In vitro fertilisation (IVF). This study aimed to quantify rates of Ovarian Hyperstimulation Syndrome (OHSS) requiring intensive care unit (ICU) admission and assess whether trends have changed between 1996-2020 commensurate with the introduction of safer IVF practices.Ovarian Hyperstimulation Syndrome (OHSS) is a life-threatening iatrogenic complication of Data regarding Intensive Care Unit (ICU) admission across England, Wales and Northern Ireland was gathered retrospectively from the Intensive Care National Audit and Research Centre (ICNARC) database. 38,957 female patients aged between 18-55 years were admitted to ICU for OHSS or related conditions between 1996-2020. The primary outcome was the rate of OHSS requiring ICU admission expressed as a proportion of the number of fresh IVF cycles conducted in that year according to Human Fertility and Embryology Authority (HFEA) records. Baseline characteristics , biochemical parameters , length of ICU stay and duration and need for organ support, were also compared between ICU patients with ‘confirmed OHSS’ and those ‘without OHSS’.There were 238 cases of ‘confirmed OHSS’ requiring ICU admission recorded between 1996-2020. Rates of OHSS requiring ICU admission declined over the study period (P=0.006); the annual rate of severe OHSS requiring intensive care admission halved when comparing those occurring between 1996-2007 and 2008-2020 . Patients spent a mean of 3.5 days in the ICU, with 86.3% of patients with ‘confirmed OHSS’ requiring at least 2 days of higher level  care. Patients with ‘confirmed OHSS’ required a shorter duration of renal, advanced cardiovascular, and advanced respiratory support than patients ‘without OHSS’ . There was no significant difference in BMI or ethnicity between those with ‘confirmed OHSS’ and those ‘without OHSS’, however women with ‘confirmed OHSS’ were younger .Although absolute rates of OHSS requiring ICU admission recorded in this study are likely to represent a significant underestimate of all clinically significant OHSS, rates of OHSS requiring ICU admission have decreased since 1996 in concordance with the introduction of modern IVF practices. The rld-wide . HCG canrld-wide . VEGF inrld-wide , 5. Reporld-wide , 6. WomeF cycles .In the United Kingdom (UK), moderate, or more severe forms of OHSS are categorized as ‘B Grade’ incidents  and shouOnly a small proportion of all clinically significant OHSS requires higher level care with admission to the intensive care unit (ICU), however there is only very limited description in the literature of rates of OHSS requiring ICU care. Thus, to assess the burden of OHSS on the health service, we used a national intensive care registry (ICNARC) to provide an estimate of the trends in clinically significant OHSS rates requiring ICU care between 1996-2020 in England, Wales, and Northern Ireland.ICNARC have the approval to hold patient identifiable data under section 251 of the NHS Act 2006 granted by the Confidentiality Advisory Group (CAG) within the Health Research Authority (HRA). The Case Mix Programme (CMP) is an audit of patient outcomes from adult, general critical care units (intensive care and combined intensive care/high dependency units) covering England, Wales, and Northern Ireland. All data collected by the ICNARC is stored, handled, and reviewed annually in line with the HRA and CAG. As per HRA guidelines, additional ethical approval for this study was not required. The approval number for the CMP is PIAG 2-10(f)/2005.Data was acquired from the Intensive Care National Audit and Research Centre (ICNARC) database , which rThe retrieved 38,957 patients were categorized into three groups 3. PatieThe numbers of ‘confirmed’ and ‘potential’ OHSS cases in 2020 were proportionately adjusted to account for the lack of availability of data between 1st October 2020 and 31st December 2020 at time of data-extraction. The number of ICUs from which the ICNARC database  collectsDemographic and clinical data were presented descriptively as count with proportion (%) for categorical data, and median (IQR) for continuous data, as appropriate. Demographic and clinical data was compared between patients ‘without OHSS’, and those with ‘confirmed OHSS’ by the Mann Whitney U test, or Fisher’s exact test, as appropriate. The Mann-Kendall test was used to assess the overall trend in OHSS rates from 1996 to 2018  women were classified as having ‘confirmed OHSS’, a further 120 (0.31%) having ‘potential OHSS’, and 38,599 (99.1%) as being ‘without OHSS’ Table 1.The annual number of ‘confirmed OHSS’ cases appeared to be greater in recent years, and this trend is exaggerated when these figures are combined with the number of ‘potential OHSS’ cases Figure 1The number of fresh IVF cycles have also increased each year. In order to evaluate the rate of OHSS requiring ICU admission per fresh IVF cycle, the number of cases were expressed as a proportion of the annual number of IVF cycles conducted in England, Wales, and Northern Ireland . This prClinical and laboratory data for patients on admission to ICU with ‘confirmed’ and ‘without OHSS’ are presented in Both serum creatinine  and urea (P<0.0001) were lower in patients with ‘confirmed OHSS’ and these women were also less likely to have an elevated blood lactate (P<0.0001). Patients with ‘confirmed OHSS’ had a lower serum sodium level than patients ‘without OHSS’ (P<0.0001). Notably, the proportion of patients with their ‘lowest serum sodium’ value signifying hyponatremia  was almost 2-fold greater in the ‘confirmed OHSS’ group compared to the ‘without OHSS’ group .Care and support needs of patients ‘without OHSS’, and those with ‘confirmed OHSS’ are presented in This is the first study to demonstrate that the rates of OHSS requiring ICU admission have decreased over the past two decades in England, Wales, and Northern Ireland. There are very limited published reports on the rates of OHSS requiring ICU admission, and although it is mandatory to report OHSS cases requiring ICU admission in Europe, this is not a requirement in the US .The rate of ‘confirmed OHSS’ requiring ICU admission per fresh IVF cycle has halved over recent years, from 0.06% in 1996-2006 to 0.03% in 2007-2019. This decline is likely to reflect the introduction of safer IVF practices including individualized dosing of gonadotropins for ovarian stimulation, using predictive markers such as AMH , 21, andThe true impact of such prevention strategies on reducing the incidence of all clinically significant OHSS remains unclear , 13, 22 In line with this data, moderate to severe OHSS rates in the United States have halved from 1.2% in 2000-2006 to 0.5% in 2006-2015 . Data frThe present study found that the majority of patients who had ‘confirmed OHSS’ were under the age of 35 years, which could partly be explained by greater accessibility of IVF treatment for these women in the UK . FurtherHyponatremia occurs in clinically significant OHSS , 42, likLimitations of this study include the need for normalization for the number of reporting centres and number of fresh IVF cycles conducted over the last two decades . FurtherRates of clinically severe OHSS requiring ICU admission in the UK have decreased over the past two decades. Due to its focus on OHSS requiring ICU admission, this study likely presents the absolute minimum prevalence of severe OHSS and thus is likely to underestimate the occurrence of all clinically significant OHSS. Although rates of OHSS have reduced, they have not been eliminated, and improved IVF practices including individualized approaches should be continued in order to minimize the residual risk of this serious iatrogenic complication of IVF treatment.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.ICNARC have the approval to hold patient identifiable data under section 251 of the NHS Act 2006 granted by the Confidentiality Advisory Group (CAG) within the Health Research Authority (HRA). The Case Mix Programme (CMP) is an audit of patient outcomes from adult, general critical care units (intensive care and combined intensive care/high dependency units) covering England, Wales, and Northern Ireland. All data collected by the ICNARC is stored, handled, and reviewed annually in line with the HRA and CAG. As per HRA guidelines, additional ethical approval for this study was not required. The approval number for the CMP is PIAG 2-10(f)/2005. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.All authors have contributed to the study and the development of the manuscript.


