These findings suggest that standardization is needed in order to implement this technique in clinical practice, thus further studies are required.Three-dimensional echocardiography (3DE) is advised for right ventricular (RV) assessment. Data regarding the optimal acquisition settings and optimization are still scarce. We aimed to evaluate the feasibility, reproducibility and validation of 3DE for RV volume and function assessment, using cardiac magnetic resonance (CMR) as gold standard. Thirty healthy volunteers and 36 consecutive patients were prospectively included. CMR was performed in the latter. Standard apical four-chamber view (A4CV), focused A4CV and modified A4CV were used for 3DE RV acquisition. Feasibility (and the effect of changes in settings) was evaluated. Intra and interobserver analyses were performed by three observers (expert vs. novice). RV parameters by echocardiography were compared to CMR. Feasibility of acquisition was 16.7% for A4CV, 80.0% for focused A4CV and 16.7% for modified A4CV. Changes in settings had no significant influence on feasibility and further analysis. Intraobserver variability was good in both expert and novice, interobserver variability was good between experienced observers. Compared to CMR, 3DE volumes were significantly lower with fair to moderate correlation (EDV: 91.1 ± 24.4 mL vs. 144.3 ± 43.0 mL ( The prognostic value of right ventricular (RV) function has been evaluated in various conditions, including pulmonary artery hypertension (PAH), ischemic heart disease and heart failure with reduced and preserved ejection fraction ,3,4,5,6.A schematic representation of the study design is shown in Sixty-six individuals, divided into two groups, were prospectively included. In the first part of the study, thirty healthy volunteers  were recruited between September 2019 and March 2020. Criteria for exclusion were: age < 18 years; history or symptoms of cardiovascular or pulmonary disease ; ongoing or previously use of vasoactive therapy  or chemo- or radiotherapy, presence of at least one of the following cardiovascular risk factors: (ex-)smoking, hypercholesterolemia, arterial hypertension, diabetes mellitus, dyslipidemia; current pregnancy; professional sports activity; inability to understand the protocol or to give written informed consent. These criteria were checked through a short questionnaire, an electrocardiogram (ECG) and a brief physical examination .In the second part of the study, thirty-six consecutive patients  with a clinical indication for CMR were enrolled between June 2020 and September 2020. CMR and transthoracic echocardiography (TTE) examination were performed within one hour. Exclusion criteria were: age < 18 years, presence of an intracorporal cardiovascular device , atrial fibrillation during the examination. Clinical and demographic data were assembled in an electronic case report form (Redcap 7.2.1). The study was carried out according to the ethical principles for medical research involving human subjects, established by Helsinki’s Declaration, protecting the privacy of all participants and the confidentiality of their personal information. All patients provided written informed consent.A comprehensive transthoracic echocardiography (TTE) using GE Vivid E95 ultrasound system  was conducted in all individuals by an experienced echocardiographer (A.M). All patients were in sinus rhythm at the moment of the echocardiography. In addition, full-volume 3D echocardiographic RV datasets were acquired. Sequential single-beat acquisition was performed as follows: a standard apical four-chamber view (A4CV), focused A4CV and modified A4CV with a temporal resolution of 20 frames per second (fps). Focused A4CV was obtained from the standard A4CV by moving the transducer laterally and subsequently tilting it anteriorly. Modified A4CV was obtained from the standard A4CV, by moving the transducer medially followed by tilting it cranially and anteriorly . The fea3DE RV analysis was performed using GE Healthcare’s 4D Auto RVQ tool of EchoPAC (version 20.3). To reconstruct a 3D RV dataset, a vertical axis was placed manually for alignment through the tricuspid valve (TV) center point and the RV apex. The tricuspid annulus and the RV apex had to be manually indicated. The result of the endocardial border determination was displayed in an end-diastolic/end-systolic multislice 3 × 3 interface, where manual corrections could be performed. This multislice model was checked in all datasets during data analysis to ensure the highest accuracy of endocardial contour tracing at all levels of the right ventricle. Manual corrections were performed if necessary. A time-volume curve and various analytical values of RV volume and function were displayed . End-diaIn healthy volunteers (group 1), a novice observer (T.D.P.) performed the quantification of RV volumes and EF. Measurements were repeated after two weeks to provide an intraobserver analysis using the same acquired images. For the interobserver analysis, the measurements were done by an experienced observer (A.M.). In patients (group 2), the second observer (A.M.) did the measurements twice within two weeks to set up an intraobserver analysis. A third medium-experienced investigator (M.L.L.) repeated the measurements for interobserver analysis. During all repeated measurements, observers were blinded from previous results.CMR imaging was performed using a 1.5 T scanner  with a phased-array cardiac coil. Steady-state free precession dynamic gradient-echo cine loops were acquired using retrospective electrocardiography, during 10- to 15-s breath-holds with the following general parameters: 8-mm slice thickness of the imaging planes, 2.9 ms repetition time; 1.5 ms echo time; 60 degree flip angle; 30–40 ms temporal resolution.CMR images were analyzed using a commercial dedicated software . RV endocardial contours were traced on all short-axis slices of end-diastolic and end-systolic phases detected by an experienced CMR analyzer (K.T.), who was blinded from 3DE measurements. The disk summation method was used for the calculation of the RV end-diastolic and the end-systolic volume. RV ejection fraction was calculated by the standard formula.t-tests and Fisher’s exact tests for continuous and binominal variables, respectively. Intraobserver and interobserver variability were expressed using intraclass correlation coefficients (ICC). The ICC were quantified by the two-way random-effects model with absolute agreement. An ICC < 0.5 was considered “poor”, 0.5 ≤ ICC < 0.75 was considered “moderate”, 0.75 ≤ ICC < 0.90 was considered “good” and an ICC ≥ 0.90 was considered “excellent” [t-tests (two-tailed) and Mann–Whitney U tests. p values <0.05 were considered statistically significant. Pearson’s correlation coefficients (r) were used to assess the relationship between 3DE- and CMR-derived RV volumes and EF. A Pearson’s correlation coefficient was considered “poor” when 0 < r < 0.3; “fair” when 0.3 ≤ r < 0.6; “moderate” when 0.6 ≤ r < 0.8 and “very strong” when r ≥ 0.8 [Statistical analysis was performed using SPSS version 26.0 . Normal distribution of continuous quantitative variables was assessed by Kolmogorov–Smirnov tests. Normally distributed continuous data were expressed as mean ± standard deviation (SD), or median (interquartiles) for skewed variables. Categorical variables were presented as numbers with percentages. The intraobserver and interobserver agreement was studied using the Bland–Altman method, whereby the mean difference was presented as the bias, and 95% limits of agreement around the bias expressed as the mean difference ± 1.96 SDs. Baseline characteristics were compared between groups using Student cellent” . Systema r ≥ 0.8 .n = 8), myocarditis (n = 6) and hypertrophic cardiomyopathy (n = 5). Baseline clinical characteristics of the patients are summarized in p = 0.042), ventricular extrasystole (p = 0.011), heart failure (p = 0.011), arterial hypertension (p = 0.021), obstructive pulmonary disease (p = 0.005), coronary artery disease (p = 0.011) and dyslipidemia (p = 0.005).Baseline demographic characteristics of the 2 studied groups, are summarized in Comprehensive standard echocardiographic examinations in healthy volunteers (group 1) were within the limits of normal. Echocardiographic and CMR characteristics of the patients (group 2) are summarized in n = 5), in focused A4CV 80.0% (n = 24) and in modified A4CV 16.7% (n = 5). Feasibility in focused A4CV, using different settings was: for 25 fps 83.3% (n = 25), for 30 fps 80.0% (n = 24) and for multi-beat acquisition 80.0% (n = 24). In patients (group 2), feasibility in focused A4CV using different settings  was the same: 72.2% (n = 26). For each observer, RV volumes in both end-diastole and end-systole decreased as the frame rate was increased. This is shown in p = 1.000) respectively, ESV: 48.3 ± 19.9 mL vs. 48.1 ± 16.4 mL (p = 0.942), respectively). RV volumes assessed using different settings