter were identified and matched.Continuous variables were reported as medians and interquartile ranges (IQR). Categorical variables were expressed as frequencies and percentages. Differences in demographic variables between patients with atrial and dysfunction were compared using Wilcoxon rank-sum tests for non-normally distributed continuous variables and the chi-squared tests for categorical variables.Kaplan-Meier plots and corresponding log-rank tests were calculated to evaluate unadjusted and matched survival estimates. The study aimed to compare the potential impact of the degree of SMR on survival between patients with isolated atrial dysfunction and patients with ventricular dysfunction. To account for potential confounding between survival and atrial or ventricular dysfunction, matching between isolated atrial and ventricular dysfunction groups was performed by first estimating propensity scores from a multivariable logistic regression model using the covariates listed below. The groups were then matched with a 1:1 coarsened exact nearest-neighbor matching method without replacement using the propensity score and matching the groups exactly on the severity of SMRs . ObservaThe propensity score was calculated from the following covariates: atrial or ventricular dysfunction, age, sex, race, inpatient status (in vs. outpatient), heart failure, diabetes, hypertension, myocardial infarction, peripheral vascular disease, prior coronary artery bypass graft surgery, cerebrovascular disease, chronic pulmonary obstructive disease, liver disease, renal failure, iron-deficiency anemia, rheumatoid disease, peptic ulcer disease, dementia, depression, cancer, substance use, and acquired immunodeficiency syndrome. Additionally, mitral valve surgery or intervention and ablation for atrial arrhythmias were matched on time from echo to intervention.As a sensitivity analysis to assess the differential impact of SMR on the hazard of death between patients with atrial and ventricular dysfunction, Cox models were fitted separately for atrial and ventricular dysfunction groups using the demographic, comorbidity, and SMR severity as time-independent covariates and mitral valve surgery or intervention as a time-dependent covariate. The proportional hazard assumption was evaluated for the MR severity and atrial or ventricular dysfunction using the survival plot, which satisfied the assumption. Because the coefficients of different models cannot be directly compared for the potentially varying residuals , we estip < 0.05 was considered significant. All analyses were conducted with RStudio 1.3.1073  with packages dplyr, gtsummary, matchit, survival, and Python (Python Software Foundation) packages pandas and regex.A two-tailed This study was conducted under IRB approval .Among the 11,987 patients, there were 6,254 (52.2%) patients with isolated atrial dysfunction and 5,733 (47.8%) patients with ventricular dysfunction. The median age of the cohort was 69  years with 46% being male and 80% of echocardiogram performed in an inpatient setting. Patients with atrial dysfunction were older and more frequently female. Compared with patients with ventricular dysfunction, some atherosclerotic comorbidities were less common in patients with atrial dysfunction, such as the history of diabetes, peripheral vascular disease, prior CABG, and myocardial infarction. Liver disease, cancer, and substance use were more common in patients with atrial dysfunction. Moderate or severe MR was more frequently present in patients with ventricular dysfunction  .Among patients with isolated atrial dysfunction, there were 2,428 (39%) with no or trace SMR, 3,069 (49%) with mild SMR, and 757 (12%) with moderate or severe SMR. Among patients with ventricular dysfunction, there were 1,690 (29%) with no or trace SMR, 2,677 (47%) with mild SMR, and 1,366 (24%) with moderate or severe SMR. Patients with a more severe form of SMR in both the atrial and ventricular dysfunction groups were older, with a higher prevalence of atrial fibrillation or flutter and severer coexisting tricuspid regurgitation. In atrial dysfunction, mild or greater SMR occurred more commonly in women while it occurred more commonly in men in ventricular dysfunction .Matching yielded 7,044 patients . Patient characteristics were balanced except for the variables not used to generate propensity scores, which were ejection fraction and left ventricular dimensions . The disSurvival curves of the matched group demonstrated comparable survival between atrial and ventricular dysfunction with no or trace SMR. In contrast, the survival was worse in ventricular dysfunction than in atrial dysfunction in patients with mild, moderate, or severe SMR . Cox proThe sensitivity analysis using the Cox proportional hazards model also demonstrated an increasing number of expected deaths with increasing severity of SMR in both atrial and ventricular dysfunctions. The magnitude of increase with a more severe SMR was larger in ventricular dysfunction than in atrial dysfunction .Understanding the difference in the prognosis of SMR between those related to atrial versus ventricular dysfunction is important considering the variable treatment response to interventions in patients with functional MR , 21, 22.This study adds to the current literature in several ways. First, the prognostic significance of SMR related to atrial and ventricular dysfunctions has been suspected  but direA single-center study reported superior survival in AFMR compared with ventricular MR in patients who underwent mitral valve operation , but howThe optimal treatment approach in terms of mitral valve intervention likely relates to the mechanistic working of MR and their prognostic significance. The simple annular dilatation alone may not explain the majority of MR occurring in the setting of atrial dysfunction. Instead, some studies have suspected it is the discrepant loading condition between LA and LV that results in malcoaptation. In such settings, a simple annuloplasty alone may not be beneficial, and in fact, the optimal treatment may be medical therapy such as hypertension treatment to optimize afterload. However, prior studies on the medical management of HFpEF have not identified beneficial therapies in this heterogeneous population . PrognosProposed treatment for AFMR is evolving with increasing mechanistic understanding of how atrial dysfunction may lead to MR . A singlThe small sample size of the patients with severe SMR precluded further stratification between moderate and severe MR. We demonstrated the incrementally worse survival across increasing SMR severities, and the finding likely extrapolates to the difference in moderate and severe MR with a larger sample. However, beyond prognostic significance, we could not infer differential therapeutic approach for different types of SMR. The population included those who underwent echocardiograms related to a health-system encounter and may not generalize to the general population in the community. Nevertheless, our inclusion of academic and community sites within the health-system network enabled us to capture individuals with a broad range of characteristics and likely minimized center-specific patient selection. Measurements important to further characterizing the ventricular function, such as left-ventricular end-diastolic dimension, were not consistently available and were not used in adjustment or matching in the main analysis but were descriptively reported. Inter-rater variability may exist among cardiologists who interpreted the echocardiograms. Although likely small in number, patients who relocated to outside of Connecticut and died would not have been captured by the vital statistics used in this study. We were not able to delineate the etiology of atrial dilation. This is an important limitation, as physiologic and pathologic enlargement of the left atrium may have prognostic differences .In this study of echocardiograms obtained across a large health system encompassing academic and community settings, patients with isolated atrial dysfunction had better survival compared with ventricular dysfunction across comparable severities of secondary mitral regurgitation. Substantially worse survival associated with mild or greater SMR in both atrial and ventricular dysfunctions warrant close monitoring at the onset of SMR irrespective of the type. Prospective evaluation of such close monitoring is needed to confirm the finding of the study.S1 TableCABG = coronary artery bypass graft; AIDS = acquired immunodeficiency syndrome.(DOCX)Click here for additional data file.S2 TableThe table summarizes estimated number of deaths under constant follow-up time, had all patient had no/trace MR, mild MR, or moderate/severe MR. The magnitude of increase with increasing severities of SMR is greater in ventricular dysfunction than in atrial dysfunction.(DOCX)Click here for additional data file.S1 FigDensity plot of the propensity score before (left) and after (right) matching. Matching was performed based on the propensity score and mitral regurgitation severity. After matching, the distribution of the propensity score became similar between atrial and ventricular dysfunction group.(DOCX)Click here for additional data file.S2 FigThe figure is a Love plot showing the standardized distances of each patient characteristic between atrial and ventricular dysfunction groups before and after matching. After matching, all covariates had <0.1 absolute standardized mean difference, indicating a good match. Horizontal lines were drawn every 4 variables to help visualize the corresponding marker.(DOCX)Click here for additional data file.