Background: Cardiovascular remodeling is essential in patients with obstructive sleep apnea (OSA), and continuous positive airway pressure (CPAP) therapy could improve these processes. Two-dimensional (2D) speckle-tracking (ST) echocardiography is a useful method for subclinical biventricular dysfunction diagnosis and thus might help as an earlier treatment for OSA patients. It is still not clear which blood serum biomarkers could be used to assess CPAP treatment efficacy. Objectives: To evaluate left heart geometry, function, deformation parameters, and blood serum biomarker  levels in patients with OSA, as well as to assess changes after short-term CPAP treatment. Materials and Methods: Thirty-four patients diagnosed with moderate or severe OSA, as well as thirteen patients as a control group, were included in the study. All the subjects were obese (body mass index (BMI) > 30 kg/m2). Transthoracic 2D ST echocardiography was performed before and after 3 months of treatment with CPAP; for the control group, at baseline only. Peripheral blood samples for the testing of biomarkers were collected at the time of study enrolment before the initiation of CPAP therapy and after 3 months of CPAP treatment (blood samples were taken just for OSA group patients). Results: The left ventricle (LV) end-diastolic diameter and volume, as well as LV ejection fraction (EF), did not differ between groups, but an increased LV end-systolic volume and a reduced LV global longitudinal strain (GLS) were found in the OSA group patients . Indexed by height, higher LV MMi in OSA patients (p = 0.007) and a higher prevalence of LV diastolic dysfunction (p = 0.023) were found in this group of patients. Although left atrium (LA) volume did not differ between groups, OSA group patients had significantly lower LA reservoir strain (p < 0.001). Conventional RV longitudinal and global function parameters ) did not differ between groups; however, RV GLS was reduced in OSA patients (p = 0.026). OSA patients had a significantly higher right atrium (RA) diameter and mean pulmonary artery pressure (PAP) (p < 0.05). Galectin-3 and sST2 concentrations significantly decreased after 3 months of CPAP treatment. Conclusions: OSA is associated with the left heart remodeling process—increased LV myocardial mass index, LV diastolic dysfunction, reduced LV and RV longitudinal strain, and reduced LA reservoir function. A short-term, 3-months CPAP treatment improves LV global longitudinal strain and LA reservoir function and positively affects blood serum biomarkers. This new indexing system for LV myocardial mass by height helps to identify myocardial structural changes in obese patients with OSA. Obstructive sleep apnea (OSA) is described as a chronic disease with repeatable respiratory pauses during sleep, followed by episodic hypoxia and sleep fragmentation . Upper aPrevious studies have shown that OSA causes the remodeling of the left ventricle (LV) and left atrium (LA). Increased LV pressure and diastolic dysfunction cause LA enlargement and structural remodeling . RecentlOSA is not only complicated by left heart disease but is usually associated with pulmonary hypertension . AccordiOSA is diagnosed during overnight polysomnography and treated with continuous positive airway pressure (CPAP). Even when OSA is diagnosed, issues such as poor patient adherence can prevent adequate treatment with CPAP overnight. Because OSA is associated with cardiovascular diseases, echocardiographic evaluation is the preferred diagnostic test. Considering that OSA is associated with cardiovascular dysfunction, an ideal blood serum biomarker should allow for the timely recognition of increased cardiovascular risk and help in the early diagnosis and treatment of cardiovascular complications. More and more new results are coming on the utility of serum biomarkers for assessing disease severity, prognosis, and response to treatment. However, blood serum biomarkers, which could evaluate CPAP treatment efficacy for the cardiovascular system, have not yet been widely investigated. Various studies have searched for biomarkers for the screening of OSA ,14,15, bGalectin-3 is a biomarker of fibrosis and inflammation and has been implicated in the development and progression of HF, and it may predict increased morbidity and mortality . HoweverInterleukin-33 is a functional ligand of ST2, involved in reducing fibrosis and hypertrophy in mechanically stressed tissues. Recent studies have demonstrated soluble ST2 to be a strong independent predictor of cardiovascular outcomes in both chronic and acute HF . In contET-1 is one of those more widely discussed biomarkers in OSA compared with galectin-3 and sST2. Harańczyk et al. investigated OSA’s influence on endothelial dysfunction, and one of their conclusions was that long-term CPAP treatment does not have any impact on changes in biomarker levels . Lin et The early detection of left or right ventricle dysfunction with echocardiographic techniques may be useful in early applications of CPAP and preventing the progression of LV hypertrophy, diastolic and systolic dysfunction, and pulmonary hypertension, as the later development of HF leads to cardiovascular death. Two-dimensional (2D) echocardiography is the gold standard for the evaluation of the cardiac remodeling associated with OSA. Conventional echocardiography is not sensitive enough to detect early cardiac dysfunction in OSA patients; thus, 2D speckle-tracking (ST) echocardiography is an informative and promising method of detecting subclinical changes in LV or LA function. In addition, it is very important to evaluate CPAP treatment effectiveness by researching parameters reflecting LV remodeling. It likely that the identification of blood serum biomarkers could be the most accurate reflection of these changes.This was a longitudinal study that assessed echocardiographic parameters and particular blood serum biomarkers in OSA patients before and after 3 months of CPAP therapy. First part of this study  was the evaluation of the quality of life in OSA patients during CPAP treatment .From January 2020 to June 2021, 34 participants with moderate-to-severe OSA were included in the trial. After receiving CPAP treatment for 3 months, 17 individuals underwent the final investigation. Thirteen patients had their 2D ST echocardiographic parameter pre- and post-CPAP treatment evaluated. Patients who dropped out were either lost in the follow-up or denied CPAP therapy.The study was authorized by the Kaunas Regional Biomedical Research Ethics Committee .2, and a completed informed consent form were the inclusion criteria.Age 18 to 65, a diagnosis of moderate to severe OSA, a body mass index equal or more than 30 kg/mSubjects under the age of 18 and adults over the age of 65 were excluded, as well as people with significant mental and/or internal organ disorders that might have an impact on the study’s protocol but who did not have clinically significant ischemic heart disease, severe valvular heart disease (grade 3), or uncontrolled arterial hypertension (AH). The exclusion criteria also included the absence of a signed informed consent form and the investigator’s discretion.All individuals received thorough clinical investigations, which included thorough physical examinations and the documentation of symptoms, medical and surgical histories, and comorbidities. At the Hospital of Lithuanian University of Health Sciences (LUHS) Kaunas Clinics Outpatient Clinic, patients were examined and had otorhinolaryngologist consultations to rule out any nasal pathology .People who were thought to have OSA were referred to the LUHS Kaunas Clinics Pulmonology Department’s Sleep Laboratory for an overnight diagnostic polysomnography (PSG). Using the Alice 6 LDx diagnostic sleep system, this investigation was conducted . Apnea was defined as the absence of airflow for longer than 10 s, and hypopnea as a decrease in airflow for at least 10 s that was also accompanied by a 3% drop in SpO2 or arousal. During the study, the apnea-hypopnea index (AHI) was measured for each hour of sleep. According to the AHI, OSA patients were divided into three categories: mild OSA AHI ≥ 5 but <15), moderate OSA (AHI ≥ 15 but <30), and severe OSA (AHI ≥ 30) [ but <15,Each patient spent an additional night in the sleep laboratory following the diagnosis of OSA for CPAP titration, which determines the ideal pressure at which the CPAP equipment eliminates aberrant breathing occurrences. To take part in the clinical investigation, patients with moderate or severe OSA were invited.2, and signed informed consent form.The control group consisted of 13 subjects. Control group subjects underwent all the same diagnostic steps as the OSA group. The inclusion criteria were: age 18–65 years old, diagnosis of mild OSA (AHI ≥ 5 but <15) or no OSA diagnosis during overnight diagnostic PSG (AHI < 5), body mass index (BMI) ≥ 30 kg/m®  serum tubes at the time of study enrolment before the initiation of CPAP therapy and after 3 months of CPAP treatment (blood samples were taken only for OSA group patients). After collecting the blood, samples were allowed to clot for 1 h at room temperature and, after that time, centrifuged at 1600× g for 10 min. Following centrifugation, serum was separated from the blood and transferred into clean 1 mL cryotubes using a Pasteur pipette. Whole blood samples were stored at −80 °C in a refrigerator.As mentioned before, three biomarkers were tested: galectin-3, sST2, and ET-1. Peripheral blood samples were collected in BD Vacutainer®, Houston, TX, USA) according to the manufacturer’s instructions.The serum concentrations (ng/mL) were analyzed using a commercially available enzyme-linked immunosorbent assay  ultrasound machine and an M3S cardiac 4.0 MHz transducer. Two experienced cardiologists conducted all conventional measurements and 2D transthoracic echocardiography studies.2 for men and ≤16.5 mL/m2 for women; normal LV myocardial mass ≤ 50 g/m2.7 for men and ≤47 g/m2.7 for women) [Conventional measurements were taken in accordance with the American Association of Echocardiography’s recommendations. . LV end-r women) .At the apical four- and two-chamber views, the LV ejection fraction (EF) was estimated using Simpson’s biplane approach. By evaluating the mitral diastolic flow velocity ratio (E/A), the E/e ratio, the volume index of the LA, and the tricuspid regurgitation velocity, LV diastolic function was assessed in accordance with established recommendations .The peak systolic velocity of the tricuspid annulus (RV S′), as measured by Tissue Doppler imaging, and the RV fractional area change (FAC), as determined by tracing the RV endocardial boundaries at the end-diastole and end-systole, were used to evaluate the RV longitudinal function .RVOT); the normal mean PA pressure was defined as <25 mmHg [The longitudinal strains of LV, LA, and RV were assessed with ST echocardiography using the TomTec GmbH  imaging system according to existing guidelines . The LV <25 mmHg .Study subjects were asked to return for a follow-up visit 3 months after treatment. CPAP treatment compliance was checked by downloading data from the CPAP device. We defined compliance with treatment as using the CPAP device for more than 4 h per night for more than 70 percent of nights and an AHI < 5.After 3 months of CPAP treatment, a 2D ST echocardiography was performed and blood samples were taken.For the control group, a 2D ST echocardiography was performed just once as a baseline (as no treatment with CPAP was initiated).We analyzed both groups of patients: control group (no OSA was diagnosed or it was mild) and those with continuous CPAP treatment . Quantitative variables were described using the mean and standard deviation or median at the 25–75th percentiles. To describe the distribution and changes in all quantitative variables, the nonparametric Mann–Whitney U-test for two dependent samples was used.Receiver operating characteristic (ROC) curve analysis was