in single-beat acquisition are compared with multi-beat acquisition in In healthy volunteers (group 1), feasibility in standard A4CV was 16.7%  and patients (A.M. experienced observer) was good to excellent for volumetric analysis and moderate to good for the assessment of ejection fraction. In healthy volunteers, intraobserver ICC in multi-beat acquisition was: for EDV 0.88 (95% CI 0.67–0.95), for ESV 0.92 (95% CI 0.79–0.97), and for EF 0.84 (95% CI 0.62–0.93). In patients, intraobserver ICC in multi-beat acquisition was: for EDV 0.92 (95% CI 0.81–0.96), for ESV 0.88 (95% CI 0.72–0.95), and for EF 0.72 (95% CI 0.38–0.88).t-test and Bland–Altman analysis of intra- and interobserver analysis, using multi-beat acquisition, is shown in Interobserver analysis in healthy volunteers  was poor to moderate for all the analyzed parameters. Interobserver analysis in patients  was good to excellent for all the analyzed parameters. In healthy volunteers, interobserver ICC in multi-beat acquisition was: for EDV 0.64 (95% CI −0.22–0.88), for ESV 0.71 (95% CI −0.11–0.90), and for EF 0.60 (95% CI 0.06–0.83). In healthy volunteers, interobserver ICC in multi-beat acquisition was: for EDV 0.96 (95% CI 0.89 to 0.99), for ESV 0.96 (95% CI 0.89–0.99), and for EF 0.81 (95% CI 0.43–0.94). ICC, student paired p < 0.001) and ESV: 48.1 ± 16.4 mL vs. 60.4 ± 21.2 mL (p < 0.001), by multi-beat 3DE and CMR respectively). Pearson’s correlation analysis showed a fair to moderate correlation between volumetric analysis by 3DE and CMR . Mean volumes measured by 3DE and CMR, paired student t-tests, Pearson’s correlation coefficients and Bland–Altman biases and limits of agreement are shown in RV volumes measured by 3DE were significantly lower than RV volumes measured by CMR . The overall reproducibility of RV analysis was comparable to other 3DE software, and other techniques, such as CMR ,22,23,24In line with previous studies ,23,26, wMulti-beat acquisition combines a high temporal and spatial resolution, but is prone to stitch artifacts in patients with rhythm disturbance and respiratory motion. Improvement in hardware technology ensures that spatiotemporal resolution continuously advances in single-beat acquisition . We obseAdditionally, the assessment of RV systolic function by CMR is also prone to bias. The source of errors in evaluation of volumes by CMR Simpson’s method are mainly the demarcation of the basal slice near the atrioventricular valves and outflow tracts, and the large motion of the base through the plane of the short axis (slice thickness was 8 mm), giving rise to significant partial volume effects at the base and apex. This is why the test–retest reproducibility of RV systolic function by CMR is significantly lower than the assessment of left ventricular systolic function .In this study, CMR volumes were calculated from multiple short-axis views. Literature showed that this technique results in higher volumes, compared to when axial images are used . FurtherThe underestimation of volumes with this relatively new software (4D auto RVQ) is comparable to initial versions of similar software, published more than a decade ago ,32. HoweThis was a single center study with a limited number of subjects. The age of the healthy volunteers was lower, compared to the patients of the second group. The reproducibility in our study was tested by offline analysis of different observers on the same full-volume datasets. No test–retest analysis was performed. Lastly, it should be noted that no interobserver variability of the CMR analyses was carried out. Larger multicentric studies are warranted to confirm our results.This study shows that 3DE acquisition of the right ventricle is feasible in different categories of patients, with no significant impact of changes in settings and that focused A4CV is by far the best imaging view. Reproducibility is good, even in novice observers, and regardless of changes in settings. However, 3DE significantly underestimates RV measurements compared to CMR. These findings suggest that standardization and further studies are needed to implement this technique in clinical practice.


Primary hyperoxaluria is a rare genetic disorder characterized by oxalate crystal deposition, including in the heart. Hyperoxaluria-associated cardiomyopathy manifests as restrictive infiltrative cardiomyopathy. We present a case of a 52-year-old male with a past medical history of type 2 primary hyperoxaluria, end-stage renal disease on hemodialysis, paroxysmal atrial fibrillation, and hypertension, who presented with dyspnea and lethargy. Transthoracic echocardiogram showed cardiomyopathy with ejection fraction (EF) of 35-40% with severe hypokinesis of apical myocardium. Endomyocardial biopsy revealed interstitial fibrosis and crystal deposition consistent with oxalate. Cardiac MRI showed late gadolinium enhancement with subendocardial, nearly transmural fibrosis of lateral wall along with mid myocardial involvement of anterior and septal wall. To the best of our knowledge, this is the first case of type 2 primary hyperoxaluria-associated cardiomyopathy utilizing transthoracic echo, endomyocardial biopsy, and cardiac MRI. Primary hyperoxaluria is a rare genetic metabolic disorder that can be divided into two subcategories: primary hyperoxaluria type 1  and primary hyperoxaluria type 2  [PH Type 2 is due to reduced activity of the glyoxylate reductase enzyme, which is responsible for removing cytosolic glyoxylate, reducing oxalate production. This enzyme is found in the kidneys and is highly concentrated in the liver. Therefore PH type 2 can be diagnosed by measuring the glyoxylate reductase activity in liver biopsy samples . Later oWe describe a case of a patient with PH Type 2 who developed hyperoxaluria-mediated cardiomyopathy diagnosed through multi-modality imaging including transthoracic echocardiogram, cardiac MRI, and confirmed with endomyocardial biopsy.A 52-year-old male with comorbidities of type 2 primary hyperoxaluria, liver cirrhosis, end-stage renal disease on hemodialysis, secondary hyperparathyroidism, paroxysmal atrial fibrillation, and hypertension presented to us with dyspnea, lethargy, and lightheadedness during hemodialysis. The patient’s clinical manifestation was significant for acute heart failure with dyspnea. Initial workup including transthoracic echocardiography (TTE) showed reduced left ventricular ejection fraction (EF) of 35-40%, grade 2 diastolic dysfunction, severe left ventricular hypertrophy, severe hypokinesis of apical and moderate hypokinesis of basal anteroseptal segments, severely calcified aortic valve annulus with moderate stenosis, moderately calcified mitral valve annulus with mild stenosis Figure . Due to 2. The catheter waveform did not show any constrictive hemodynamics. Endomyocardial biopsy revealed interstitial fibrosis and crystal deposition consistent with oxalate cardiomyopathy , right ventricular pressure 60/23mmHg), pulmonary artery pressure , pulmonary capillary wedge pressure  ejection fraction of 35%. Delayed gadolinium enhancement showed diffuse subendocardial and transmural fibrosis in the lateral wall of LV and mid-myocardial involvement of anterior and septal walls consistent with an infiltrative process Figure . The T2-Unfortunately, the patient continued to deteriorate clinically and went to hospice care before he passed away.Our case describes primary hyperoxaluria type 2 induced cardiomyopathy who underwent multimodality imaging, including TTE and cardiac MRI. Although both primary hyperoxaluria subtypes are rare, PH type 2 is the less common subtype. In fact, Wachter et al. discussed the first case of cardiomyopathy secondary to PH type 2. A 41-year-old man with right-sided heart failure on dialysis-dependent renal insufficiency was found to have a reduced left ventricular systolic function and an echo-dense myocardium on an echocardiogram . Since tDespite the difference in the pathogenesis of subtypes of PH, the results are similar - deposition of oxalate crystals in the cardiac tissue causing different manifestations, including conduction abnormality or cardiomyopathy. In a comprehensive analysis of the PH registry in Japan, 31 out of 38 patients had EKG, or echocardiographic abnormalities, most common of which were increased left ventricular mass (42%), left atrial size (31%), pulmonary hypertension (23%), and diastolic dysfunction (15%). Cardiomyopathy (EF <50%) was present in 11% of patients . The TTE can be characterized by a “sparkling high-intensity echocardiographic pattern,” which can be due to the increased deposition of oxalate  crystals . HoweverThe treatment options are limited, including kidney, or combined kidney-liver transplantation . Kidney In conclusion, PH type 2 is a rare genetic disorder that can involve the heart. To the best of our knowledge, we present the first case of PH 2-associated cardiomyopathy utilizing cardiac MRI, which can be an excellent non-invasive diagnostic tool.