Anthracycline cardiotoxicity has become one of the most common complications of anthracycline therapy. Regular follow-up of chemotherapy patients with myocardial deformation parameters might be helpful for early diagnosis of myocardial damage and protective intervention. This study aimed to investigate the value of three-dimensional speckle tracking imaging (3D-STI) in diagnosing and predicting potential cardiotoxicity in breast cancer patients undergoing anthracycline therapy through meta-analysis based on global cases collection.Relevant case-control studies published prior to November 2021 were extracted to assess cardiotoxicity by 3D-STI in breast cancer patients undergoing chemotherapy. Weighted mean difference (WMD) and 95% confidence interval (CI) were used as pooled statistics. Meta regression and subgroup analysis were employed to identify sources of heterogeneity and publication bias was evaluated by Egger’s test and funnel plot.p < 0.001; global longitudinal strain (GLS) WMD = 2.19, 95% CI ; p < 0.001; global circumferential strain (GCS) WMD = 1.69, 95% CI ; p < 0.001; global radial strain (GRS) WMD = –1.72,95% CI ; p < 0.001, and global area strain (GAS) WMD = 6.25, 95% CI ; p < 0.001 were decreased. A medium degree of heterogeneity was shown for values of LVEF  while values for GLS , GCS  and GRS  showed a large degree of heterogeneity. Egger’s test and funnel plot showed no significant publication bias in GLS, GCS and GAS data .A total of 1,515 breast cancer patients from 14 studies were enrolled and followed up for 4 or 6 cycles of chemotherapy. Following chemotherapy, absolute values of Left ventricular ejection fraction (LVEF) WMD = –1.59, 95% CI ; 3D-STI has utility for the non-invasive and objective evaluation of changes in left ventricular function in breast cancer patients undergoing chemotherapy with anthracyclines. The current findings have clinical potential for the early evaluation of myocardial injury caused by chemotherapy toxicity. Anthracyclines constitute a basic chemotherapeutic medicine for breast cancer but cardiotoxicity is the most common and serious adverse effect . The resDuring or within 1 year post-treatment, 2–5% of patients develop early onset chronic progressive cardiotoxicity. This common form of cardiotoxicity usually manifests as dilated cardiomyopathy finally. A further 2–10% of patients will develop late-onset chronic cardiotoxicity 1 year after the completion of treatment and since compensatory mechanisms and physiological reserves maintain normal cardiac function until a threshold point is reached, patients may have no obvious symptoms for a long time after chemotherapy . TherefoLeft ventricular ejection fraction (LVEF) values are widely used in the clinic to assess patients with myocardial toxicity but the accuracy and sensitivity of such values in determining myocardial injury at early stage has been questioned. By the time decreases in LVEF values are severe enough to be observed, myocardial dysfunction is already in a state of advanced deterioration . TherefoSpeckle tracking echocardiography (STE) has been used over the last decade in the non-invasive evaluation of cardiac mechanics and function. Its utility for diagnosis and longitudinal strain measurement following anthracycline treatment has been established , 4. WherThree-dimensional speckle tracking imaging (3D-STI) represents an advanced form of echocardiographic technology with utility for the detection of myocardial injuries at earlier stages. 3D-STI allows tracking of out-of-plane speckle motion and has higher measurement reproducibility. Since multi-section images during the same cardiac cycle can be resolved, the evaluation time is reduced.The current study is a meta-analysis of observational studies of conventional echocardiography and 3D-STI with respect to altered myocardial function during breast cancer chemotherapy. The value of 3D-STI parameters in monitoring of early stage myocardial injuries in the longitudinal, radial and circumferential planes of the left ventricle has been explored.English-language databases, Pubmed, Cochrane, Embase and Web of Science, and Chinese databases, CNKI, Wanfang, and VIP were searched for relevant articles published before November 1, 2021. The search terms used were as follows: “echocardiography,” “three-dimensional speckle tracking,” “three dimensional echocardiography,” “three-dimensional ultrasound,” “3-D echocardiography,” “cardiotoxicity,” “speckle tracking,” “anthracycline,” “breast cancer.” Relevant references of the literature were manually searched.Three dimensional strain analysis is mainly used to measure myocardial deformation in three-dimensional space. After importing the 3D gray-scale images into the workstation, the system will automatically track the endocardial surface, and the region of interest can be manually adjusted if necessary. The system automatically generates a color-coded 17 segmental illustration of the bull eye and strain parameter curve of each segment . The weiInclusion criteria were as follows: (1) prospective and retrospective studies using conventional echocardiography and 3D-STI to assess cardiotoxicity in breast cancer patients during chemotherapy; (2) during the completion of anthracycline chemotherapy, adjuvant hormonal therapy, radiotherapy, or other treatments were not performed at the same time; (3) Ultrasound assessment of myocardial toxicity before chemotherapy and after the fourth or sixth cycle of chemotherapy; (4) inclusion of relevant parameters, such as left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS), and global area strain (GAS).Exclusion criteria were as follows: (1) publications with incomplete data; (2) reviews, conference papers, letters from readers or editorial comments; (3) duplicate publications; (4) publications with unclear chemotherapy regimens; (5) publications with unclear follow-up dates.Eligible articles were screened according to the inclusion and exclusion criteria by two researchers and the quality scored according to the Newcastle-Ottawa-Scale (NOS) on a scale of 0–9. Literature was selected according to its score and information extracted as follows: first author, study country, publication time, study sample size, chemotherapy protocol, accompanying diseases, echo timing, vendor, workstation, LVEF, GLS, GCS, GRS, and GAS data.I2 and Q-tests were used to assess heterogeneity: high heterogeneity: I2 > 50% and p < 0.05; medium heterogeneity: 25% ≤ I2 ≤ 50%; low heterogeneity: I2 < 25%; no heterogeneity: p ≥ 0.05  and 95% confidence interval (CI). p ≥ 0.05 . HeterogA total of 1,399 publications were initially identified of which 14 –20, descI2 = 44.4%, p = 0.037). Analysis by random effect model found decreased LVEF after anthracycline chemotherapy WMD = –1.59, 95%CI , p < 0.001 (see forest plot in p = 0.045).Fourteen publications compared LVEF values before and after chemotherapy with moderate heterogeneity among the studies  and random effect model analysis found lower values following chemotherapy than before WMD = 2.19, 95% CI , p < 0.001 (see forest plot