conducted to describe the predictive value of strain parameters; the correspondent area under the curve with its 95% confidence interval was calculated.p < 0.05.IBM SPSS Statistics for Windows, version 27.0 , was used for statistical analysis. Statistical significance was considered to be p = 0.03). OSA group subjects were older compared to the control group. BMI did not differ significantly between either group. In total, 26 OSA group patients and 10 control group subjects had various chronic diseases, but the most common were AH and diabetes mellitus  4.97; 95% confidence intervals CI 1.17–21.10; mellitus .Based on the receiver operating characteristic (ROC) test , we obtap = 0.015 and p = 0.035 respectively). Indexed by height, a higher LV Mmi in OSA patients (p = 0.007) and a higher prevalence of LV diastolic dysfunction (p = 0.023) were found in this group of patients. Though the LA volume did not differ between groups, the OSA group patients had significantly lower LA reservoir strain (p < 0.001).LV end-diastolic diameter and volume, as well as LV EF, did not differ between the groups, but increased LV end-systolic volume and reduced LV global longitudinal strain (GLS) were found in OSA group patients (p = 0.026). OSA patients had a significantly higher RA diameter and mean PAP (p < 0.05) ) did not differ between the groups; however, the RV GLS was reduced in OSA patients ( < 0.05) .The LV diameter, Mmi, and LV ejection fraction did not change after treatment. The LV global longitudinal strain improved, as well as the LV diastolic function parameters. We found that LV diastolic dysfunction was more prevalent in the OSA group. CPAP treatment improved LV diastolic function after 3 months.p = 0.008). Right ventricle geometry, function, and deformation parameters did not change.We found no LA volume changes after treatment, but LA reservoir function significantly improved 3 months after treatment with CPAP  as an element and sign of CPAP treatment efficacy.Our results show that OSA is related to increased LV end-systolic volume and LV MMi (as indexed by height) and is more prevalent in LV diastolic dysfunction. Although the conventional echocardiographic parameters of LV and RV function did not differ, 2D ST echocardiography revealed subclinical dysfunction in both ventricles and LA, as the LV GLS, RV GLS, and LA reservoir strain were significantly lower in OSA patients compared to the controls. CPAP treatment had a positive effect on LV longitudinal and LA reservoir function (LV GLS and LA reservoir strain significantly improved) and was related to a significant reduction in serum biomarker  concentration.Various studies have searched for possible useful biomarkers that can be used for OSA screening; however, there are only a few that could be used to evaluate the efficacy of CPAP treatments for the cardiovascular system in OSA patients. CPAP is an efficient treatment for OSA, but adherence remains challenging. Response to treatment is quite complicated, as patients usually feel only subjective component changes, such as those relating to daytime symptoms. Thus, it is very important to show improvement in a patient via objective data—for example, serum biomarker reduction and cardiac function improvement, as was investigated in our study. Furthermore, different clinical trials have had different perspectives on the evaluation of the cardiovascular system, as the same echocardiographic parameters were not used.It is very difficult to describe the necessary criteria for perfect OSA biomarkers; Montesi et al.  looked fGalectin-3 is a biomarker of fibrosis and inflammation and is involved in the development and progression of HF, and it may predict increased morbidity and mortality. Several meta-analyses have shown that increased galectin-3 expression levels are associated with mortality and acute and chronic HF . An inteThe prognostic value of sST2 in HF patients with OSA was discussed in the clinical study by Kopeva et al. The main finding was that sST2 might be used as a diagnostic biomarker for the prognosis of adverse cardiac events in HF patients with preserved EF, as higher sST2 concentration levels are associated with a higher frequency of adverse cardiac events in follow-up periods . DanielsET-1 is a mediator that participates in endothelial dysfunction progress caused by the irreversible process of vascular remodeling, resulting in an effect on systemic and pulmonary circulation. . As a reIt has been observed that OSA group patients have a more prevalent AH ratio. Periodic hypoxemia and hypercapnia due to apnea–hypopnea episodes cause sympathetic nerve activation and elevate serum catecholamine, leading to an increase in heartrate and blood pressure. Over time, these hemodynamic changes lead to LV hypertrophy, diastolic dysfunction, and HF ,43. A prDetailed echocardiographic parameters in OSA patients, but without treatment options, were overviewed in a review by Sascau et al. . The maiThe treatment of OSA with CPAP reduces hypoxia episodes; improves hemodynamic parameters such as arterial stiffness, blood pressure, and pulmonary vasculature resistance; and normalizes hormonal (sympathetic hyperactivity) as well as metabolic alterations . The effMeta-analyses by Sun et al. reviewed the impact of CPAP on LV EF in patients with OSA . A signiThe results of a recent meta-analysis showed that CPAP treatment improves the biventricular function of OSA patients, and ST echocardiography should be a routine diagnostic test for these patients rather than conventional echocardiography due to its limitations . AccordiInteresting results were published in a study by D’Andrea et al. . The autPrevious studies have revealed that, in patients with OSA, repetitive hypoxia episodes during sleep cause myocardial ischemia, increased afterload, and subclinical LV dysfunction, especially longitudinal LV deformation impairment . Kim et 2.7), as height-based indexing preserves the effect of obesity on LV mass [OSA is associated with LA remodeling and dysfunction, occurring even before LV hypertrophy and LV diastolic dysfunction. Wan et al. showed that the LA reservoir and conduit function reduce in OSA patients irrespective of LV hypertrophy presence; meanwhile, active pump function increased . Accordi LV mass . In our According to our clinical study results, subclinical dysfunction in RV was found. PH is diagnosed in approximately 40 percent of OSA patients . GeneralThis clinical trial has some limitations that should be highlighted. The main limitation of this study is the relatively small patient sample. Both groups of our study patients (those who did not start or who discontinued CPAP treatment and those who used the CPAP device and had good compliance) were similar to each other. We believe that patients enrolled in the study could be representative of all patients with moderate or severe OSA. One more limitation is that blood serum biomarkers were not tested for in the control group (patients with mild OSA or without an OSA diagnosis). Thus, it was not possible to compare data between healthy subjects and make relevant conclusions.OSA is associated with the left heart remodeling process—increased LV myocardial mass index, LV diastolic dysfunction, reduced LV and RV longitudinal strain, and reduced LA reservoir function. A short-term, 3-month CPAP treatment does not change the geometry of left heart chambers, but it does improve LV global longitudinal strain and LA reservoir function and positively affects blood serum biomarkers. This new indexing system for LV myocardial mass via height helps to identify myocardial structural changes in obese patients with OSA. Further research is needed to investigate galectin-3, sST2, and ET-1 correlations with echocardiographic parameters in treatment with CPAP.


Broken Heart Syndrome, also known as Takotsubo Syndrome (TS), is sudden and transient dysfunction of the left and/or right ventricle which often mimics Acute Coronary Syndrome (ACS). Japan was the first country to describe this syndrome in the 1990s, and since then it has received a lot of attention from researchers all around the world. Although TS was once thought to be a harmless condition, recent evidence suggests that it may be linked to serious complications and mortality on par with Acute Coronary Syndrome (ACS). The understanding of TS has evolved over the past few years. However, its exact etiology is still poorly understood. It can be classified into two main types: Primary and Secondary TS. Primary TS occurs when the symptoms of myocardial damage, which is typically preceded by emotional stress, are the reason for hospitalization. Secondary TS is seen in patients hospitalized for some other medical, surgical, obstetric, anesthetic, or psychiatric conditions, and the dysfunction develops as a secondary complication due to the activation of the sympathetic nervous system and the release of catecholamines. The etiopathogenesis is now proposed to include adrenergic hormones/stress, decreased estrogen levels, altered microcirculation, endothelial dysfunction, altered inflammatory response via cardiac macrophages, and disturbances in the brain-heart axis. The role of genetics in disease progression is becoming the focus of several upcoming studies. This review focuses on potential pathophysiological mechanisms for reversible myocardial dysfunction observed in TS, and comprehensively describes its epidemiology, clinical presentation, novel diagnostic biomarkers, and evolving principles of management. We advocate for more research into molecular mechanisms and promote the application of current evidence for precise individualized treatment.  Takotsubo cardiomyopathy,  is characterized by an acute akinesia/hypokinesia of the mid and apical segments of the left ventricle and hyperkinesia of the basal segment, leading to left ventricular dysfunction . The namAround 2% of individuals presenting with clinical manifestations of ACS have been reported to have TS (up to 10% if only women are considered) . UnfamilThe exact pathophysiology underlying TS remains an enigma . In the Endothelial dysfunction due to falling estrogen levels and mental stress due to the trigger was a hypothesis used to explain the higher prevalence in postmenopausal women, further supported by an animal study ,15,16. AThere has been a significant lead in evidence for Broken Heart Syndrome over the past few years and thus the current review attempts to compile and appraise the evolving molecular mechanisms and principles of management for TS.The pathophysiology of Takotsubo Syndrome is elusive, the specificities of which are still being investigated, which makes the diagnosis and treatment more strenuous. Several mechanisms for TS development have been proposed. A plethora of research suggests that the primary cause of TS is a physically or emotionally stressful trigger . The secSome of the modifiable risk factors for Takotsubo Syndrome were researched in a systematic review. In the absence of any coronary artery disease, the study found a high prevalence of cardiovascular risk factors in patients with TS. These risk factors included obesity (17%), smoking (22%), and pre-existing medical conditions such as hypertension (54%), dyslipidemia (32%), and diabetes (17%). Other comorbidities included psychological disorders (24%), pulmonary diseases (15%), malignancies (10%), neurologic diseases (7%), chronic kidney disease (7%), and thyroid diseases (6%) . These fThe current evidence suggests gender be a non-modifiable risk factor for TS. Several reviews show a marked gender discrepancy with a higher prevalence of TS in females, especially postmenopausal women. This association can be explained by the effect of sex hormones on hypothalamo-sympathoadrenal outflow  and coroDespite the ambiguity in the pathogenesis of TS, the current evidence agrees upon the impact of stressors in causing TS. Sudden somatic and/or emotional stress causes a rise in the levels of catecholamine, resulting in