Although the predictive value of galectin-3 for heart failure with preserved ejection fraction has been demonstrated, the diagnostic value remains unclear. The present study was performed to address this issue.Galectin-3 has diagnostic value for heart failure with preserved ejection fraction.This is a diagnostic experiment. We conducted an observational study of 223 patients with combined symptoms of heart failure and diseases that can lead to heart failure with preserved ejection fraction. Patients were grouped into the heart failure group and control group in accordance with the 2016 European Society of Cardiology heart failure guidelines for heart failure with preserved ejection fraction. Baseline information and serum galectin-3 concentration were assessed within 24 h after admission.Serum galectin-3 concentration was significantly higher in the heart failure group compared with the control group. Binary logistic regression analysis showed that higher galectin-3 concentration was associated with the occurrence of heart failure with preserved ejection fraction. The area under the curve of galectin-3 was 0.763, indicating that galectin-3 has moderate diagnostic value for heart failure with preserved ejection fraction. Galectin-3 >15.974 ng/mL identified heart failure with preserved ejection fraction with 76.0% sensitivity and 71.9% specificity.P < 0.01, and the sensitivity is 76.0% while the specificity is 71.9% at the threshold 15.974 ng/mL) and was higher than that of interventricular septal thickness or E/A ratio.There was a correlation between galectin-3 and heart failure with preserved ejection fraction, and galectin-3 was an independent predictor of heart failure with preserved ejection fraction. The diagnostic value of galectin-3 for heart failure with preserved ejection fraction was moderate (AUC: 0.763, 95% CI: 0.696–0.821,  Heart failure is a well-known and severe cardiovascular syndrome that continues to cause substantial death. According to the 2018 cardiovascular survey report, despite the gradual decline in population mortality rate, heart disease continues to account for a high proportion of deaths, ranking first among all causes of death, and the absolute number will continue to rise . Recent Galectin-3 is a soluble β-galactoside-binding lectin secreted by activated cardiac macrophages and is involved in the pathophysiological processes of inflammation and fibrosis . It can Although the mechanism of action of galectin-3 in the progression of heart failure has been clarified, determining how to use this biomarker still requires investigation. Studies are exploring the diagnostic value of galactose lectin 3 in heart failure, for example: Kanukurti et al. obtained the diagnostic threshold of 10.1 ng/mL, and suggested that galectin-3 and NT-proBNP should be combined for the diagnosis of HFpEF ; anotherThis is a diagnostic experiment. We conducted an observational study of 223 patients with combined symptoms of heart failure and diseases that can lead to HFPEF such as hypertension, coronary heart disease, and atrial fibrillation. Patients who met these conditions were consecutively admitted to the Department of Cardiovascular Internal Medicine of No.1 Affiliate Hospital of Shantou University Medical College from July 2018 to September 2018.According to ESC guidelines for heart failure, the upper limit for normal level of BNP in the non-acute setting is 35 pg/mL, while that for N-terminal pro-BNP (NT-proBNP) is 125 pg/mL; in the acute setting, higher values should be used . The diagnostic value of BNP applies similarly to heart failure with reduced ejection fraction and HFPEF. On average, the values are lower for HFPEF than for heart failure with reduced ejection fraction . EchocarThe diagnostic criteria for HFPEF include the following:Typical symptoms of heart failure;Typical signs of heart failure;Small left ventricle with normal or slightly reduced left ventricular ejection fraction (≥50%);The presence of left ventricular structural changes  and/or left ventricular diastolic dysfunction. Key functional alterations are an E/e' ratio ≥13.Patients diagnosed with HFPEF in accordance with the above criteria were eligible for inclusion in the experimental group (HF group). Otherwise, patients were included in the control group. Nineteen subjects with left ventricular ejection fraction <50%, five combined with acute coronary syndrome, and seven who suffered from malignant tumors were excluded. Patients were systematically characterized and clinical data upon admission were recorded in detail. All patients underwent echocardiography upon admission by a skilled echocardiologist. On admission, we assessed several variables, including demographic features, such as age, sex, history of hypertension (including duration of hypertension and pressure level), diabetes, coronary artery disease, atrial fibrillation, New York Heart Association (NYHA) basal functional status, and history of drug therapy. All patients signed a written consent form and the Ethics Investigation Committee approved the study.Blood samples were collected on the day subjects underwent echocardiography. Collected supernatants were centrifuged at 3,000 rpm for 15 min at 4°C. Serum concentration of galectin-3 was measured using an enzyme-linked immunosorbent assay protocol without cross-reactivity with collagens or other galectins. Detailed echocardiography was performed to evaluate parameters of diastolic function in accordance with published recommendations and guidelines .The objective of this analysis was to compare the diagnostic value of galectin-3 in HFPEF with the relatively common echocardiographic criteria of HFPEF.P value < 0.05 was considered statistically significant.Baseline features were compared between the two groups (HF group and control group). Continuous variables were tested for normal distribution using the Kolmogorov–Smirnov test. Results are presented as mean  for continuous variables, and as number (%) for categorical variables. Receiver operating characteristic (ROC) curves were established, and the area under the ROC curves (AUC) was calculated. AUCs were compared using the DeLong test. Sensitivity and specificity above the third and highest point of the Youlden index were used as indicators. We supplemented the analyses of diagnostic capacity by adjusting for age, sex, renal function, diabetes, hypertension, and atrial fibrillation. All statistical analyses were performed using SPSS software . A two-sided P < 0.001). Regarding echocardiogram data, the interventricular septal thickness, left ventricular posterior wall thickness, left atrial diameter, E peak, E/A ratio, and E/e ratio were higher in patients in the HF group, whereas left ventricular ejection fraction and e peak were lower in this group.In accordance with the 2016 ESC guidelines for heart failure, 192 patients were enrolled. Among them, 96 met the criteria of HFPEF and were included in the HF group, while the remaining 96 were included in the control group. Baseline features are shown in P < 0.01]. Interventricular septal thickness and E/A ratio also significantly increased the risk of HFPEF, OR and 95%CI were 1.571, ; 4.938, , respectively, p values were all <0.01  1.574, 95%CI: 1.368, 1.812, 0.01 see .P < 0.01), and galectin-3 >15.974 ng/mL identified HFPEF with 76.0% sensitivity and 71.9% specificity. The AUC rose to 0.850 when galectin-3 was combined with interventricular septal thickness and E/A value, while the sensitivity rose to 94.8%. ROC analyses are shown in To evaluate the diagnostic value of galectin-3 level for HFPEF, an ROC curve was constructed using MedCal software based on galectin-3 concentration. The AUC was 0.763 , 0.696–0.821, In the present study, we found that galectin-3 secretion was significantly increased in patients with HFPEF. This observation is consistent with recent findings –17, 40. Binary logistic regression analysis showed that higher galectin-3 concentration was associated with the occurrence of HFPEF. Therefore, galectin-3 is an independent risk factor for HFPEF and can predict its occurrence. In this study, binary logistic regression analysis of galectin-3 concentration and HFPEF was consistent with previous studies and confirmed the value of using galectin-3 concentration for predicting HFPEF. Other studies made similar observations , 43–46, In fact, galectin-3 has proven to be predictive of morbidity and poor prognosis in many other diseases, not just heart failure. In diabetes, galectin-3 may mediate b-cell fibrosis through an inflammatory pathway, leading to impaired insulin secretion . In patiTo determine the diagnostic value of galectin-3 for HFPEF, an ROC curve was constructed and the AUC was calculated. The AUC was 0.763, indicating that galectin-3 has moderate diagnostic value for HFPEF. At the cutoff point of 15.974 ng/mL, the diagnostic sensitivity and specificity of galectin-3 for HFPEF was 76.0 and 71.9%, respectively, and were significantly higher than those of the other two risk factors . There are prior reports on the diagnostic capacity of galectin-3 for heart failure, although most of these involved comparisons with BNP and other indicators. Javier Carrasco-Sánchez et al. obtained an AUC of 0.630 for galectin-3, and although this result was not ideal, it was superior to that of NT-proBNP . In our in vitro cell experiment showed increased secretion of galectin-3 after stretching cardiac muscle cells . Galectin-3 has moderate diagnostic value for HFPEF. Owing to the overall lack of evidence in this area, more studies are necessary to verify our conclusions.In this study, increased galectin-3 level was observed in patients with HFPEF. Galectin-3 level was demonstrated to be a risk factor for HFPEF  and Key R&D Project of Science and Technology Department of Sichuan Province (No. 2020YFSY0045).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.