in p = 0.108).GLS values before and after chemotherapy showed a high degree of heterogeneity among 14 publications . The forest plot of GCS WMD = 1.69, 95% CI , p < 0.001 is shown in p = 0.978).All 14 papers evaluated differences in GCS values before and after anthracycline chemotherapy and with highly heterogeneous results  which were analyzed by a random effect model. GRS WMD = –1.72, 95%CI , p < 0.001 decreased significantly after chemotherapy (see p = 0.001)  .I2 = 96.9%, p < 0.001). Analysis by random effect model showed that GAS values WMD = 6.25, 95% CI , p < 0.001 decreased after chemotherapy (see p = 0.499)  .Sources of heterogeneity were explored by meta regression analysis. Regression model covariates were set as follows: (1) Sample size: ≥ 60: 1, < 60: 0; (2) Study country: China: 1, elsewhere: 0; (3) Chemotherapy cycle: 4 cycles: 1, 6 cycles: 0; (4) instrument and equipment type: GE vivid series: 1, non GE vivid series: 0; (5) Quality of included literature (NOS scores): ≥ 7: 1, ≥ 5: 0.p < 0.05). The relationship between the source of GCS heterogeneity and the above covariates did not achieve statistical significance (Meta regression analysis showed that LVEF heterogeneity arose from sample size, that of GLS and GRS from the source country and that of GAS from sample size, chemotherapy cycle and study country (all ificance .Publications were classified according to the factors affecting heterogeneity in the meta regression results and subgroup analysis was conducted. Subgroup analysis showed that LVEF heterogeneity arose from sample size and inclusion of only the large sample group reduced heterogeneity to zero. GLS and GRS heterogeneity arose from the study country of origin and was improved by inclusion of literature from countries other than China. No source of heterogeneity could be identified from analysis of the GAS subgroup.Sensitivity analysis was conducted by sequential elimination of individual articles. Values for LVEF, GLS, GCS, GRS, and GAS did not change significantly, indicating a good degree of stability.Advances in anti-tumor chemotherapy research have led to huge improvements in breast cancer survival rates. However, CTRCD remains the most common complication of anthracycline therapy, attracting the attention of clinicians, and affecting overall patient prognosis.It is thought that anthracycline cardiotoxicity arises with the inhibition of topoisomerase 2β which activates the cell death pathway and reduces mitochondrial biogenesis. Cumulative dosage of anthracyclines, age, preexisting fundamental cardiovascular disease, atrial fibrillation, hypertension, diabetes, and smoking history are all risk markers for cardiotoxicity .Patients’ left ventricular function is often monitored clinically by means of LVEF. A decrease in LVEF of > 10% or a value of LVEF of < 50% post-chemotherapy is considered to indicate cardiotoxicity . However3D-STI strain parameters reflect myocardial deformation in longitudinal, radial and circumferential spatial directions. GLS represents myocardial deformation from the base to the apex, reflecting contraction of the longitudinal fibers under the endocardium. Longitudinal myocardial movement is central to contraction of the left ventricle. GCS represents the circumferential shortening of left ventricular myocardial fibers in the short axis. GRS reflects deformation toward the center of the left ventricular cavity, indicating thickening and thinning of the left ventricular wall during the cardiac cycle. GAS is the product of longitudinal and circumferential strain, as the left ventricular endocardial surface deforms during systole and diastole. It reflects the change in relative area, combining longitudinal, and circumferential shortening effects .The current meta-analysis found that WMDs of LVEF in breast cancer patients after chemotherapy were lower than those prior to chemotherapy. This suggests a reduction in patients’ ventricular systolic function post-chemotherapy. A previous study  has showThe current study found lower absolute values of the 3D-STI parameters, GLS, GCS, GRS and GAS, after chemotherapy, which may predict the development of anthracycline cardiotoxicity. Most publications produced consistent results with only two exceptions. Ruan et al.  reportedThe decrease in GLS was the most consistent parameter throughout the 14 publications and it has been previously remarked that this parameter may be the earliest to show abnormalities . It may There may also be segmental differences in cardiotoxicity. Coutinho Cruz et al.  found 24Some publications cited herein stress the value of GAS in predicting early post-anthracycline myocardial injury due to its inclusion of both longitudinal and circumferential strain and its sensitivity to local cardiac deformation. Zamorano et al.  found reThe biggest limitation of 3D-STI is its reliance on image quality which is affected by chest radiotherapy, mastectomy and breast implant surgery, all of which create challenging acoustic windows and reduce image quality. Furthermore, the frame rate of real-time 3D echocardiography is too low to accurately capture all phases of the cardiac cycle. The result is the underestimation of 3D speckle-tracking echocardiography-derived strain measurements . Thus, tOne limitation of the current study is the inevitable degree of publication bias. Most eligible studies were conducted in China and ethnic and regional variations need to be considered. Moreover, many studies did not carry out long-term follow-up leading to under-observation of chronic delayed cardiac toxicity. Not all 3D STI-related parameters were reported in the studies, so the number of patients included in this meta-analysis was relatively small. Because of the limited evaluation of left ventricular rotation, torsion and strain rate parameters, the relevant parameters were not included in this study. In addition, data allowing analysis of the relationship between anthracycline type or cumulative dose and subsequent reduction of STI parameters was incomplete. Moreover, the combination of anthracyclines with other drugs were not analyzed.In summary, this meta-analysis presents a further evidence for the early detection of changes in myocardial function in breast cancer patients undergoing anthracycline chemotherapy by the 3D-STI myocardial deformation parameter, which may prove to be a new monitoring method to facilitate prognosis for chemotherapy patients. However, the predictive and diagnostic threshold of this parameter for post-chemotherapy myocardial toxicity still needs long-time follow-up and more multicenter studies.The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.LZ and RZ were responsible for the concept and design, jointly consulting and reviewing the literature, and conducting data analysis and data interpretation. PS and JC were responsible for drafting or critically revising the manuscript of the research content and putting forward constructive opinions. LY gave final approval to the submitted manuscript. All authors contributed to the article and approved the submitted version.