transient left ventricular dysfunction . StressoThe etiopathogenesis can be explained by cardiovascular and neuropsychiatric mechanisms.The major cardiovascular hypotheses explaining the pathophysiology of TS have been categorized into vascular, myocardial, or both. In the vascular category, the cause of TS can be attributed to acute coronary spasm of multiple vasculatures, aborted myocardial infarction with spontaneous recanalization, or acute increased ventricular afterload. Multivessel coronary vasospasm was seen in 5–10% of individuals spontaneously and in 28% of individuals when provoked . HoweverUnder the myocardial category, the cardiac cause or manifestation is acute left ventricular outflow tract obstruction (LVOTO) and direct catecholamine-mediated myocardial stunning. Several studies support the LVOTO hypothesis which also leads to symptoms commonly associated with TS. For example, LVOTO compromises the forward stroke volume, and oxygen supply-demand mismatch and can lead to hypotension or cardiogenic shock in severe cases ,11. A reTakotsubo Syndrome is believed to be a consequence of several psychiatric and neurological conditions as it is closely linked with various organs, especially the brain . DepressA study by El-Sayed et al. demonstrated that patients with anxiety and mood disorders show increased susceptibility to Takotsubo Syndrome presumably because they are linked to an increased likelihood of stressful occurrences . If thisThe understanding of the molecular and cellular mechanisms behind Broken Heart Syndrome has evolved predominantly over the past few decades. This has enabled better understanding of the disease process  and has The βARs play a pivotal role in regulating the response of cardiac myocyte to catecholamines in times of stress and exercise. The distribution of βARs is not the same throughout the cardiac myocardium. It follows a spatial organization with concentration at the cardiac apex as shown in These mechanisms of adrenergic action contribute ‘transient’ severe wall motion abnormalities in TTS patients, which suggests the protective role of the mechanisms in maintaining myocardial integrity. Myocardial protection could be triggered by two distinct mechanisms. The first includes protective mechanism is linked with adrenoceptors. When exposed to supra-physiological epinephrine concentrations, beta 2-adrenoceptors switch from Gs to Gi coupling, resulting in a negative inotropic response that mitigates the extent of acute myocardial injury. The second is phosphoinositide 3-kinase/protein kinase B (AKT) survival pathway, which is transiently activated during the acute phase of TTS. Coronary angiogenesis and cardiac growth after birth both rely on the kinase AKT. Mechanistic target of rapamycin and glycogen synthase kinase 3 (GSK3) are two of its downstream targets that are known to play important roles in regulating metabolism, cell proliferation, and even cell survival. To keep cells alive, multiple mechanisms work in tandem, including direct apoptosis inhibition, inhibition of proapoptotic transcriptional factors, augmentation of antiapoptotic transcriptional factors, and inhibition of the GSK3 to improve cell metabolism. Several clinical studies demonstrating ‘inverse perfusion-metabolism mismatch,’ which is commonly observed during myocardial stunning, confirm that myocardial function down-regulation is a protective mechanism caused by a severe reduction in perfusion ,54,55.Estrogen plays an important role in TS due to its cardioprotective action . EstrogeThe pathophysiologic and molecular mechanisms are largely unknown and the limited studies conducted lack significant samples for a conclusive declaration. An excess of catecholamines is said to be the possible pathophysiologic phenomenon that contributes to the development of TS . This isThe ADR1 and ADR2 genes code for the β1 and β2 receptors, respectively. Polymorphism in these genes contributes to the increased sensitivity of the heart to catecholamines and adrenergic stress. Common β1 polymorphisms, that include Arg389 and Ser49 are proposed to play a role by causing a functional alteration or a gain of function mutation. In a case-control study by Vriz et al., some associations have been found between β1 adrenergic receptor polymorphisms and the occurrence of TS. However, no significant difference was found with β2 receptor variation . A possiGene Polymorphism in the BAG3 gene that contributes to endothelial cell apoptosis regulation may contribute to the pathophysiology of TS by affecting the coronary microcirculation . AnotherCirculating microRNAs have been indicated in the possible pathogenesis of TS by sensitizing the heart to an adrenergic stimulus. In a study on rat cardiomyocytes, miR-16 and miR-26a were found to enhance the inotropic effect of adrenaline along with ventricular basal hypercontractility and apical hypokinesis . JaguszeA higher prevalence of neuropsychiatric disorders has been found in patients with TS . The recA catena of studies has shown monocyte and macrophage infiltration of the myocardium in TS . AlthougSome other molecular mechanisms are also implicated in BHS:Nuclear myocardial perfusion investigations have shown that apical perfusion is impaired at one and six months but eventually recovers . EndotheIn TS, the apex of the heart receives less perfusion than the base, causing one of the core problems in TS. This is because there is a considerable overexpression of structural genes at the apex of TS hearts compared to their bases or apexes in normal hearts. Moreover, there is also a large downregulation of metabolism-related genes .During the acute phase, patients with TS have higher retention of ultra-small superparamagnetic iron oxide particles in both ballooning and non-ballooning left ventricular segments . This may be due to the fact that ultra-small supramagnetic iron oxide particles are primarily phagocytosed by activated tissue-resident macrophages, and macrophages appear to be the primary cellular protagonists of myocardial cellular inflammation in acute Takotsubo Syndrome, whereas acute myocarditis is predominantly lymphocyte-mediated. Furthermore, it has been observed that serum interleukin-6 and chemokine (C-X-C motif) ligand 1 concentrations, as well as classic CD14+ CD16 monocytes, are elevated in patients with Takotsubo Syndrome, but intermediate CD14+ CD16+ and non-classic monocytes are decreased. At 5 months follow-up, the prevalence of M1 macrophages and the persistence of the intermediate (CD14+ CD16+) monocyte subgroup is highly suggestive of a less reparative and more pro-inflammatory state compared to patients with acute myocardial infarction at similar stages. It is unknown, however, whether this inflammatory activity causes or contributes to TS. Regardless, these findings shed light on the low-grade chronic inflammatory substrate that contributes to the progression of acute takotsubo into long-term heart failure .The Broken Heart Syndrome is mostly associated with negative emotions and their impacts and thus is proclaimed to be the ‘Broken Heart’ syndrome. The significance of ‘positive emotions’ in TS is poorly defined ,80. PosiTakotsubo or stress-induced cardiomyopathy clinically manifests as an acute coronary syndrome. However, the onset of this condition is triggered by some intense emotional or physical distress or both. The most common physical exam findings for TS are acute substernal chest pain 75.9%), dyspnea (46.9%), and syncope (7.7%) according to the International Takotsubo Registry study %, dyspne. Other sPatients can also develop complications such as a cardiogenic shock, which presents as hypotension, respiratory distress, diaphoresis, oliguria, and cold extremities seen in 10% of patients with TS . PulmonaPrimary Takotsubo Syndrome: Patients with primary Takotsubo Syndrome typically visit an emergency room, a hospital with specialized cardiac care, or their primary care physician because they are experiencing acute cardiac symptoms. Some of these patients may or may not have easily recognizable sources of stress . However, while comorbid conditions may increase the risk of experiencing a catabolization of catecholamines, they are not the primary cause. These patients have what is known as primary Takotsubo Syndrome, and the clinical management of their condition is contingent on the manifestations of the condition. (2) Secondary Takotsubo Syndrome: Most cases happen in people who are already hospitalized for treatment of something else, be it physical (such as an injury or illness), mental (such as depression), or procedural (such as labor or delivery). An acute Takotsubo Syndrome develops as a result of the primary condition or its treatment when the sympathetic nervous system is suddenly activated or when catecholamine levels are elevated. In these situations, we propose that a secondary Takotsubo Syndrome diagnosis be made. They need to have both the condition that brought on TS and its cardiac complications addressed in their care [Takotsubo Syndrome has two distinct clinical forms: primary and secondary. Medical professionals encounter cases of Takotsubo Syndrome in a wide range of clinical settings. Primary Takotsubo Syndrome is the most common type, but secondary cases do occur. (1) eir care .Broken Heart Syndrome has a very similar symptomatic presentation to ACS, and hence may be misdiagnosed. Therefore, in patients presenting with ACS-like clinical features, Broken Heart Syndrome should be considered as a possible differential diagnosis. Treatment as per ACS, with anticoagulation and fibrinolysis, poses a risk of serious bleeding complications, and even death in such patients. Similarly, misdiagnosis of BHS as cardiogenic shock due to LVOTO caused by extensive myocardial infarction and subsequent treatment with catecholamine inotropics can have disastrous results. In addition, patients lack any coronary lesion to explain the left ventricular wall motion abnormality (LVWMA) typically seen in TS. Therefore, prompt coronary angiography, including left ventriculography, is essential for detecting and differentiating TS from ACS. Moreover, it is imperative to mention here that ACS can also set off TS, so the two conditions are linked . AlternaThus, it becomes very important to have clinical clarity in the diagnosis of Broken Heart Syndrome and to have a high index of suspicion. This is largely helped by diagnostic criteria such as the Mayo Clinic Criteria ,93, GothIt is important for timely diagnosis that other differentials are well-demarcated and that differences are cleanly understood. TS can lead to life-threatening complications, the most common being Acute Heart Failure (12–45%) and thus requires close observation and risk assessment . MultiplLyon et al., 2016, suggested a more comprehensive risk stratification score based on major and minor risk factors to help guide management . The manCurrently, natriuretic peptides and troponins are recommended biomarkers that help in reliably differentiating TS from ACS . Both naCatecholamines, their precursors and degradation products are also significantly raised in some patients, although they are not routinely used in clinical practice . CreatinMany studies have demonstrated an increase in pro-inflammatory biomarkers with the onset of TS. Scally et al. demonstrated the presence of a monocytic infiltrate in both the ballooning and non-ballooning segments, an increase in pro-inflammatory cytokine levels , and a change in the distribution of monocyte subsets. A few of these changes have seen to persist for at least 5 months, indicating chronic inflammatory changes .However, IL-6 levels have been shown to be significantly higher in patients with ACS.13 In fact, Santoro et al. found that TS was characterized by an increase in anti-inflammatory cytokines  in the acute phase . This isCatecholamine-induced myocardial stunning has emerged as a major proposed pathogenesis of TS . ReportsOther studies have shown that the increase in