Takotsubo cardiomyopathy (TTS) has become a recognised clinical entity since the Japanese scientist Sato first described it in 1990.Despite an increasing number of confirmed cases, especially during the COVID-19 pandemic, its pathophysiology remains incompletely understood, and decision-making differs in the diagnosis and treatment. In addition, it is not evident whether a significant increase in TTS is due to better understanding among practitioners and widespread access to coronary angiography, or if it is a reflection of an actual increase in incidence.We analysed a series of international research studies from 1990 to 2021. Beyond epidemiology and clinical presentation, we evaluated and summarised fundamental knowledge about various predisposing factors, with particular attention to the iatrogenic impact of certain drugs, namely antidepressants, chemotherapy, and antiarrhythmics.Furthermore, we highlighted the main pathophysiological theories to date. In addition, based on published studies and clinical cases, we investigated the role of numerous diagnostic approaches in the differential diagnosis of TTS and identified predictors of TTS complications, such as cardiogenic shock, ventricular fibrillation, and left ventricular thrombi. Accordingly, we sought to propose a diagnostic algorithm and further treatment management of TTS under the presence of possible complications to help practitioners make more informed decisions, as the initial presentation continues to pose a challenge due to its close similarity to acute coronary syndrome with ST-elevation.meta-analyses, can be of particular interest to practising cardiologists and researchers in developing clinical guidelines.In conclusion, this article examines Takotsubo cardiomyopathy from different perspectives and, along with future systematic reviews and  In addition, the incidence of Takotsubo syndrome has been increasing This article aims to review the current situation of TTS, briefly summarize pathophysiological mechanisms, discuss various risk factors, propose a diagnostic algorithm and different treatment strategies of the patients with stress-induced cardiomyopathy, and highlight future challenges.2The exact prevalence of TTS is uncertain because it can be misdiagnosed and hardly distinguished from acute coronary syndrome (ACS) without advanced diagnostic tools. In the United States Nationwide Inpatient Sample discharge records the reported prevalence of TTS was 5.2/100,000 for females and 0.6/100,000 for males, thus accounting for 0,02% of hospitalizations Important to note a considerable increase in the incidence of TTS during the COVID-19 pandemic. As reported in the retrospective large cohort Cleveland Clinic study, the proportion of TTS cases among all ACS patients before and during the pandemic was 1,8% and 7,8%, respectively The multicenter GEIST  Registry analysed the recurrence rate of TTS which accounted for 4.0% among 749 consecutive patients with TTS and a median follow-up of 830 days. Relatively younger age and the presence of cardiovascular risk factors such as arterial hypertension were significantly higher in patients with recurrence episodes According to the International Expert Consensus Document on Takotsubo Syndrome, about 90% of TTS patients are women aged 67–70 Based on the analyses of various types of studies, Okura et al. have demonstrated that emotional stress was strongly related with TTS development in about 20–39%, while physical stress was seen in 35–55% of all cases Moreover, TTS has been described in children, including premature neonates 3The main predisposing factor includes female sex in a postmenopausal period. Some researchers linked the predominance of women to the absence of cardioprotective effects of androgens, which are observed in men. In particular, testosterone inhibits oxidative stress by activating cardiomyocyte antioxidant enzymes via androgen receptors In addition to hormonal changes, genetic and psychogenic factors, mental disorders, and other comorbidities influence TTS development .Table 1POf note, despite the clear presence of mental disorder as a clinical substrate and trigger of TTS, psychiatric treatment during hospitalisation was provided in only 32% of cases. Furthermore, psychiatric disorders were not frequently managed during follow-up The effect of race on the incidence and prognosis of TTS has also been studied. For example, small-sampled research has demonstrated an increased in-hospital mortality rate among patients of African-American (AA) descent In 2020, Jabri et al. carried out a cohort study that showed a significant increase in the number of confirmed TTS associated with the COVID-19 pandemic In addition, based on retrospective case series, complications and mortality rates in secondary TTS associated with COVID-19 are higher in older patients (>70 years), patients with lower blood pressure (<110 mm Hg), lower left ventricular ejection fraction (LVEF < 45%), presence of right ventricle (RV) involvement, and mitral regurgitation 44.1Despite the high prevalence of depression and other psychiatric disorders among patients with TTS, certain antidepressants may still contribute to TTS development. Therefore, a series of clinical cases were analysed to identify the drugs contributing to TTS . AccordiSNRIs block the capture of neurotransmitters in the presynaptic membrane, which increases the level of noradrenaline. This process leads to activation of the sympathoadrenal system. The mechanism of action of SSRIs on the development of TTS is not fully understood, although overdoses and drug interactions have been reported. In 2002, a study showed that only fluoxetine increased norepinephrine concentrations among SSRIs, contributing to the development of TTS. In addition, it was found that its extracellular concentrations in the prefrontal cortex at a dose that increased extracellular monoamines  were 242 nM, enough to block 5-HT(2C) receptors, which is a possible mechanism for fluoxetine-mediated catecholamine increase Therefore, before starting antidepressant therapy, physicians are advised to obtain a comprehensive medical and family history, paying attention to sudden cardiac death and heart failure. Furthermore, according to the analysed data, tricyclic antidepressants, SSRIs, and SNRIs should not be prescribed in patients with heart disease due to a high risk of drug-drug interaction resulting in an increased sensitivity of cardiomyocytes to catecholamines. For that reason, in case of drug-induced TTS, these drugs should be withdrawn and, if possible, replaced with other medications .4.2Carbone A. et al. have found that TTS development was associated with a broad spectrum of antitumoral drugs used in various cancers. For example, treatment with 5-fluorouracil, capecitabine, trastuzumab, and immune checkpoint inhibitors was found in 36.5%, 9.7%, 9.7%, 9.7% of TTS cases, respectively 4.3In addition, based on a series of clinical cases, antiarrhythmic drugs have been identified as risk factors for TTS development, especially drugs such as flecainide, sotalol, amiodarone, lidocaine, and xylocaine . FlecainAlthough it was difficult to distinguish which factor may have played a significant role in TTS development, a detailed cardiovascular assessment, prior to initiating antiarrhythmic therapy, and routine ECG screening for QT interval prolongation will minimise the risks of life-threatening arrhythmia resulting in the development of “stunned” myocardium with the features of apical ballooning syndrome in susceptible patients.5The pathogenesis of TTS remains elusive and unclear. However, the main pathogenic hypotheses include catecholamine surge, switching in G-coupled proteins, systemic inflammation, endothelial dysfunction, coronary vasospasm and excessive activation of the sympathetic nervous system (SNS) .Table 4POne of the most popular theories of pathogenesis is activation of the sympathetic nervous system (SNS) in response to stress, which results in over-release of catecholamines There are two phases in the catecholamine hypothesis. The first phase is characterised by a massive release of catecholamines in response to stress. The second phase reflects cardiovascular reaction to a rapid increase in plasma level of catecholamines. As a result, apical dysfunction, myocardial stunning, and paradoxical vasodilation develop, culminating in a decrease in cardiac output, systemic hypotension, and acute heart failure Even though a high level of circulating catecholamines was found in patients with stress-associated TTS, the role of catecholamine effects is still not entirely understood It has been demonstrated that the effect of catecholamines on β2-adrenoreceptors leads to activation