To assess the diagnostic value and clinical performance of cardiac ultrasound in patients with chronic heart failure and hypertension.  In this prospective study, between August 2017 and January 2020, 50 patients with chronic heart failure and hypertension were recruited and assigned to the study group and 50 healthy individuals during the same period after physical examinations were included in the control group. Cardiac ultrasound examinations were performed on the participants, and the results were compared and analyzed. P < 0.05).  The study group had a higher left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular ejection fraction (LVEF), and late diastolic peak flow velocity (A wave) and showed lower early diastolic peak flow velocity (E wave) and late diastolic peak flow velocity/lower early diastolic peak flow velocity (E/A) ratio levels than in the control group. The study group had 15 patients with grade I cardiac function (ultrasound detection rate of 100%), 18 patients with grade II cardiac function (ultrasound detection rate of 100%), and 17 patients with grade III cardiac function (ultrasound detection rate of 100%). Grade I cardiac function patients showed the lowest LVEDD, LVESD, and E/A and the highest LVEF than grade II patients, followed by grade III patients. The study group showed higher LVEF and echocardiographic estimation of the pulmonary arterial systolic pressure (PASP) and lower right ventricular lateral wall systolic excursion velocity and tricuspid annular plane systolic excursion (TAPSE) than the control group. Chronic heart failure with hypertension was associated with high levels of right atrial total emptying volume (RAVIt), right atrial passive emptying volume (RAVIp), right atrial active emptying volume (RAVIa), and right atrial active emptying fraction (RAVIaEF) and low levels of right atrial total emptying fraction (RAVItEF) and right atrial passive emptying fraction (RAVIpEF) versus the healthy status (all  Cardiac ultrasound is a noninvasive operation with low cost, high repeatability, and accurate detection, which can identify right heart function impairment at an early stage, assist clinical treatment, and improve patient prognosis, so it is worthy of promotion and application. Chronic heart failure (CHF) is a common clinical complication of cardiovascular diseases , which rIn this prospective study, between August 2017 and January 2020, 50 patients with chronic heart failure and hypertension were recruited and assigned to the study group, and 50 healthy individuals during the same period after physical examinations were included in the control group. The study was approved by the Ethics Committee of the Jincheng People's Hospital, No. 201JC8/71.Inclusion criteria were as follows: ① patients who met the diagnostic criteria for CHF in the Chinese heart failure diagnosis and treatment guidelines 2018; ② patients who met the diagnostic criteria for primary hypertension in the Chinese guidelines for the prevention and treatment of hypertension (2018 revision); and ③ patients who provided written informed consent and voluntarily participated in the study.Exclusion criteria were as follows: ① patients with incomplete clinical data; ② patients with severe dysfunction of the liver, kidney, and other organs or malignant tumors; and ③ patients with congenital mental retardation or mental illness.Ultrasound Doppler for cardiac ultrasound diagnosis was performed in all eligible participants, using the PHILIPS EPIQ7C whole-body application ultrahigh-end cardiac ultrasound sonographer  with theThe LVEDD, LVESD, LVEF, early diastolic peak flow velocity (E wave), late diastolic peak flow velocity (A wave), and the E/A ratio were recorded and compared between the two groups. The data of the indexes in the observation group were compared under different cardiac functional status classifications. LVEF, right ventricular lateral wall systolic displacement velocity, TAPSE, and pulmonary arterial systolic pressure (PASP) were recorded. PASP was calculated by measuring the transvalvular pressure difference using the tricuspid systolic reverse flow spectrum. The values of RAVIt (RAVIt = RAVImax–RAVImin), RAVIp, RAVIa, RAVItEF, RAVIp EF (RAVIp EF = RAVIp/RAVImax), and RAVIaEF (RAVIaEF = RAVIa/RAVIpre) were calculated and compared.RAVIa indicates the right atrial pumping function, and the peak right atrial filling rate in systole , peak right atrial emptying rate in early diastole , and peak right atrial emptying rate in late diastole  were recorded according to the obtained right atrial volume change rate curve.x ± s) using the t-test. Comparisons between multiple groups were conducted using the one-way method of analysis, and two-by-two comparisons were performed using the LSD-t-test. Differences were considered statistically significant at P < 0.05.SPSS22.0 software was used to process the data. The count data were expressed as (n (%)) and processed using the chi-square test, and the measurement data were expressed as  years, and course of CHF of (6.05 ± 1.68) years) were comparable with those of the included healthy subjects  years, mean BMI of (23.68 ± 2.57) kg/m2, course of hypertension of 0 years, and course of CHF of 0 years) (P > 0.05)  years, mean BMI of (24.01 ± 2.14) kg/m > 0.05) .P < 0.05) , which were significantly higher than those of the control group . The E wave and the E/A ratio of the study group were markedly lower than those of the control group  ( < 0.05) .The study group had 15 patients with grade I cardiac function (ultrasound detection rate of 100%), 18 patients with grade II cardiac function (ultrasound detection rate of 100%), and 17 patients with grade III cardiac function (ultrasound detection rate of 100%).P < 0.05)  .P < 0.05)  .P < 0.05)  .Chronic heart failure refers to the inability of the myocardium to contract properly and provide sufficient blood for normal metabolism to satisfy the needs of the body. Primary hypertension is one of the most common factors in the development of CHF . It has In the present study, the diagnosis of hypertensive left ventricular hypertrophy with left heart failure was performed by cardiac ultrasound. The cardiac ultrasound allows the observation of cardiac blood flow as well as cardiac fluctuations and facilitates the clinician's judgment of the patient's myocardial lesions, cardiac atrial wall thickness, and ventricular chamber size. Cardiac ultrasound features advantages such as high reproducibility, noninvasiveness, and high sensitivity compared with traditional electrocardiography, especially for atrial enlargement and early ventricular structural changes. In addition, cardiac ultrasound diagnosis presents dynamic changes in patients with hypertensive left ventricular hypertrophy with left heart failure, which improve the accuracy of clinical diagnosis and facilitate clinicians to observe the structure of patients' heart chambers, which is of high diagnostic value for hypertensive left ventricular hypertrophy with left heart failure.E wave and E/A results; moreover, grade I cardiac function patients showed the lowest level of LVEDD, LVESD, and E/A and the highest level of LVEF than grade II patients, and then grade III patients. Research has demonstrated that cardiac ultrasound is considered a key diagnostic modality for the cardiac function, with the advantages of less damage, simpler operation, and repeatability, which contribute to enhance the accuracy of disease diagnosis. The results of the present study also confirmed the accuracy of the examinations of the patients' cardiac function, which was similar to the previous research results. Furthermore, the study group herein outperformed the control group in terms of LVEF, RASP, right ventricular lateral wall systolic excursion velocity, and TAPSE. Chronic heart failure with hypertension in the present study was associated with high levels of RAVIt, RAVIp, RAVIa, and RAVIaEF and low levels of RAVItEF and RAVIpEF versus the healthy status. In the present study, the study group had elevated RAVIt