norepinephrine is not consistently seen in all patients with TS. Akashi et al. observed that around half of the patients studied did not show a significant elevation. The elevation could have also been a result of acute heart failure induced by TS, but the authors concluded that the very high catecholamine levels and patterns of regional sympathetic activation seen in some patients pointed towards a direct correlation . NeuropeMicroRNAs have emerged as important mediators in the pathogenesis of TS. In a study by Couch et al., miR-16 and miR-26a were found to enhance the negative inotropism of adrenaline on apical cardiac myocytes and positive inotropism on the basal segment. These microRNAs are also associated with anxiety and depression, potentially explaining the role of preexisting mental illness in increasing the vulnerability of the myocardium to an acute emotional trigger . MiR-1 aThe ECG in a patient with TS initially shows ST-elevations in the precordial leads, the distribution of which is dependent on the regional pattern of ventricular ballooning. ST elevations were the most common finding in the InterTAK Registry study (44% of patients), followed by T wave inversions (41%), ST-segment depression (8%) and left bundle branch block (5%) . Rarely,ST segment elevation (STe) over the precordial leads is a common finding on admission. They tend to be less prominent than those seen in STEMI. However, the V1 lead is less likely to be involved as it denotes the anterior and paraseptal right ventricular walls, which TS rarely extends to. The diffuse nature of ST elevations is probably due to the diffuse involvement of the ventricular wall, extending beyond the region supplied by a single vessel. The -avR lead points to the left ventricular apex , and frequently shows ST elevations, reliably differentiating it from ACS. In fact, it is a common fixture in the multiple algorithms developed by Frangieh et al. for differentiating ST elevation TS from STEMI. This study found that ST elevations in -avR along with ST elevations in anteroseptal leads  had a 100% specificity and positive predictive value for diagnosing ST elevation TS. On the other hand, ST depressions in V2, V3, and V4 had a 100% specificity for diagnosing STEMI . HoweverT wave inversions, without ST elevations, may be present in patients who are evaluated later in the disease course. They closely accompany ST elevations, following a similar pattern of distribution but more widespread . T wave QT prolongation develops around 24–48 h after the trigger (when present) or initial presentation, which is not commonly seen in STEMI and may be a helpful distinguishing feature. The prolongation is often significant (>500 ms) and predisposes the patient to life-threatening ventricular tachyarrhythmias and hence is an important risk stratification tool ,118. OthA coronary angiogram is a crucial diagnostic step to dependably differentiate TS from ACS. Most patients present with chest pain and ST elevations on ECG, along with raised cardiac enzymes, and almost invariably require urgent coronary angiography. Usually, no obstructed coronary arteries are found, however, they may coexist in around 15% of patients ,122. TheIn the event of TS coexisting with obstructive CAD, biplane ventriculography should be utilized. The ventricles should be visualized at the same angle with careful observation for a wall motion abnormality not consistent with the distribution of the affected arteries ,126. PriThe most important non-invasive imaging modality is the Transthoracic Echocardiogram with color and tissue doppler. Left ventricular ejection fraction  was reduced in 86.5% of TS in the acute phase, compared to 54.2% of patients  with acute coronary syndrome . EchocarCMR offers a high diagnostic sensitivity for detecting myocardial inflammation in patients with TS. The anterolateral segment is most commonly affected by focal TS. CMR is necessary to differentiate this rare form of TS from ACS or myocarditis. In its most basic form, right ventricular involvement manifests as dilatation of the RV with hypo- to akinesia of the free wall and apex. As a result of the abnormalities in LV wall motion caused by TS go beyond the territory supplied by any one coronary artery, the systolic dysfunction seen on speckle-tracking echocardiography appears circular. When more than four segments of the WMSI are dysfunctional, TS can be diagnosed with a sensitivity of 83% and specificity of 100% ,133,134.Supportive care and the management of complications and comorbidities make up the bulk of treatment. The next focus is on preventing complications and supporting recovery. Since an initial clinical differentiation between ACS and TS is difficult to make, suspected patients should be started on treatment according to the ACS guidelines, particularly morphine, oxygen, heparin, and aspirin . Given tFurther treatment is better individualized as per the hemodynamic stability of the patient. For hemodynamically stable patients, manage systolic heart failure. The main drugs indicated are ACE inhibitors (such as lisinopril) and low-dose beta-blockers (such as metoprolol tartrate). For hemodynamically unstable patients the treatment is dictated by the status of LVOT obstruction. In patients with no LVOT obstruction, there are a few options for inotropic support, including dobutamine, dopamine, and even levosimendan, but it is important to keep in mind that all three can cause tachycardia and worsen Takotsubo cardiomyopathy. Patients on inotropic therapy need close observation for the emergence of LVOT. If inotropes are ineffective, vasopressors can be used as a backup. It is important to think about advanced treatments when traditional methods have failed; high-pressure balloon catheter inserted into the aorta (IABP) and devices for ECMO assistance of the left ventricle form the terminal resort. In some cases (up to 25%), the LVOT becomes obstructed. In addition to being difficult to treat, LVOT obstruction reduces the LV’s ability to pump blood. If the LVOT is blocked, inotropic support should be avoided because it can lead to cardiogenic shock. Increasing systolic function of the left ventricle (LV) may be attainable with intravenous fluids. If tolerated, a short-acting, low-dose beta blocker may help alleviate LVOT obstruction, though its use should be cautious in patients with hypotension. A mechanical aid for the heart’s failing left ventricle or advanced treatments maybe considered as a last resort. Patients may also require ECMO support ,135,136.Stress cardiomyopathy patients undergoing treatment for HF focus on decongestive therapy and hemodynamic support for states of low cardiac output. Patients with pulmonary congestion who do not have hypotension or low cardiac output are treated with venodilators  and diuretic agents to decrease venous return. Patients with systemic arterial hypertension may benefit from the use of arterial vasodilators; however, they must be monitored closely for worsening of left ventricular outflow tract obstruction (LVOTO). When treating hypertension, low-dose beta-adrenergic receptor blockers may be helpful in cases of LVOTO due to their ability to decrease basal hypercontractility and, consequently, relieve obstruction in the heart’s aortic valve. As a bridge to mechanical support with a left ventricular assist device or to recovery, vasopressor drugs  should be considered if inotropic agents are insufficient. Patients in shock who develop LVOTO with or without MR present a significant therapeutic challenge. Since they have the potential to increase basal hypercontractility, inotropic agents should be avoided in cases where obstruction is already a problem. If the patient is already taking inotropic medications, it may be beneficial to reduce the dosage or suspend the medication and administer intravenous fluids in order to facilitate the clearance of the obstruction. A low dose of a short-acting beta-adrenergic receptor blocker  can be tried to reduce the LVOTO if it is severe and the patient is not bradycardic, with the hope of improving cardiac output. Peripherally acting vasopressor drugs  may be indicated in the treatment of shock with LVOTO because they raise blood pressure without raising LV obstruction; however, if they fail to improve LVOTO, these agents may worsen cardiac output. A mechanical cardiac assist device should be considered if medical treatment fails to improve cardiac function. Extracorporeal membrane oxygenation is commonly used to aid patients experiencing severe shock .ACE inhibitors and ARBs are said to promote the recovery of the left ventricle. Beta-blockers are proposed to act by attenuating the apical ballooning . Singh eSince aldosterone further enhances the cardiovascular effects of systemic catecholamines, an Aldosterone receptor blocker (Spironolactone) may be used. Angiotensin receptor-neprilysin inhibitors may also be used in cases of heart failure . Beta-blBroken Heart Syndrome does not end with an acute episode and the left ventricular function may return to normal within a few weeks, but several complications may occur before systolic function recovers pushing the in-hospital mortality rate is as high as 5% . These cTwelve percent to forty-five percent of patients develop systolic HF during the acute phase ,142. OldNearly a quarter of patients experience arrhythmias. Five percent to fifteen percent of patients experience atrial fibrillation, and this condition is linked to decreased LVEF and an increased risk of cardiogenic shock . In the In the classic apical ballooning forms, LVOTO and mitral valve systolic anterior motion due to the Venturi effect cause MR in 14% to 25% of patients  due to hStroke and embolization can result from LV thrombus formation (which occurs in 2% to 9% of cases) ,151; thiPatients with stress cardiomyopathy have been reported to experience intramyocardial hemorrhage and ventricular wall rupture, both of which are indicative of severe ischemia-reperfusion injury . The risFor a long time, TS was thought to be a non-life-threatening condition; however, recent research has shown that TS is a potentially fatal illness with high morbidity and mortality during the acute phase and outcomes that are comparable to those of ACS . MortaliThe exact etio-pathogenesis for TS is still obscure, but over the years of extensive research, we have made significant leaps and have framed the treatment for the disease. Many of the molecular mechanisms underlying TS have been elucidated through the integration of genomics, proteomics, transcriptomics, metabolomics and mircobiomics which may aid in the advancement of precision medicine. The implementation of various ‘omics’ can help translate individualized and precise helping better prognosis and lesser complications. Development and provision of suitable treatment options for each patient require knowledge of the molecular mechanisms by which each mutation contributes to disease pathogenesis. New technological developments, such as an innovative approach to systematically assessing the functional significance of multiple variants in vivo, would be required to achieve this goal. Furthermore, technologies such as artificial intelligence can help in risk stratification, while computational cardiology models can be employed to prevent the recurrence of complications ,159.Broken Heart Syndrome or Takotsubo Syndrome (TS) is a condition that manifests clinically as an acute coronary syndrome (ACS). It is characterized by hypokinesia of the basal segment and various other wall motion abnormalities. It is believed to be a consequence of several psychiatric and neurological conditions. The pathophysiology of this condition is elusive, the specificities of which are still being investigated, which makes the diagnosis and treatment more strenuous. The recent growth in molecular evidence has laid foundations for future research which will help establish new drug targets helping us a step closer to precision medicine.