of nitric oxide synthase (NOS), which stimulates nitric oxide (NO) synthesis Several studies have shown that activation of β-adrenoreceptors stimulates the proliferation of neonatal cardiomyocytes Another hypothesis of TTS pathogenesis is endothelial dysfunction, which may represent an essential link between stress and myocardial dysfunction. Endothelial dysfunction has been suggested as a plausible causative factor explaining the subepicardial and/or microvascular vasospasm. In a prospective observational study, authors investigated changes in endothelial function and concluded that 22 TTS patients demonstrated impaired flow-mediated vasodilatation compared to 21 matched controls . Transient myocardial ischemia related to endothelial dysfunction and subsequent cardiomyocyte stunning might be the possible causes of the reversible LV dysfunction in TTS TTS was also associated with a chronic inflammatory state 1.The cytokine storm leads to increased release of tumour necrosis factor-α, IL-6, IL-1β, and catecholamines into the bloodstream, contributing to TTS development 2.Activation of the sympathetic nervous system causes catecholamine-induced myocardial stunning and, as a result, TTS 3.An immense emotional stress caused by a cataclysm and a high mortality rate may trigger TTS development. In comparison, according to the US nationwide study, the highest incidence of TTS cases was identified in Vermont and Missouri  The growth of TTS during the COVID-19 pandemic can not be overlooked and is explained by three leading theories to date:Furthermore, the series of ongoing research on the pathogenetic mechanisms of TTS attempts to explain the development of the syndrome at the molecular level. In particular, overexpression of microRNA-16 and microRNA-26a specifically reduced baseline contractility of apical but not basal cardiomyocytes in vitro and functionally interacted to predispose to the cardiac depression seen in TTS 6Today TTS is commonly divided into two clinical subtypes: primary and secondary . Primary7As described above, a typical TTS patient is a postmenopausal woman over 50 years old with symptoms similar to myocardial infarction, such as sudden onset chest pain, dyspnea, or syncope, provoked by emotional stress and characterized by the development of apical ballooning. In the meantime, concomitant CAD is reported among patients with TTS, with a prevalence ranging from 10 to 29%. Therefore, patients with TTS and obstructive CAD are often misdiagnosed as a classical acute coronary syndrome, and differentiation can be challenging Underlying chronic conditions , cerebrovascular events , or seizures may often predispose to TTS, which underpins the role of extracardiac factors in the development of the disease. In this regard, symptoms may include atypical clinical manifestations . Besides, TTS can manifest at a younger age, and patients are often admitted with the symptoms of acute heart failure and cardiogenic shock, pulmonary edema, or stroke According to the International Takotsubo Registry, among 1750 patients from 9 countries, atypical presentation, including younger age, neurologic symptoms, ST depression, and lower level of B-type natriuretic peptide (BNP), accounted for 20% of all cases, while outcomes and prognosis were comparable between patients with a typical and atypical presentation 8TTS was first classified as primary cardiomyopathy in 2006 It should be noted that patients with TTS are presented with the same set of clinical features as patients with ACS. Therefore, it is assumed that the characteristic clinical signs and ECG patterns allow the diagnosis of ACS and coronary angiography per the current guidelines The first scenario is the presence of coronary culprit lesion plus WMA corresponding to the involved coronary artery, which confirms (N-)STEMI. The second scenario is characterised by the coronary culprit lesion with WMA, which extends beyond the involved coronary artery, which may be due to the coexistence of two conditions, both (N-)STEMI and TTS. Finally, the third scenario is the absence of coronary culprit lesion, but the presence of WMA, which extends beyond a single epicardial coronary distribution, which subsequently requires a differential diagnosis of MINOCA, myocarditis, and cardiomyopathy, including TTS, by performing cardiac magnetic resonance (CMR) The laboratory and various instrumental methods for the diagnosis of TTS have different diagnostic values.8.1In addition to slightly elevated Troponin T, as a result of acute myocardial damage, Takotsubo cardiomyopathy is characterised by a marked increase in plasma levels of B-type natriuretic peptide (BNP) and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) with its subsequent peak elevation within 24–48 h after onset of initial symptoms. Furthermore, the ratio of peak levels of NT-proBNP/troponin T was demonstrated to be most accurate in identifying patients with TTS among those admitted with (N)-STEMI Besides, in an acute phase of TTS, a higher elevation of growth differential factor-15 and proinflammatory cytokines has been described compared to STEMI. On the other side, many cardiac markers, such as troponins, creatine kinase-MB, or markers of vascular stress , are lower in TTS patients than in STEMI 8.2ECG has a low value for TTS diagnostics due to its similar criteria to acute coronary syndrome. In TTS, ECG patterns of ST-elevation (STE) or T-wave depression (if present) demonstrate dynamic changes with the gradual resolution of ST-segment elevation, subsequent T-wave inversion, and QTc prolongation over days to weeks Also, some differences in ECG features among AA patients with TTS have been described with the prevalence of diffuse T-wave inversion and more prolonged QTc 8.3a)LV regional WMA, which frequently involves apical and midventricular segments with the ballooning pattern. Conversely, the basal myocardial segments are often hyperkinetic. As a rule, WMA extends beyond a single epicardial coronary distribution;b)Transient LV dysfunction, often with a circumferential pattern, and a complete resolution of LV systolic function over 3–6 months;c)Improvement in E/e ratio during follow-up may be considered an additional useful indicator of LV function recovery;d)Distal Left Anterior Descending artery flow visualisation.In contrast, echocardiography is essential in visualising WMA extending beyond the territory of the involved coronary artery, which is the main indication of TTS. Therefore, echocardiography criteria may include the following Moreover, echocardiography is a valuable method for diagnosing and visualising acute and long-term TTS complications, such as wall rupture, acute mitral regurgitation, left ventricle outflow tract obstruction (LVOTO), and RV involvement, pericardial effusion, thrombus formation, heart failure 8.4Although coronary anatomy in most TTS cases is normal or near-normal, it is crucial to evaluate coronary arteries in TTS diagnostic workup to exclude alternative diagnoses When echocardiography is inconclusive or unavailable, the angiographic biplane left ventriculography helps evaluate both LV function and its morphology by identifying the characteristic TTS patterns The biplane left ventriculography is recommended along with cardiac catheterization through LV opacification in case of suspected ACS and non-obstructive coronary lesions 8.5a)LV dysfunction in a noncoronary regional distribution pattern with or without RV involvement;b)Myocardial edema located in the segments with WMA (akinesia or hypokinesia);c)Absence of significant necrosis or fibrosis;d)Absence of high-signal areas  in late gadolinium enhancement images;e)Complete normalisation of LV ejection fraction on the follow-up CMR imaging.CMR is an essential instrumental method due to its value for differential diagnosis and exclusion of myocarditis or myocardial infarction. The main CMR signs of TTS are the absence of late gadolinium enhancement and the presence of edema in a noncoronary regional distribution pattern (NCRDP). Complete CMR criteria include the following Therefore, CMR is the gold standard for determining myocardial status 8.6CCTA provides information on both coronary arteries and regional LV contraction Beyond coronary artery disease itself, multislice computed tomography (MSCT) helps detect myocardial fibrosis and late iodine enhancement, thus is effectively used as an additional diagnostic tool in differential diagnosis with myocardial infarction and acute myocarditis Routine CCTA can also provide a quantitative measurement of the coronary artery inflammation process by calculating the weighted pericoronary fat attenuation index (pFAI) 8.7Cardiac nuclear imaging has been successfully used in evaluation