and decreased RAVItEF compared to the control group. During the increment of pulmonary artery pressure, the right atrial volume also enlarges to ensure the injection of blood volume into the right ventricle, but the total emptying capacity is diminished, indicating changes in the right atrial structure in the advanced stage which results in the diminished RAVItEF. The increase of RAVIp and decrease of RAVIpEF indicate that with the increase of right ventricular pressure, the resistance of right atrial inflow into the right ventricle increases, which leads to the decrease of right atrial ductal capacity. The RAVIa and RAVIaEF of the study group were significantly higher than those of the control group, suggesting a compensatory increase in right atrial myocardial capacity in the early stage of elevated pulmonary artery pressure; however, the progressive increase in pulmonary artery pressure causes a loss of the compensatory myocardial contractile function and leads to a reduced right atrial pump function in the chronic heart failure group. Thus, a lower overall right atrial ejection fraction and a higher right atrial volume index are indicative of abnormal right atrial function.The results of the current study showed higher LVEDD, LVESD, and LVEF and lower The hemodynamic indexes are the most direct reflection of the cardiac function, in which LVSP and the maximum rate of increase of left intraventricular pressure can determine the systolic performance, and LVEDP and the maximum rate of decrease of the left intraventricular pressure together determine the diastolic performance. The addition of the Shenfu injection to the conventional western medicine treatment provides the effect of restoring yang, relieving deficit, benefiting qi, and removing heat. The Shenfu injection solution is a compound drug, and it is mainly composed of red ginseng and Aconiti Lateralis Radix Praeparata. It is mainly used to treat palpitation, coughing, stomach pain, diarrhea, and paralysis caused by Yang deficiency and Qi deficiency. The Shenfu injection solution significantly improves noninvasive hemodynamic indices in the hearts of patients with chronic systolic heart failure, increases output and cardiac output per beat, decreases peripheral vascular resistance, increases left ventricular ejection fraction, and lowers plasma B-type brain natriuretic peptide concentration. The limitation of this study lies in the absence of testing of diagnostic efficacy and the sensitivity and specificity of ultrasound diagnosis, which will be further investigated in the future.Cardiac ultrasound is a noninvasive operation with low cost, high repeatability, and accurate detection, which can identify right heart function impairment at an early stage, assist clinical treatment, and improve patient prognosis, so it is worthy of promotion and application.


Trimethylamine N-oxide (TMAO) has been associated with cardiovascular outcomes. However, the diagnostic value of TMAO and its precursors have not been assessed for functionally relevant coronary artery disease (fCAD) and its prognostic potential in this setting needs to be evaluated.Among 1726 patients with suspected fCAD serum TMAO, and its precursors betaine, choline and carnitine, were quantified using liquid chromatography tandem mass spectrometry. Diagnosis of fCAD was performed by myocardial perfusion single photon emission tomography (MPI-SPECT) and coronary angiography blinded to marker concentrations. Incident all-cause death, cardiovascular death (CVD) and myocardial infarction (MI) were assessed during 5-years follow-up.p < 0.001); however, diagnostic accuracy was low . In prognostic analyses, TMAO, choline and carnitine above the median were associated with significantly  higher cumulative events for death and CVD during 5-years follow-up. TMAO remained a significant predictor for death and CVD even in full models adjusted for renal function , p = 0.003; HR = 1.66 , p = 0.025). Prognostic discriminative accuracy for TMAO was good and robust for death and CVD .Concentrations of TMAO, betaine, choline and carnitine were significantly higher in patients with fCAD versus those without (TMAO 5.33 μM vs 4.66 μM, TMAO and its precursors, betaine, choline and carnitine were significantly associated with fCAD, but with limited diagnostic value. TMAO was a strong predictor for incident death and CVD in patients with suspected fCAD.NCT01838148.The online version contains supplementary material available at 10.1007/s00392-022-01992-6. During the last decade, translational research has highlighted intestinal microbiota as possible mediators between dietary habits and both the development and progression of coronary artery disease (CAD) –5. The cBeyond possible therapeutic opportunities, this insight suggests that TMAO and/or its precursors might have prognostic and/or diagnostic utility in the non-invasive detection of CAD, particularly the more aggressive CAD phenotype leading to myocardial ischemia during everyday activities . Even more importantly, TMAO may provide prognostic utility in identifying those at incident risk for hard clinical endpoints including death and MI. For this indication, TMAO and/or its precursors may help physicians in the selection of patients for cardiac work-up including invasive or non-invasive coronary imaging , 24. GivThis analysis is part of a large ongoing prospective diagnostic study  designed to advance the early detection of fCAD , 27. ThePatients were recruited from 2010 to 2016 at the University Hospital of Basel, Switzerland. Enrolled patients were suspected to have fCAD and were referred for rest/stress myocardial perfusion single-photon emission tomography/computer tomography (MPI-SPECT). MPI-SPECT/CT was the preferred cardiac imaging technique in patients with a wide range of pre-test probabilities for fCAD during that time. Patients requiring chronic dialysis were excluded.The likelihood for the presence of fCAD was quantified by the integrated clinical judgment of the treating cardiologist using a visual analogue scale (VAS) ranging from 0 to 100% twice: once before stress testing integrating all medical information available at that time, such as age, sex, cardiovascular risk factors, previous cardiac history, symptoms and baseline ECG data; second, after stress testing, integrating symptoms the patient experienced during exercise/stress, the workload achieved, and ECG changes recorded during exercise/stress. The cardiologist was blinded to both biomarker measurements and MPI-SPECT images at the time of assessment.transplantr-package in R. Cystatin-C was measured by SomaLogic using the SomaScan® assay, which uses single-stranded DNA-based protein affinity reagents that are modified to mimic amino acid chains, enhancing protein-nucleic acid interaction [Venous non-fasting blood samples for determination of TMAO, choline, betaine, carnitine, and high-sensitivity cardiac troponin (hs-cTn) T , 26, 29,eraction . These seraction .Expert interpretation of MPI-SPECT/CT images combined with information obtained from invasive coronary angiography and whenever available fractional flow reserve measurements were used in the adjudication of fCAD.All patients underwent a routine rest/stress dual isotope  or single isotope (99mTc sestamibi for stress and rest) MPI-SPECT protocol as described previously , 31, 32.The prognostic endpoints were all-cause death, cardiovascular death and MI during long-term follow-up. Patients were contacted by telephone or standardized follow-up letter 1 year, 2 years and 5 years after enrolment with ongoing follow-up. In case of an event, further information was obtained from hospital records, general practitioner/cardiologists records, or the national death registry blinded to biomarker concentrations.U test. Baseline characteristics were compared by Kruskal test for continuous data and Fisher test for categorical data. Diagnostic accuracy of the clinical assessment, TMAO, betaine, choline, carnitine, and their combination for fCAD was quantified by the area under the