The role of high-flow arteriovenous fistula (AVF) in cardiovascular morbidity in hemodialysis (HD) patients is very likely under-recognized. We assessed the relationship between high access flow (Qa) and myocardial fibrosis in HD patients.Myocardial fibrosis was assessed by native T1 relaxation times on non-contrast cardiac magnetic resonance imaging and a potential marker of fibrosis. Serum levels of galectin-3, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and monocyte chemoattractant protein 1 (MCP-1) were measured in 101 HD patients who underwent regular monitoring of AVF Qa. A high-flow AVF was defined as a Qa >2 L/min.Hemodialysis patients showed significantly higher galectin-3 value and increased T1 relaxation time compared to healthy volunteers, suggesting increased myocardial fibrosis in uremic cardiomyopathy. In HD patients, 20 (19.8%) had a Qa > 2L/min, and they had significantly higher cardiac output, cardiac index, left ventricular mass, and increased T1 times than those with a Qa ≤ 2 L/min. Also, serum galectin-3 and NT-proBNP levels were much higher in the high Qa group, indicating a close relationship between the high Qa, increased myocardial fibrosis, and the risk of heart failure (HF) in HD patients. It is interesting that a higher AVF Qa for myocardial fibrosis was independent of several traditional cardiovascular risk factors as well as serum levels of NT-proBNP and MCP-1.A supra-physiologically high Qa can be related to myocardial fibrosis and increased risk of HF in HD patients. Regular Qa monitoring could allow early detection of a high-flow AVF that could arise cardiac complications. Patients with end-stage renal disease (ESRD) on hemodialysis (HD) have very high mortality, and sudden cardiac death (SCD) is the single most common form of death, accounting for 20% to 30% of all deaths in this population , 2. As aThe creation of a new functioning arteriovenous fistula (AVF) in HD patients causes an acute decrease in systemic vascular resistance and a secondary increase in cardiac output (CO) –15. The As myocardial fibrosis has been proven reversible and treatable only under timely intervention, risk identification and early detection of myocardial fibrosis can be extremely important in HD patients. In this regard, we focused on the association between high intra-access Qa and the extent of myocardial fibrosis in chronic HD patients. For detection of myocardial fibrosis in HD patients, non-contrast cardiac magnetic resonance imaging (MRI) and circulating biomarker have been widely used , 22, 23 In this study, the degree of myocardial fibrosis was assessed with non-contrast cardiac MRI–derived native T1 relaxation time and an emerging myocardial fibrosis biomarker, galectin-3. In addition, levels of the traditional cardiac risk marker, N-terminal (NT)-pro hormone BNP (NT-proBNP), and inflammatory cytokines were measured to examine their association with access Qa and cardiac fibrosis.n = 5); current or prior symptoms of CHF with moderate or severe valvular heart disease or a decreased ejection fraction <30% (n = 9); central venous stenosis (n = 3); refusal to measure access flow using Transonic US (n = 35); and other (n = 3). Ultimately 101 patients were included in the study. Baseline demographic data, including age, sex, comorbidities, and clinical data regarding the underlying cause of renal disease, were obtained. Body mass index was calculated as body weight (kg)/2. Venous sampling was performed immediately prior to each patient's mid-week HD session. Laboratory analyses included white blood cells, hemoglobin, blood urea nitrogen, creatinine, albumin, calcium, and phosphate levels. The study was approved by the Hallym University Sacred Heart Hospital Institutional Review Board and was conducted in accordance with the Declaration of Helsinki. Informed consent was obtained from HD patients and healthy volunteers (HVs).The associations of high intra-access Qa with cardiac parameters and fibrosis were assessed. Patients with an AV graft were not included. In Korea, when AVG placement is needed, a graft of 6 mm diameter is generally used. So, the mean flow of AVG is mostly within 800–1,400 ml/min. So, none of the patients with AVG had an intra-access flow over 2 L/min in our facility. So, a total of 156 patients with AVFs were screened, and 55 were excluded. The exclusion criteria were as follows: history of severe lung disease, such as chronic obstructive pulmonary disease over grade 3 or 4 or asthma or extensive lung cancer  was used to collect samples from 40 HVs and 101 HD patients. Blood samples were collected at the beginning of dialysis and incubated for 20–30 min at room temperature and then centrifuged for 20 min at 1,000 g. Isolated serum was aliquoted and stored at −70°C until further analysis. We quantified concentrations of NT-proBNP, galectin-3, tumor necrosis factor alpha (TNF-α), and monocyte chemoattractant protein 1 (MCP-1) using ELISA kits  according to the manufacturer's instructions.via the venous HD line into the access flow stream. After passing through the heart, the US sensor on the arterial HD line recorded the dilution curve resulting from the saline indicator. Then CI was calculated with conventional Stewart-Hamilton analysis. Mean blood pressure (BP) was obtained with an automated BP cuff. In addition, a Qa/CO ratio was obtained by the HD03CO with a reversed blood lines connection and saline injection. Intra-access Qa was measured regularly once a month, and the mean access flow over 6 months was used in this study. Inter-observer and intra-observer variability in Qa was assessed with the intraclass correlation coefficient. The inter-observer and intra-observer variability was 0.95 and 0.92, respectively. Cardiac parameters, including CO, Qa/CO, and CI, were measured twice.Ultrasound (US) dilution technique (Transonic®) is a widely used non-invasive method to monitor intra-access Qa. This is easy to use and generates accurate measurements [25]. Recently, a more updated form (Transonic HD03 cardiac function monitoring) enables cardiac function screening of CO and the cardiac index (CI) with the concomitant intra-access Qa measurements. In this study, intra-access Qa and cardiac parameters were simultaneously measured with the Transonic HD03CO cardiac monitor . Briefly, a 30 ml bolus of saline  was introduced Cardiac MRI was performed in 35 of the 101 HD patients and in 14 HVs. Of the patients who did not receive MRI, 32 refused, 25 failed to hold their breath or lie still during the test, and the rest had a contraindication to the MRI test. We obtained multimodal imaging data using a 3-T MRI device . In HD patients, MRI was consistently performed on non-dialysis or post-dialysis days according to the availability of MRI. Left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LV ESV), left ventricular end-diastolic volume (LV EDV), CO, stroke volume (SV), left ventricular mass (LVM), and LVM index (LVMI) were automatically calculated and indexed to body surface area with a weight acquired immediately prior to scan.via workstation) and standardized to a similar size and shape. After the removal of any segments affected by artifacts, a global T1 time was calculated from the mean of all remaining segments. We calculated a septal T1 time by averaging the acceptable anteroseptal, inferoseptal, and septal segments . Mid-septal T1 time was derived from an average of included septal segments from the midshort-axis slice (segments 8 and 9). The reproducibility of the T1 map was assessed by blind reanalyzes of 20 randomly selected images by the same observer. Ten participants were selected at random to determine intra-observer reproducibility, and the correlation coefficients were 0.86–0.96 for all parameters, indicating excellent agreement.Two blind observers analyzed anonymized images in random order to determine T1 relaxation time. From the raw T1 images, LV contours were defined and copied onto color-enhanced spatially co-registered maps. Using the anterior right ventricular-LV insertion post as a reference, T1 maps were segmented according to the American Heart Association's 16-segment model. Regions of interest were delineated by user-defined semi-automated border delineation  level of galectin-3 was determined as the cutoff value for myocardial fibrosis. All statistical analyses were performed with SPSS , and p <0.05 was accepted as significant.Variables with normal distributions were expressed as means ± standard deviations. Categorical variables were expressed as percentages and compared using the chi-square test. Correlations between continuous variables were tested with either the Pearson's A total of 101 stable HD patients with AVFs and 40 age- and sex-matched HVs were included. Flow chart of patient inclusion are shown in p < 0.001). Also, the mean Qa/CO and CI were significantly increased in this group, too .Baseline demographics, biochemical characteristics, and CV risk factors were compared according to a mean Qa of 2 L/min . Most ofCardiac MRI was performed in 35 of the 101 HD patients and 14 of the 40 HVs. Baseline characteristics of 35 patients who underwent MRI studies were comparable compared with the entire patients .2 in the HD group vs. 4.6 and 55.6 g/m2 in the HV group, respectively . However, differences between the two groups in LVEF, LV EDV, LV EDVI, ESV, and LV ESVI did not reach statistical significance.As shown in R = 0.568, p = 0.001, CI; R = 0.500, p = 0.005). In addition, transonic US–derived Qa correlated very well with MRI-derived CO and CI as well as LV EDV, SV, and LVMI  and 0.421 (p = 0.006). All these findings could indicate that a high intra-access Qa may account for the absolute difference in native T1 values in uremic cardiomyopathy. Moreover, native T1 relaxation times showed a close link with LVMI, indicating the close relationship between the high-flow AVF, increased cardiac mass, and advanced myocardial fibrosis , myocardial fibrosis  and two proinflammatory cytokines (TNF-α and MCP-1) were measured in 101 HD patients and 40 HVs. As expected, serum levels of all four markers were significantly higher in the HD group compared to the HV group .r = 0.378, p = 0.019) and septal T1 values , suggesting the usefulness of galectin-3 for estimating myocardial fibrosis , and the intra-access Qa . Overall, the close relationships between a higher AVF access Qa and myocardial fibrosis might be independent of several traditional risk factors as well as serum levels of NT-proBNP and MCP-1.To examine the independent relationship between a high intra-access Qa over 2 L/min and the degree of myocardial fibrosis, we performed stepwise multiple regression analyses. As shown in p < 0.001).With a galectin-3 cutoff value of 12.3 ng/ml  for detecting the presence of myocardial fibrosis, a Qa >2 L/min increased the risk for myocardial fibrosis by 9.6-fold with this cutoff value  and the Hallym University Research Fund 2020 (HURF-2020-43).