of myocardial perfusion and its metabolic activity SPECT demonstrates perfusion reduction due to regional myocardial wall thinning at the apex, which helps diagnose TTS Cardiac positron emission tomography (PET) features a mismatch between impaired myocardial glucose metabolism and normal myocardial perfusion in TTS, also known as «inverse flow metabolism mismatch» and can be employed in differential diagnosis with ACS Combined PET/CMR scanners can also provide a more comprehensive and non-invasive modality in the differential diagnosis of TTS from myocarditis, which is critical as the clinical course and prognosis vary considerably 8.8a)An extensive area of myocardial thinning;b)Evidence of Lewy body-like cytoplasmic inclusions in dorsal nuclei of the nervus vagus;c)Interstitial oedema with the accumulation of mononuclear leukocytes, lymphocytes, macrophages, polymorphonuclear leukocytes, mast cells, and eosinophils;d)Focal myocardial fibre degeneration and necrosis with foci of inflammatory cells ;e)Contraction bands with or without overt myocyte necrosis.Some microscopic changes of TTS have been found in recent studies Researchers hypothesise that it is possible to make a differential diagnosis at autopsy and to diagnose TTS. Therefore, it is crucial for forensic medical examinations, treating physicians, and close relatives to understand the actual cause of the patient's death. Unfortunately, to date, there are few reports on the pathomorphological features of the heart (both macroscopic and microscopic), which means that more research is needed to look more closely at the pathophysiology of TTS and to identify independent predictors of fatal complications.99.1There are currently several approaches to TTS pharmacotherapy. Also, some studies suggest that haemodynamically stable patients should be given anticoagulants (heparin) or dual antiplatelet therapy (aspirin and clopidogrel) to prevent complications and recurrent TTS meta-analysis to investigate the efficacy of drug therapy after patients were discharged meta-analysis and systematic review protocol studying the effect of aspirin on Takotsubo Syndrome have now been published It has been shown that single antiplatelet therapy with aspirin or dual therapy with aspirin plus clopidogrel can reduce major adverse cardiovascular events during hospital admission, including stroke 9.2HF is treated with standard therapy, including beta blockers in a compensated condition, ACE inhibitors, or angiotensin receptor blockers (ARBs), and diuretics 9.31.Without left ventricular outflow tract obstruction (LVOTO).These patients usually develop hypotension. Either sympathomimetics or inotropic therapy can restore blood pressure. Given the pathogenesis of TTS, sympathomimetics  can worsen the patient's condition, so dobutamine/dopamine is the drug of choice because of their positive inotropic effect. If the patient develops moderate to severe LVOTO, inotropic therapy should be discontinued. If there is evidence of decreased blood supply to internal organs and persistent hypotension, vasopressor therapy can be used, which increases cardiac output and thus blood pressure. Severe hypotension and cardiogenic shock can lead to left ventricular dysfunction. In this case, mechanical circulatory support must be used to keep patients alive 2.With left ventricular outflow tract obstruction (LVOTO).As already mentioned, inotropic therapy must be discontinued. Fluid resuscitation and beta-blockers are the therapy of choice in this case (in the absence of pulmonary congestion). In addition, an alpha-agonist (phenylephrine) can be used to increase the blood pressure and therefore the afterload, which may improve the patient's condition. Mechanical circulatory support  should be used if the conservative therapy is ineffective According to 2020 Mayo Clinic data, 11% of patients develop CS in the first 72 h after admission, and 20–25% develop LVOTO Levosimendan, a non-catecholamine inotrope that does not increase myocyte uptake of cytoplasmic oxygen, is a rational therapeutic option in cardiogenic shock associated with TTS. In addition to its direct action as a calcium-sensitising agent, levosimendan has been found to mediate the opening of adenosine triphosphate (ATP)-dependent potassium channels in vascular smooth muscle cells 1.Stage A (At risk): no tachycardia, hypotension, and normal lactate values. At this stage, only close monitoring of the patient's condition is necessary;2.Stage B (Beginning): hypotension (relative), tachycardia without hypoperfusion, and normal lactate values. Levosimendan and ultra-short-acting beta blockers  should be administered;3.Stage C (Classic): hypoperfusion, elevated lactate values, cardiac index < 2.2 L/min/m*2. In the absence of LVOTO, venoarterial extracorporeal membrane oxygenation (VA-ECMO) is required if there is a left ventricular thrombus, and LV or BiV Impella if no thrombus is found. If LVOTO is developed, the inotropic therapy should be discontinued, and ultra-short-acting beta blockers  should be prescribed instead. However, if the patient does not improve, VA-ECMO or LV/Biventricular (BiV) Impella should be started, depending on the presence or absence of thrombus, respectively;4.Stage D (Deteriorating): hypoperfusion and deterioration (Not refractory shock). Treatment is the same as for stage C;5.Stage E (Extremis): hypoperfusion, deterioration, refractory shock. VA-ECMO is needed at this stage;Depending on the stage of CS 9.4The most commonly used drug for treating thrombosis in TTS is warfarin, a vitamin K antagonist. The optimal duration of treatment is three months, but depending on the size and location of LV thrombi, it can be prolonged 9.51.Telemetry monitoring should be carried out for at least three days ;2.Beta-blockers should be discontinued, and potassium and magnesium should be given in patients with a QT interval > 500 ms;3.It is advisable to be alert to the list of antiarrhythmic drugs that prolong QT interval. Although intravenous amiodarone is the most commonly prescribed medication for treating life-threatening arrhythmia, a few cases of torsade de pointes have been reported 4.In the case of torsades de pointes, intravenous magnesium is the first-line pharmacological treatment approach. In patients with prolonged QT interval and unresponsive to magnesium treatment, isoproterenol was shown to prevent torsades de pointes. Synchronised cardioversion is the preferred method for hemodynamically unstable patients who have a pulse. Patients with pulseless torsades should be defibrillated 5.A dual-chamber permanent pacemaker or defibrillator may be considered in persistent bradycardia or persistent prolongation of the QT interval. Bradyarrhythmias can be dangerous if they lead to complete atrioventricular heart block (AV-block). In the Stiermaier T et al. study, researchers suggested that patients in this situation need a permanent ventricular pacemaker with long-term follow-up, indicating that bradyarrhythmias in TTS require implantation of a permanent pacemaker According to 2018 data, the prevalence of arrhythmias among 286 patients with TTS demonstrated that ventricular tachycardia (VT) and ventricular fibrillation (VF) accounted for two-thirds of the arrhythmic episodes 10NACRAM trial is a multicenter, randomised, placebo-controlled trial consecutively testing the early use of intravenous N-acetylcysteine followed by oral administration of ramipril for 12 weeks in TTS management. The use of these medications is reasoned by their inhibiting effects on nitrosative stress and expression of the activator thioredoxin interacting protein. Both processes are presumably related to TTS pathogenesis. NACRAM evaluates the reduction of myocardial edema on magnetic resonance imaging of the heart. It also analyses the improvement of LV systolic function measured by global longitudinal strain on echocardiography, evaluates the quality of life and inflammation markers. NACRAM is likely to become the first prospective study that will evaluate treatment options of acute attacks of stress-induced cardiomyopathy Also, hormone therapy is currently being researched. The advantages of estradiol are still being studied and assessed in treating the chronic phase of TTS. Animal experimental trials have demonstrated a significant reduction in stress-induced LV dysfunction and arrhythmias. It indicates the importance of the sex hormone in the clinical management of TTS after complete recovery of LV function established by echocardiography. It has also been demonstrated that oestrogen has a cardioprotective effect against myocardial damage in the context of ischemia or reperfusion To date, mineralocorticoid receptor antagonists and angiotensin-neprilysin