receiver operating curve (AUC) and compared with the method described by DeLong et al. [Normality testing was done using visual assessments (histograms and QQ-plots) and as Shapiro–Wilk test. Continuous variables are presented as median and respective interquartile range (IQR) and categorical variables are presented as frequencies and respective percentages. The Agresti-Coull method was used to calculate confidence intervals of proportions. Measures of central tendency of the biomarkers were compared by Mann–Whitney g et al. . Based og et al. , 11, 34,p value < 0.05 was considered statistically significant.Kaplan–Meier curves for concentrations of TMAO, betaine, choline and carnitine below and above the median as well as stratified by the upper reference limit of the established biomarker hs-cTnT (URL 14 ng/L), were constructed and compared by log rank testing. Quantification of the predictive accuracy of TMAO and precursors was done by time dependent AUCs whilst accounting for censoring (timeROC package) . Cox regOverall, 1726 consecutive patients with suspected functionally relevant coronary artery disease (fCAD) were included in this analysis , 478 patients (28%) were adjudicated to have fCAD. A total of 421 (24%) patients underwent coronary angiography with 284 patients within the 3 months after enrolment. Anamnesis revealed 764 (44%) to have known history of CAD. During follow-up, 88 patients experienced an incident MI, 223 patients died overall, 115 of which died due to cardiovascular reasons (CV death). Characteristics of patients stratified by fCAD are shown in Table p < 0.001, Fig. p < 0.001, Fig. Median TMAO concentrations were significantly higher in patients with fCAD than in those without fCAD , TMAO and the three precursors were significantly higher in patients adjudicated to have fCAD . The baseline characteristics of this subgroup are presented in Supplemental Table 2.In patients with normal eGFR (p < 0.001), NT-proBNP  and age . These correlations were weaker for betaine, choline and carnitine .TMAO concentrations were significantly, albeit weakly, correlated with hs-cTnT  and its precursors . Similar findings emerged in the subgroup of patients without known CAD . TMAO and its precursors did not significantly increase the AUC provided by the quantitative clinical assessment by the treating physician before  and after  stress testing  versus VAS alone, Supplemental Fig. 4C + 4D). TMAO  and its precursors were significant predictors of fCAD in the univariable model, with TMAO remaining a significant predictor even after adjusting for age, sex and CAD history . When adjusting for renal function  or when adjusting for further for pre-defined patient characteristics, cardiovascular risk factors and medical history (model 2), neither TMAO nor its precursors remained significant predictors. In patients with normal eGFR, TMAO and the three precursors were only significant predictors in the univariable model but were no longer significant after adjusting further .In the overall cohort, diagnostic accuracy for detection of fCAD was quantified and showed modest but statistically significant value for TMAO with a ROC AUC of . The cumulative event incidence for 5-years death was 12.9% (223 events), for 5-years CV death 6.7% (115 events) and for 5-years MI 5.1% (88 events), and the composite 5-years MACE (MI and cardiovascular death) was 11.8% (203 events).P < 0.001, each; Supplemental Fig. 5 and 6). Similar results emerged for choline and carnitine.In Kaplan–Meier analyses, TMAO concentrations above the median had substantially higher all-cause, CV mortality and mace events versus patients below the median  of marker-combination with low and normal eGFR levels, Kaplan–Meier survival analyses revealed significantly highest cumulative all-cause death events in patients with low eGFR combined with a TMAO above the median  and 5-years CV death , and modest accuracy for the other markers and endpoints  and patients adjudicated to have fCAD had significantly higher marker levels compared to those without. Notably, high TMAO in combination with low-eGFR were at significantly higher risk of all-cause death compared to low-TMAO combined with low-eGFR (n = 921). This is in line with previous findings demonstrating clearance of TMAO by the kidney and showing its association with reduced renal function [Third, while the AUC for fCAD for TMAO and its precursors was relatively low, it was statistically significant. Plasma levels of TMAO and its precursors  did not provide incremental diagnostic value for prediction of fCAD to clinical judgment of the cardiologist. Nonetheless, all markers were significant risk factors for fCAD in the univariate model, with TMAO remaining significant in models adjusted for age, sex and CAD history. Fourth, in contrast, concentrations of TMAO, carnitine and to a lesser extent choline were significant predictors of incident adverse events including either MI, CV-death, or all cause death. This finding is in concordance with previous reports where TMAO has been shown to be associated with all-cause and CV-death [Fifth, time-dependent ROC curve analysis showed consistent moderate-to-good prognostic accuracy of TMAO and its precursors for all-cause and CV-death during follow-up. The prognostic value for TMAO persisted also in fully adjusted models, highlighting possible implications for routine clinical practice given similar observations in recent studies [patients , 40. Intpatients —thereforfunction –45. Basefunction –48. TakiCV-death , 20–22. CV-death , 49. Fif studies , 36. Ove studies Several therapeutic strategies could result in a reduction of TMAO concentrations: reduction in intake of red meat, rich in TMA precursors; use of targeted treatment of selected microbiota, e.g. by application of specific oral antibiotics to eradicate the intestinal microbiota responsible for TMA production; and inhibition of flavin monooxygenase in the liver , 34, 50.This study has important strengths, including central adjudication of fCAD, adjudication of hard outcomes, and prospective examination of the relationship of TMAO with respect to fCAD and incident MI, CVD death, and all-cause mortality over a long-term follow-up of 5 years. In addition, the study examines the relationship of multiple nutrient TMAO precursors betaine, choline and carnitine in a large prospective study of patients in need of active decision making. Also, several limitations should be considered when interpreting the findings of this study: first, these data were generated in a single-center study. While single-center studies are by definition prone to selection bias, generalizability of these findings seems high as standardized patient consenting, clinical work-up with MPI-SPECT/CT as the initial imaging modality was performed in patients with a wide range of pre-test probability for fCAD, and longer term outcome ascertainment was complete. Second, despite using a very stringent methodology for the adjudication of fCAD, we might still have misclassified a small number of patients, which would result in an underestimation of the true accuracy of TMAO and its precursors for fCAD. This is overcome by the examination of the relationship between TMAO and time dependent incident hard adverse events. Third, the cohort consisted of a predominantly Caucasian population, not allowing the analysis of other ethnicities due to their under-representation. Finally, we cannot comment on the dietary association of TMAO or precursor level, as this was not recorded in the frame of the study, nor the possible role of TMAO and its precursors in patients with terminal kidney failure on chronic dialysis, as these subjects were excluded.In conclusion, TMAO and its precursors choline and carnitine showed potential prognostic value for short- and long-term risk-stratification for hard clinical events including CV-death, albeit with limited diagnostic utility in patients with suspected fCAD.Supplementary file1 (DOCX 999 KB)Below is the link to the electronic supplementary material.