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Introduction: Myocardial infarction (MI) is a challenging clinical and public health problem and is a leading cause of morbidity and mortality worldwide. Heart failure (HF) is a common sequela of acute myocardial infarction (AMI), with an incidence of up to 40% among hospitalized patients and has important implications for treatment and prognosis. Sodium–glucose co-transporter 2 inhibitors (SGLT2i), such as empagliflozin, have been shown to reduce the risk of hospitalization and cardiovascular mortality in patients with symptomatic HF and have therefore been included in the European and American heart failure guidelines. However, trials investigating the effects of this drug class in patients following acute myocardial infarction are lacking.Study and Results: The EMMY trial was conducted to assess the safety and efficacy of empagliflozin in patients with acute myocardial infarction (AMI). A total of 476 patients with AMI were randomly assigned to empagliflozin (10 mg) or matching placebo once daily within 72 h of percutaneous coronary intervention. The primary outcome was the N-terminal pro-hormone of brain natriuretic peptide (NT-proBNP) change over 26 weeks. Secondary outcomes included changes in echocardiographic parameters. NT-proBNP reduction was significantly greater in the empagliflozin group ). Absolute left-ventricular ejection fraction improvement was 1.5% (P = 0.029) greater, mean E/e′ reduction was 6.8% (P = 0.015) greater, and left-ventricular end-systolic and end-diastolic volumes were lower by 7.5 mL (P = 0.0003) and 9.7 mL (P = 0.0015), respectively, in the empagliflozin group, compared with placebo. Seven patients were hospitalized for HF (3 in the empagliflozin group). Other predefined serious adverse events were rare and did not differ significantly between groups.Lessons learned: The EMMY trial shows that early use of the SGLT2 inhibitor empagliflozin after acute myocardial infarction (MI) improves natriuretic peptide levels and markers of cardiac function and structure supporting the use of Empagliflozin in HF related to a recent MI. Heart failure (HF) is a common sequela of acute myocardial infarction (AMI), with an incidence up to 40% among hospitalized patients8,9. Serum N-terminal pro-brain natriuretic peptide (NT-proBNP) is routinely used as a diagnostic parameter of HF to predict outcomes, and to monitor the effects of therapy10–14.The primary classification of HF is based on left ventricular ejection fraction (LVEF) , Table 115–19. The use of SGLT2i was therefore recently recommended in the European and American heart failure guidelines as part of first-line therapy for HFrEF20,21.Sodium–glucose co-transporter 2 inhibitors (SGLT2i) have been shown to reduce the risk of hospitalization for HF as well as all-cause mortality and cardiovascular mortality in chronic heart failure with reduced EF (HFrEF) , 315–19.22. The most recent American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Failure Society of America (HFSA) guidelines also advocate SGLT2i use in patients with HFmrEF and HFpEF21.Empagliflozin, a SGLT2i, was the first drug shown in the EMPEROR-Preserved trial to improve the primary outcome of hospitalization for heart failure and cardiovascular death in HF patients with mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF)23.In addition, in patients with obesity, who usually have higher rates of HF hospitalizations and worse health status, dapagliflozin has been shown to improve cardiovascular outcomes leading to greater symptom improvement with the additional benefit of causing modest weight lossThe favorable effects of SGLT2i on HF raise the question on the effect and safety of early start of empagliflozin following myocardial infarction (MI). However, until recently, no data was available for the use Empagliflozin in this patient population.26.The EMpagliflozin in patients with acute MYocardial infarction (EMMY) trial was conducted to assess the safety and efficacy of empagliflozin in patients with acute myocardial infarction (AMI)27 for 26 weeks on cardiac function and heart failure biomarkers (NT-proBNP) in patients with large acute MI, with or without diabetes, in comparison to a placebo, in 11 Austrian sites.EMMY was a prospective, multi-center, randomized, double-blind, placebo-controlled trial designed to evaluate the effect of empagliflozin 10 mg once daily (PO) initiated within 72 h after percutaneous coronary intervention (PCI) in addition to guideline-recommended post-MI therapyThe primary outcome was a change in the NT-proBNP levels from randomization to week 26. Secondary endpoints included changes in LVEF, echocardiographic parameters for diastolic dysfunction, left-ventricular end-systolic (LVESV) and end-diastolic volume (LVEDV) at 6 and 26 weeks, and changes in ketone body, glycated haemoglobin concentrations and body weight. Additional endpoints were hospitalizations due to heart failure or other causes, duration of hospital stay and all-cause mortality. Key safety outcomes were the incidence of serious adverse events (SAEs), severe hypoglycaemic events, number of genital infections, number of ketoacidosis events, and acute liver or renal injury.The patients included in the study were aged 18–80 years with a confirmed acute large MI (creatine kinase > 800 IU/L), high-sensitivity troponin T level or troponin I level , and an estimated glomerular filtration rate > 45 mL/min/1.73 m2. Those with diabetes mellitus other than Type 2, a blood pH< 7.32, haemodynamic instability, acute symptomatic urinary tract infection or genital infection, an ongoing SGLT2i treatment or an SGLT2i treatment within 4 weeks prior to enrolment, were excluded.A total of 476 patients were enrolled within 72 h after a PCI for acute MI and randomized in a 1:1 ratio to either oral empagliflozin 10 mg/day (n =237) or matching placebo once daily (n =239) via a Randomizer Software. Randomization was stratified by site, presence of Type 2 diabetes and by gender. Follow-up visits were scheduled at 6, 12, and 26 weeks.The median age was 57 years (52–64), 18% were females and 13% had type 2 diabetes. Baseline characteristics were similar between treatment groups with a median baseline creatine kinase of 1673 (1202–2456) IU/L, troponin T of 3039 (2037–4856) ng/L, NT-proBNP of 1294 (757–2246) pg/mL, and median systolic blood pressure of 125 (117–131) mmHg.Guideline-recommended post-MI medical therapy was initiated before randomization with >96% of patients receiving angiotensin converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor–neprilysin inhibitor, beta-blocker and statins, and ∼40% receiving mineralocorticoid receptor antagonists.P = 0.026).Mean NT-proBNP levels declined in both groups during the study, but at week 12 and 26 the NT-proBNP level was 13% and 15% lower in the empagliflozin group, respectively, after adjustment for baseline NT-proBNP concentration, gender, and diabetes status (p = 0.014) and 1.5% (p = 0.029) higher LVEF in week 6 and 26, respectively. Left-ventricular diastolic function, as assessed by E/e′ ratio, was significantly improved, being 6.8% lower than placebo at 26 weeks (P  = 0.015). Echocardiographic parameters reflecting structural cardiac changes were significantly improved in the empagliflozin group, showing smaller LVESV  and LVEDV  values.Left-ventricular systolic and diastolic function improved in both groups. Those in empagliflozin had a 1.7% (p = 0.11). Body weight decreased more in the empagliflozin group . Within the small subgroup of participants with diabetes, there was no significant between-group difference in the degree of haemoglobin A1c lowering at week 26 (p = 0.11).Ketone body (beta-hydroxybutyrate) concentrations showed a significantly greater increase in the empagliflozin group compared with placebo at 26 weeks  days in both groups. There was a total of 72 adverse events with 63 hospitalizations, with no significant difference between the groups. Seven hospitalizations were due to heart failure .There were three deaths during the study, all in the empagliflozin group, which were considered unrelated to treatment as the causes were large MIs, cardiogenic shock and lung cancer.The results of this trial indicate that early administration of empagliflozin after AMI is superior to placebo in reducing NT-proBNP levels and improving markers of cardiac function and structure at 26 weeks.28,29, EMPEROR-Reduced30,31, DAPA-HF32–34.These results strengthen the already known benefits of SGLT2 inhibitors in reducing the risk for HF hospitalization and cardiovascular death in patients with HFrEF as well as in high-risk groups, those with type 2 diabetes or chronic kidney disease. The trial supports the rapid expansion in indications for the use of SGLT2 inhibitors in a wide spectrum of HF  of more than 45 mL/min per 1.73 m2 , and does not provide expectations and benefits in a higher risk patient population. The results are further limited by the fact that only 18% of participants were women and the majority of the participants did not have type 2 diabetes mellitus.The clinical outcomes remain therefore unclear as the sample is too small and the follow-up too short to assess potential differences in actual clinical events between groups. Regardless of the limitations, the EMMY trial represents an important step forward for SGLT2 inhibitors in the management of post-MI heart failure and increases the optimism that these drugs may provide clinical benefit to the post-MI population.35 and EMPACT-MI36 trials are both enrolling MI survivors with new cardiac dysfunction to test SGLT2 inhibition in this setting. Further insights will be provided by these trials, as they will test whether dapagliflozin and empagliflozin, respectively, can lower the risk for HF hospitalization and death in patients with new cardiac dysfunction after MI. EMPACT-MI will additionally evaluate patients with preserved EF with or at high risk of new onset HF in the setting of MI.Larger trials should be performed in order to assess and fully understand the safety and efficacy of SGLT2 inhibitors after MI. To that end, the ongoing large  DAPA-MIBoth trials are enrolling patients with an eGFR down to 20 mL/min per 1.73 m2, enabling a broad evaluation of the possible renal safety and efficacy of SGLT2 inhibitors. The trials are expected to be completed in 2023.The EMMY trial shows that early use of the SGLT2 inhibitor empagliflozin after acute myocardial infarction (MI) improves natriuretic peptide levels and markers of cardiac function and structure supporting the use of empagliflozin in HF related to a recent MI.The trial showed that compared with a placebo, empagliflozin led to a significant decline in mean NT-proBNP levels, improvement of left-ventricular systolic and diastolic function and echocardiographic parameters reflecting structural cardiac changes. However, empagliflozin does not seem to have an impact on adverse events, duration of hospital stay or the number of HF hospitalizations.The EMMY trial represents an important step forward for SGLT2 inhibitors in the management of post-MI heart failure and supports the rapid expansion in indications for the use of SGLT2 inhibitors in a wide spectrum of HF. Larger trials are underway to assess and fully understand the safety and efficacy of SGLT2 inhibitors after MI.