receptor inhibitors , which are effectively used in patients with chronic systolic heart failure, have not been studied among patients with TTS. However, these drugs may be of scientific interest for further research A randomised interventional controlled trial involving 90 patients who have recovered from TTS is currently underway. The researchers are conducting a three-arm pilot trial of early rehabilitation, including standardised physical exercise training, cognitive behavioural therapy, and comparing the results with the standard clinical care. Key indicators are the “restored cardiac energetic status assessed by 31P-magnetic resonance spectroscopy, cortisol awakening response, global longitudinal strain by echocardiography, and the 6-minute walk test” 11meta-analyses, and clinical cases  values;b.ST-segment elevation;c.Atrial fibrillation;d.High C-reactive protein.Independent predictors of atrial fibrillation:a.Peak BNP 1620 ± 1459 ng/L;b.Peak CRP 116 ± 96 mg/L;c.LVEF 48 ± 15 %.Independent predictors of ventricular fibrillation (VF):a.Increased heart rate and blood pressure;b.T-wave inversion (V4-V5);c.QT interval prolongation;d.Left ventricular basal hypercontraction.A recent study showed that neutrophil/lymphocyte ratio is an independent predictor of hospital-acquired complications, including pulmonary edema, cardiogenic shock, death, stroke, and LV thrombi Interleukins (IL) are hypothesised to influence TTS development, and their role as independent predictors of complications is also considered. For example, in 2016, Santoro et al. found that elevated levels of IL-6 and IL-10 on admission to hospital correlated with a high incidence of in-hospital complications. Patients with IL-6 > 51 pg/ml and/or IL-10 > 1.3 pg/ml were more likely to develop cardiogenic shock, pulmonary oedema, stroke, and recurrent TTS In comparison to ACS, lower levels of IL-6 and higher levels of TNF-a and INF-g were found in patients with TTS, indicating a different response of cellular molecules in the two pathological processes. Researchers suggested that the higher levels of TNF-a and INF-g in patients with TTS may be related to their ability to remove damaged cells, while the higher levels of IL-6 in patients with ACS may indicate the process of atherosclerosis 12meta-analysis of 31 studies involving 1664 patients reported a 5% relapse after six years meta-analysis involving 3513 patients, Kato et al. reported a relapse rate from 0 to 10% TTS is usually favourable and resolves with complete recovery in 4–8 weeks in>90% of patients. Relapses are rare. Thus, in a study by Templin et al. relapse rate was 1.8% per year Risk factors for developing relapses are severe LV dysfunction, increased susceptibility to emotional stress, dynamic fluctuations in the sensitivity of cardiac adrenergic receptors, and women over 50 years old According to Matabuena Gomez-Limon J et al. (1.8–6.6 years), long-term consequences include LV wall movement abnormalities, myocardial infarction, recurrent events of TTS, heart failure, and others Moreover, atrial fibrillation is known to increase the risk of ventricular arrhythmias and cardiac arrest In 2016 the retrospective study demonstrated paradoxical results of better intrahospital and long-term outcomes for patients with underlying diabetes mellitus who suffered from TTS 1313.1meta-analysis showing that ACE inhibitors, and not beta-blockers, reduce the risk of recurrence Until now, there has been no consensus regarding the pharmacological prevention of TTS. Thus, Santoro et al. found that the recurrence rate was lower with the use of beta-blockers (1.81%) compared with the control group (2.86%). The relapse rate with ACE inhibitors, aspirin, and statins was statistically less significant and amounted to 0.5% compared to 0% in the control group 13.2It is necessary to alleviate stress in everyday life to prevent TTS, and antidepressants should not be taken, especially SNRI, without prescription. Thus, obtaining proper medical history and identifying susceptible patients before starting antidepressants are vital in clinical practice. In addition, close follow-up care with a psychiatrist and a cardiologist is recommended to reduce TTS recurrences and long-term complications.13.3As a preventive measure, it is advised to reduce the consumption of caffeine drinks and quit smoking since these are the risk factors that impair endothelial function and/or coronary blood flow reserve and increase adrenergic stimulation 14In summary, TTS is an increasingly recognized condition that can lead to less favourable outcomes comparable to those of acute coronary syndrome despite a self-limiting clinical course. Moreover, the two conditions can coexist, making diagnosis even more challenging. The existing knowledge about this syndrome is primarily based on consensus documents and current international registries. Therefore, controlled clinical trials and further research are needed to determine the optimal diagnostic approach, treatment, and prevention strategies.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


The number of cardiovascular procedures using the coronary sinus (CS) as a gateway is constantly increasing. The present study aimed to define specific structures within CS, which could potentially complicate CS cannulation and to develop a new Thebesian valve (TV) classification system.2 [interquartile range (IQR): 56.5–127.1 mm2] and median CS length was 38 mm (IQR: 29.5–45 mm). The CSO area and CS length correlated with each other and with the right atrium’s dimensions.The study was performed on 560 consecutive unfixed cadaveric hearts during routine autopsy examination (1–3 days post-mortem). Basic CS dimensions were measured and the presence and dimensions of the TV and the Vieussens valve (VV) were assessed. Thebesian valves were classified according to their morphology into six main types: remnant fold, semilunar, fenestrated, chord, fused strands, and mixed shaped. The median age of hearts was 48 years (range 16–95 years), and 38.9% were female. Thebesian valve was present in 79.5%. The most common TV type was semilunar (54%) followed by fenestrated (8.2%), remnant fold (5.5%), fused strands (4.8%), chord (4.0%), and mixed shaped (3.0%). In 1.1% of hearts, TV totally covered the coronary sinus ostium (CSO). The VV was detected in 67.9%. Potentially occlusive VV was found in 1.1% hearts and in all of which it coexisted with obstructive TV. The median CSO area was 87.9 mmWe identified six types of TVs, among which only 1.1% TVs caused total occlusion of CSO. The obstructive TV co-existed with potentially occlusive VV what might hinder CS cannulation. This is the largest study to be performed on unfixed heart specimens to assess the complete coronary sinus (CS) anatomy.The study proposes a new classification of the Thebesian valve (TV), which includes six morphological types.An occlusive TV coexisted with an obstructive Vieussens valve in 1.1% of the examined hearts.In hearts with no TV, the CS ostium area and the CS length correlated significantly with each other and with the right atrium’s transverse and longitudinal diameters.The coronary sinus (CS) is the central vein of the coronary venous system, which runs in the posterior part of the coronary groove as a continuation of the great cardiac vein from the Vieussens valve (VV) to its ostium located in the inferomedial part of the right atrium, between the inferior vena cava orifice and the inferior tricuspid annulus.,The CS opening is frequently covered by a fold of endocardial tissue termed the Thebesian valve (TV). The role of the TV in normal physiology is not fully understood, but it is believed that it may prevent blood regurgitation into the CS during the contraction of the atrium.The CS has increasingly been used as a passage for various cardiovascular procedures: left ventricular lead placement in cardiac resynchronization therapy, mapping and ablation of different arrhythmias, percutaneous mitral annuloplasty, retrograde cardioplegia delivery, coronary venous retroperfusion, and targeted drug delivery or placement of a coronary sinus reducer in refractory angina.Despite the high clinical importance of the coronary venous vasculature, knowledge of its anatomy remains limited. Cadaveric studies on formalin-fixed hearts are still the most reliable source of anatomical knowledge of the venous system of the heart. Additional data have been obtained by imaging-based studies using venography, cadaveric coronary vein endoscopy, cardiac computed tomography, or cardiac magnetic resonance.The purpose of this study was to assess the CS anatomy with regard to the coronary sinus ostium (CSO). In particular, we aimed to identify specific