In cardiorenal syndrome (CRS), heart failure and renal failure are pathophysiologically closely intertwined by the reciprocal relationship between cardiac and renal injury. Type 1 CRS is most common and associated with acute heart failure. A preexistent chronic kidney disease (CKD) is common and contributes to acute kidney injury (AKI) in CRS type 1 patients . The remaining CRS types are found in patients with chronic heart failure (type 2), acute and chronic kidney diseases (types 3 and 4), and systemic diseases that affect both the heart and the kidney (type 5). Establishing the diagnosis of CRS requires various tools based on the type of CRS, including non-invasive imaging modalities such as TTE, CT, and MRI, adjuvant volume measurement techniques, invasive hemodynamic monitoring, and biomarkers. Albuminuria and Cystatin C (CysC) are biomarkers of glomerular filtration and integrity in CRS and have a prognostic impact. Comprehensive “all-in-one” magnetic resonance imaging (MRI) approaches, including cardiac magnetic resonance imaging (CMR) combined with functional MRI of the kidneys and with brain MRI are proposed for CRS. Hospitalizations due to CRS and mortality are high. Timely diagnosis and initiation of effective adequate therapy, as well as multidisciplinary care, are pertinent for the improvement of quality of life and survival. In addition to the standard pharmacological heart failure medication, including SGLT2 inhibitors (SGLT2i), renal aspects must be strongly considered in the context of CRS, including control of the volume overload (diuretics) with special caution on diuretic resistance. Devices involved in the improvement of myocardial function  have also shown beneficial effects on renal function. The network organ interactions of the heart and kidneys are intimately involved in the pathophysiology of cardiorenal syndrome (CRS) ,2. In adVarious organ systems and mechanisms contribute to the pathophysiology of the syndrome, including hemodynamic changes, neurohormonal mechanisms, inflammatory reactions, oxidative stress mechanisms, and various less-defined mechanisms. Various biomarkers assessing heart function and damage, glomerular filtration, and renal tubular damage are currently used or under study to diagnose and assess the prognosis of CRS. Further diagnostic opportunities offered by cardiac ultrasound and magnetic resonance imaging (MRI) can be used to evaluate CRS patients . VariousThis review aims to summarize pathophysiological concepts, diagnosis, and treatment of CRS, focusing on type 1 and 2 CRS.CRS is a group of disorders that bear out the reciprocal relationship between cardiac and renal injury. Different observational and retrospective studies have shown the prevalence and burden of each of the five types of CRS. CRS type 1 is the most common. The nature of epidemiologic data limits clear delineation between cardiorenal syndrome types 2 and 4. Overall, the presence of cardiac or renal dysfunction strongly inhabits a poor prognosis of the contrary organ .Type 1 CRS  is characterized by the acute worsening of cardiac function leading to AKI a 11]. T. T11]. TCRS type 2 is characterized by chronic pathological changes in cardiac function leading to kidney injury or dysfunction, and chronic renal disease has been observed in 45-63% of chronic heart failure (CHF) patients b. HoweveType 3 CRS is characterized by acute worsening of kidney function leading to heart disease. A wide spectrum of cardiac dysfunction includes cases with acute decompensated heart failure, acute coronary syndrome, and arrhythmias as defined by the RIFLE  and AKIN (Acute Kidney Injury Network) criteria c 11,15],1511,15]AKI seems to involve almost 70% of patients in ICUs, where 5–25% of patients can develop severe AKI, with mortality rates ranging from 50 to 80% . ADHF stType 4 CRS, also defined as chronic renocardiac disease, is characterized by cardiovascular involvement in patients affected by CKD at any stage d. It is Type 5 CRS takes place when cardiac and renal injury occur at the same time as it occurs in sepsis and in systemic inflammatory response syndrome (SIRS) e 18]. T. T18]. TVarious mechanisms playing a role in the onset of CRS have been identified, while several others are still under study. There is a close relationship between heart failure endpoints  with the degree of renal impairment ,23. The One further pathophysiologic concept is that increased central venous pressure and increased intra-abdominal pressure may be decisively involved in the development of CRS in patients with cardiac impairment. The kidneys require continuous and abundant perfusion. Necessary for their function is sufficient filtration pressure, depending on the large difference between driving arterial pressure and venous outflow. The substantial increase in venous pressure and intra-abdominal pressure in heart failure patients also leads to renal venous congestion and a decrease in filtration pressure ,30. ConsDecreased cardiac output activates neurohormonal pathways to increase tissue perfusion. Excessive activation of the RAAS system, and in particular high levels of angiotensin II, has been shown to have negative effects on both the heart and the kidneys. The vasoconstrictive capacity of angiotensin II significantly increases the afterload of the left ventricle, while at the same time, the continuous vasoconstriction of the coronary arteries can lead to myocardial ischemia and endothelial dysfunction, especially after myocardial infarction . AngioteFurther mechanisms and molecular pathways, such as inflammation, oxidative stress, and imbalance of regulation mechanisms, such as ADH, have been suggested for the pathophysiology of CRS type 5. For COVID-19 disease, a recent systematic review has elucidated the detrimental prognostic impact of CRS in 637 patients  included in 15 studies with CRS or evidence of both cardiac and renal complications following SARS-CoV-2 infection [Establishing the diagnosis of CRS requires various tools, including non-invasive imaging modalities, adjuvant volume measurement techniques, invasive hemodynamic monitoring, and biomarkers.GFR remains the gold standard for assessing renal function. However, measuring true, real-time GFR remains difficult in the setting of ADHF or CHF because formulas estimating GFR have been validated when creatinine is in a steady state. Moreover, creatinine represents an imperfect surrogate that entails important limitations. First, creatinine reflects only GFR and not tubular injury directly, whereas tubular injury may help to better predict and characterize AKI and the progression of chronic kidney damage . In addiA diagnosis of CRS type 2 should be based on a clinical picture of either CHF with preserved or reduced LVEF on echocardiography, joined with biochemical signs of renal dysfunction, the onset or progression of which is reasonably secondary to congestive heart failure (HF). The findings indicative of renal dysfunction in the context of a CRS type 2 should include increased Cr or, in subjects with poor muscle mass, a Cr value in the near-normal range, provided that it is associated with low values (<60 mL/min/1.73 m²) of eGFR, calculated using the Modified Diet in Renal Diseases study (MDRD) or Cockcroft–Gault equations. Further laboratory findings that are useful for a better diagnostic definition of renal damage are represented by the coexistence of albuminuria or anemia, or