Acute heart failure (AHF) is a frequent cardiovascular emergency presenting with high mortality as well as readmission rates. The aim was to investigate the predictive value of estimated plasma volume status (ePVs) and left atrial diameter (LAD) for the prognosis of patients with AHF.Clinical profiles were collected from 259 cases of AHF patients at the Affiliated Hospital of Putian University between September 2019 and October 2021.P = 0.001), LAD , and Nt-pro-bnp  as predicting factors for MACE. Kaplan-Meier analysis indicated that the risk for cardiogenic death increasing with ePVs (p < 0.05).Six patients lost follow-up, resulting in 253 patients enrolled. Cardiogenic death and heart failure readmission during follow-up were defined as major cardiovascular events (MACE) group, other patients were defined as Non-MACE group. Apart from age, no significant differences were found between the two groups in demographics and comorbidities. The comparison between the two groups was statistically significant in terms of ePVs, LAD, and N-terminal-pro B-type natriuretic peptide (Nt-pro-BNP). On binary logistic regression analysis, ePVs (OR = 2.061, 95% CI 1.322∼3.214, Estimated plasma volume status and LADs have some predictive value in assessing cardiogenic death and heart failure readmission in patients with AHF. Heart failure is a life-threatening and costly condition caused by structural and functional irregularities within the heart. It results in systolic and diastolic dysfunction, failure of cardiac output to meet the metabolic needs of the body, and inadequate perfusion of organs and tissues, leading to a series of clinical syndromes . Age-adjHematocrit is the proportion of erythrocytes to the whole blood volume and can reflect the severity of anemia and blood volume load. Anemia leads to myocardial ischemia and hypoxia, which results in compensatory increases in stroke volume and heart rate, secondary to myocardial remodeling, cardiac structural changes, and reduced cardiac systolic and diastolic functions . In agedPlasma volume (PV) was a marker of volume overload based on the Duarte formula estimated on the basis of erythrocyte volume and hemoglobin . EstimatThe left atrium is an important factor in maintaining left ventricular filling, which has reserve function, pipeline function and pump function. Atrial function was closely related to the occurrence of heart failure. Left atrial dysfunction could be used as an independent predictor of the prognosis of heart failure . Left atAcute heart failure (AHF) is a common critical disease in the Department of cardiovascular medicine, with high mortality and readmission rate. Currently, there are few reports on the relationship between estimated plasma volume status and left atrial diameter on the prognosis of patients with acute heart failure. We have analyzed the factors influencing cardiovascular events in patients with acute heart failure in order to enhance the management of patients with heart failure and reduce readmission and mortality rates in patients with acute heart failure.The study conformed to the declaration of Helsinki, and obtained the Affiliated Hospital of Putian University ethics review board for approval.It was a retrospective study and collected data on the Hospital Digital Information System. Such data did not involve identifiable personal data; therefore, informed consent was not required to approve our study.A total of 259 patients with acute heart failure presented at The Affiliated Hospital of Putian University from September 2019 to October 2021 were enrolled. Acute heart failure diagnosis in line with Universal definition and classification of heart failure published in the European Journal of Heart Failure in 2021 . ExclusiDemographic, clinical parameters and laboratory test results were assembled. All data collected through medical records.Blood samples were drawn on admission by the nurse in the vacuum vessel treated with ethylene diamine tetra-acetic acid. The automated hematology analyzer  measured parameters such as hematocrit and hemoglobin using the electrical impedance method for complete blood count. ePVs was derived by 100 × (1–hematocrit)/hemoglobin in g/dL. Automatic fluorescence immunoanalyzer  measured N-terminal B-type natriuretic peptide (NT-pro-BNP) by dry immunofluorescence method.For all patients, measurements were taken using a GE Vivid 7 echocardiography device . Measured the left atrial diameter (LAD) under the long axis of the parasternal left ventricle. Measurement of left ventricular ejection fraction (LVEF) by Simpson’s method under apical four-chamber and two-chamber views.After discharge patients were followed up at 1, 2, 3, 6, and 12 months. Follow-up methods included outpatient follow-up, phone calls, WeChat, etc. The incidence of end-point events were recorded and follow-up was terminated after cardiogenic death. End-point events were defined as major cardiovascular events (MACE) during the follow-up period, including cardiogenic death and readmission for heart failure.t-test for comparison. The categorical variables were shown as proportions, and the chi-square test was used for differences between categorical variables. All factors at entry that were statistically significant between groups with a p-value <0.05 and variables considered of relevant clinical interest were included in the logistic regression to identify the independent predictors of the endpoint event. Receiver operating characteristics (ROC) curve assess the predictive value of left atrial diameter and ePVs for MACE. Kaplan-Meier survival curves were used for survival analysis and log-rank tests were used for comparison of differences. The difference was considered statistically significant at a P-value < 0.05 (two-tailed test).The statistical package for social sciences software  was used for all statistical analyses. The continuous variables were shown as mean ± standard deviation and were tested by independent samples p > 0.05). The age and rate of lower limb edema of MACE group was higher than that of the non-MACE group. The values were detailed in Six patients were lost to follow-up, and 253 patients were finally enrolled. There were 75 cases in the MACE group, of which 44 were cardiogenic deaths. There were 178 in the Non-MACE group. In the MACE group, 46 were males and 29 were females, average age was (68.15 ± 11.65), comprising 18 patients with coronary artery disease, 24 patients with hypertension and 20 patients with diabetes. In the non-MACE group, 120 were males and 58 were females, average age was (62.03 ± 11.70), comprising 40 patients with coronary artery disease, 55 patients with hypertension and 38 patients with diabetes mellitus. No statistical significance was found between the two groups in terms of gender, smoking, body mass index and comorbidities , ePVs, blood urea nitrogen (BUN), Sodium, albumin, C-reactive protein (CRP), D-dimer, Nt-pro-bnp, LVEF, and LAD were all significantly different between the two groups. White-blood cells (WBC), total cholesterol (TC), low-density lipoprotein cholesterol (LDL), creatinine, high-density lipoprotein cholesterol (HDL), BUN/creatinine, uric acid, triglycerides (TG), potassium, and hemoglobin A1c were not significantly different between the two groups. The values were detailed in r = 0.122, p < 0.05), LAD , E/e’ ratio . The Nt-pro-bnp was correlated with LAD . The LAD was correlated with E/e’ ratio . The values were detailed in In correlation analysis, the ePVs was correlated with Nt-pro-bnp (P = 0.001), LAD  and Nt-pro-bnp  were MACE predictors in acute heart failure patients. The values were detailed in Analysis of binary logistic regression indicated that ePVs  with an optimal cut point value of 4.98 for predicting MACE, 64% sensitivity and 71.3% specificity; The LAD area under the curve was 0.668  with an optimal cut point value of 38.5 mm for predicting MACE, 64% sensitivity and 70.8% specificity  and a low ePVs (ePVs < 4.98) group (n = 183). At 1 year follow-up, cardiac mortality was higher in the group with high ePVs than in the group with low ePVs (P = 0.027)  group (= 0.027) . Kaplan = 0.027) .This single-center retrospective study evaluated the predictive value of ePVs and LAD in patients with AHF. The study showed that ePVs were higher in MACE group than in controls, and the LAD was larger than in controls. ePVs, LAD, and Nt-pro-bnp were MACE predictors in acute heart failure patients. ROC analysis showed that the optimal ePVs threshold for MACE was 4.98 with sensitivity of 64%, and specificity of 71.3%. At 1 year follow-up, cardiac mortality was higher in the group with high ePVs than in the group with low ePVs.Acute heart failure is defined as signs and/or symptoms of rapid or progressive heart failure that are severe enough to warrant emergency medical attention. Patient with AHF required urgent assessment and initiation or intensification of treatment . AHF is Congestion was the main cause of hospitalization for acute decompensated heart failure and was associated with a poor prognosis . It was The left atrium could be compensated by pressor function in the early stage of heart failure. With the continuous increase of left ventricular end-diastolic pressure, the left atrium will continue to expand and eventually exceed its own regulatory range, and eventually decompensated, leading to the reduction of left atrial function in all aspects . Left atThere were some limitations to the study. Firstly, the major limitation of our study is the population size and the size of the MACE group, which are really small to confidently assess such a clinical endpoint. Secondly, due to the high clinical workload, the index of left atrial diameter was used instead of left atrial volume. Finally, there was no dynamic observation of the patient’s volume profile, which may have had some impact on the results.Estimated plasma volume status and LAD have predictive value for assessing the incidence of cardiogenic death and heart failure readmission in acute heart failure patients. It is easy to detect, cheap and has promising utility for the prediction of cardiovascular death and heart failure readmission in patients with AHF.The original contributions presented in this study are included in this article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by Ethical Review Board of the Affiliated Hospital of Putian University. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.XC and GL designed and produced the manuscript. KX analyzed the data. CD conducted study and reviewed the manuscript. All authors contributed to the final manuscript, read and approved the submitted version.