both. Cardiac index and total peripheral resistance as assessed by pulmonary artery catheter are hypothetically important measures to evaluate the hemodynamic compromise involved in CRS. However, no prognostic benefit could be confirmed in the ESCAPE trial by pulmonary artery catheter monitoring .Biomarkers in the context of CRS can be primarily divided into three groups; biomarkers of renal tubular injury, markers of glomerular filtration and integrity, and finally, cardiac biomarkers. Biomarkers may be important for the early identification of renal or cardiac injury and the prognostic evaluation of CRS. Biomarkers may also be helpful in the discrimination of various CRS phenotypes and in guiding targeted therapeutic interventions.Albuminuria and cystatin C (CysC) are the biomarkers of glomerular filtration and integrity in CRS. Albuminuria also has an adverse prognostic value for cardiovascular death, all-cause death, and heart failure re-admissions ,6. The pAmong the markers of renal function applicable to the CRS studies, CysC is one of the most widely exploited as a diagnostic tool for use as a replacement or supplement for creatinine. This protein, with a chain structure consisting of 120 amino acids, is present in almost all tissues and body fluids. Urine Cystatin C is a marker of proximal tubule injury/dysfunction since it is fully metabolized in the proximal tubule except with renal injury or dysfunction. On the other hand, serum CysC levels reflect glomerular filtration ,48. FurtNumerous other biomarkers have been evaluated for the accurate detection of AKI and/or for the prediction of the progression of CKD. While these novel biomarkers may contribute to our pathophysiological understanding of AKI and cardiorenal disease, establishment in routine clinical practice remains to be determined, partly due to higher costs associated with their measurement and the lack of diagnostic or prognostic relevance or superiority compared with established biomarkers. Recently, a prognostic superiority of novel biomarkers compared with established measures (such as creatinine) was not confirmed for NGAL  for worsening renal function (WRF) and AHF ,62,63,64Finally, cardiac biomarkers are also important in CRS. NT-proBNP is a widely used cardiac biomarker for the diagnosis and prognostic stratification of heart failure . ST2 is Trans-thoracic echocardiography and renal ultrasound provide important information on heart and kidney failure in patients with cardiorenal syndrome and are the imaging methods of choice in the diagnostic work-up . UltrasoKidney ultrasound can exclude obstructive uropathy as a cause of renal failure . Kidney Computer tomography (CT) of the heart may be useful for the evaluation of coronary artery calcification (CAC) indicating coronary artery disease. CAC is an independent predictor of cardiovascular morbidity and mortality in CKD patients . CT techCardiac magnetic resonance imaging (CMR) is a gold standard approach for the accurate assessment of biventricular function, ventricular geometry and mass, valvular pathologies, pericardial effusion, and of myocardial structure, including the localization and quantification of myocardial scars and inflammation ,76. AddiFunctional magnetic resonance (MR) imaging of the kidneys has gained interest recently, especially for the detection of early changes in AKI or for the prediction of the progression of CKD. The application of these methods to CRS is fairly novel. Blood oxygen level-dependent (BOLD) MR imaging of the kidneys in mice with experimental myocardial infarction revealed that R2* in the kidney increased after induced myocardial infarction and that the response was higher in animals with larger infarcts and over time . These BCardiorenal syndrome (CRS) is characterized by complex interactions between different physiological systems, whereby dysfunction of the heart negatively affects kidney function and vice versa. There is emerging evidence on the beneficial effects of heart failure treatment also on CRS outcomes. Current treatment options for both HF and CRS include beta-adrenergic blockers (BB), diuretics/ultrafiltration, angiotensin-converting-enzyme-inhibitors (ACEI), angiotensin-receptor-blockers (ARB), mineraloreceptor antagonists (MRA), angiotensin-renin-neprilysin-inhibitors (ARNI), sodium-glucose co-transporter 2 inhibitors (SGLT2i) and cardiac resynchronization (CRT) . RecentlVolume management and diuretics have a narrow therapeutic path in AHF and CRS. Diuretics play a key role in treating CRS since they quickly alleviate symptoms caused by fluid expansion in the patient. They positively affect hypertension, increased intra-abdominal pressure, and renal congestion . Diureti2 [Heart failure with reduced ejection fraction (HFrEF) is routinely treated with BB, ACEI, ARB or ARNI, MRA, and SGKT2i with class I level of evidence . BB have2 .2. For this reason, about 80% of patients with renal failure corresponding to CKD stages 3 and 4 (eGRF < 60 mL/min/1.73 m2) discontinue treatment with RAAS inhibitors or only receive submaximal doses [Tolvaptan, an oral vasopressin V2-receptor antagonist, was developed for the improvement of ADHF outcomes by targeting the reduction of volume overload and avoiding exuberant intravascular volume depletion, thereby inhibiting harm to renal function. However, the EVEREST trial did not confirm a reduction in long-term mortality or heart failure-related morbidity in ADHF patients . RAAS inal doses . Howeveral doses . Finerenal doses ,108,109.al doses .A recently established pilar of pharmacological HF therapy are the SGLT2i, initially introduced as oral antidiabetic agents, both in HFrEF and HFpEF ,114,115.Another milestone of HF treatment in HFrEF patients with left bundle branch block (LBBB) is cardiac resynchronization therapy (CRT) . In addiComplex network organ interactions of the heart and kidneys are intimately involved in the pathophysiology of cardiorenal syndrome (CRS), including interactions with the central nervous system (CNS). The five CRS types can be differentiated by pathophysiological pathways. While GFR remains the gold standard for assessing renal function, albuminuria is associated with an increased risk of mortality, heart failure-related hospitalizations, and clinical, echocardiographic, and circulating biomarkers of congestion. However, the precise clinical role of novel biomarkers, which may contribute to our pathophysiological understanding of AKI and cardiorenal disease, remains to be determined. Imaging modalities progress to comprehensive approaches encompassing the evaluation of kidneys, the heart, and the CNS. Functional magnetic resonance imaging of the kidneys may prove decisive for the detection of early changes in AKI or for the prediction of the progression of CKD. The prognostic impact of CRS among patients with COVID-19 infection highlights the need for special assessment and management of CRS in patients with certain comorbidities. Several mainstays of heart failure medication  also have positive effects on the progressive course of CKD, again highlighting the necessity of differentiation between acute effects of glomerular pressure and true kidney injury or progression of kidney disease with tubulointerstitial fibrosis. As a novel therapeutic agent, the non-steroidal selective MRA finerenone has shown beneficial effects on cardiovascular and renal events in patients with diabetic nephropathy and albuminuria.