structures within the CS that could complicate electrophysiological and cardiac invasive procedures by examining human cadaveric hearts that had not undergone formalin fixation. We also intended to develop a new TV classification system.This cross-sectional observational study was performed between June 2014 and December 2019 at the Department of Forensic Medicine of Poznan University of Medical Sciences, Poznan, Poland. The study was performed on 560 consecutive cadaveric hearts during routine autopsies. All hearts were examined 1–3 days post-mortem, and none had been previously preserved with formalin. The exclusion criteria were as follows: cardiac cause of death, cardiac injury, any anatomical heart anomalies, a medical history of severe cardiac pathologies , previous cardiac surgery or invasive intracardial procedures, and macroscopic signs of putrefaction. Demographic and clinical data were obtained from the departmental records and available medical histories. The study was approved by the Ethical Committee of Poznan University of Medical Sciences .All examined hearts were dissected from bodies in a routine manner along with parts of the great vessels. First, macroscopic measurements of basic heart parameters, including heart length and width, right atrium (RA) longitudinal and transverse dimensions, and left ventricle (LV) and right ventricle (RV) thickness, were performed. The heart’s length was measured from the apex to the superior border of the base in the middle. The width was measured at the widest part of the transverse diameter. The RA long axis was measured from the midpoint of the medial aspect of the tricuspid annulus to the superior point of the atrial wall in the plane of the interatrial septum. The transverse dimension of the RA was measured as the greatest distance from the septal to the free wall surfaces of the RA in a plane perpendicular to the long axis. The thickness of the free walls of the LV and RV and the interventricular septum was measured at the mid-ventricular level. All measurements were performed with an electronic calliper .Table 1 and Figure 1.To examine the right atrium anatomy in detail, a long lateral section from the apex of the RV to the orifice of the superior vena cava was made, cutting the posterior cuspid of the tricuspid valve. The morphology of the CSO and the presence and morphology of the TV were recorded in all heart specimens. The vertical and transverse diameters of the CSO were also measured. In all examined hearts, the CSO had an elliptic shape. For this reason, the CSO area was calculated according to the commonly used formula for the surface area of an ellipse . The craniocaudal and transverse dimensions of the TV were also measured. The TV was studied with particular attention to its morphology and location and its coverage percentage of the CSO. The coverage percentage was calculated according to the formula of Mehra: maximum transverse dimension of the TV/transverse diameter of the CSO × 100.The CS was opened by a longitudinal incision along its free wall without touching the TV if present. The presence and morphology of the VV were also noted including the number of cusps and their shape . If a VV was detected, the diameter of each leaflet was measured, and the coverage percentage of the CS was calculated according to the above-mentioned Mehra formula.Figures 3. Moreover, for each CS tributary from the LV territory, the following measurements were performed: ostium diameter measured at the point of CS entry and length, defined as the distance between the ostium of the coronary vein and the first dichotomous division of the vessel measured along the course of the vein.The presence and number of veins draining into the CS (CS tributaries) were also evaluated. The detailed anatomy of CS tributaries is shown in χ2 test as appropriate, and continuous variables were analysed using the nonparametric Mann–Whitney U test . Interactions between the variables were evaluated using Spearman’s correlation test. A two-tailed alpha of 0.05 and a P-value of <0.05 were considered statistically significant.Statistical analysis was performed using Statistica version 13.7. The appropriate study sample size was estimated using a proportion based on the largest previous study.2 (IQR: 20–27 kg/m2). The median weight of the hearts was 370 g (IQR: 314–401 g). There were statistically significant differences in most macroscopic parameters between female and male cadavers. Details are presented in Table 2.Of the 560 hearts, 38.9% were from female cadavers. The median age of the autopsied subjects was 48 years (range: 16–95 years), and the median body mass index (BMI) was 23.6 kg/mn = 445) of the hearts. In terms of shape, the most common was type II—semilunar (54%), followed by type III—fenestrated (8.2%), type I—remnant fold (5.5%), type V—fused strands (4.8%), type IV—chord (4%), and type VI—mixed shaped (3%) (Table 1). The median percentage of CS coverage by the TV  was 55% (IQR: 40–73%). The potentially obstructive TV (type IIb) was identified in 2% (n = 11) of all specimens including 1.1% (n = 6) that covered 100% of the CSO. Using the smallest (3-F) electrophysiology catheter, we were able to cannulate all fenestrated and mixed-shaped valves, as well as two of the six TVs completely covering the CSO.The TV was present in 79.5% (P < 0.0001). There were also significant differences between male and female hearts in median maximal diameter of the CS  and median CSO area . Table 3 presents the detailed results of macroscopic measurements of the heart structures.The median length of the CS in the entire sample was 38 mm (IQR: 29.5–45 mm) and was significantly greater in male specimens , RA longitudinal diameter , and CSO area . Similarly, there were strong correlations between the CSO area and the RA transverse  and longitudinal  diameters. The detailed correlation test results are displayed in Table 4.The CS length positively correlated with the RA transverse diameter , followed by five , three , six , and two tributaries . There were no significant differences in the number of tributaries from the LV territory in terms of sex, age, BMI, or basic heart parameters (Table 4).The CS most frequently had four tributaries from the LV territory (Table 5. The median percentage of CS coverage by the VV was 41.2% (IQR: 35–49%). A potentially occlusive VV was found in six (1.1%) hearts, in all of which it coexisted with a TV completely covering the CSO. Using a 3-F electrophysiology catheter, we were able to catheterize four of the six potentially occlusive VVs.The VV was present in 67.9% of the heart specimens. Most frequently, it was composed of two concave cusps (32.1%). Details are shown in Cardiovascular procedures using the CS as a gateway have significantly increased over the past decades, and successful CS cannulation constitutes a significant challenge in modern cardiology. Data suggest that up to 10% of all CS catheterizations fail.in vivo conditions, thus avoiding the tissue shrinkage that occurs after fixation. In hearts where the TV was absent, the median CSO area was 97.9 mm2. The CSO area strongly correlated with the CS length. According to the authors it could be related to the increased blood flow causing also stretching of myocardial sleeve covering the CS and thus increasing the CS length and the CSO area. This finding may be partially explained by sex differences. Most heart parameters were significantly higher in male than in female hearts. Interestingly, the CSO area and CS length positively correlated with the RA transverse and longitudinal dimensions. In living hearts, the CS parameters and RA dimensions change with the heartbeat, with minimum values during the atrial systole. A previous study assessing patients with primary pulmonary hypertension using echocardiography revealed a strong correlation between RA size and CS diameter. However, the CS diameter was not related to the pulmonary arterial or RV pressure or to the extent of tricuspid regurgitation, suggesting that the CS might behave as an extension of the RA, like the inferior vena cava.One of the important factors determining the success of CS cannulation is the CSO area. To our knowledge, this is the first study to perform measurements on unfixed heart specimens, close to ,et al.,in vivo visualization of the TV with an illuminated endocardial fibreoptic endoscope, reported that the TV was present in 54% of the examined hearts. This lower prevalence may have resulted from CSO dilatation caused by the blood flow during the cardiac cycle and the difficulty in visualizing residual or thin TVs.The CSO is frequently covered by the TV, which exhibits high morphological variability. Studies with small sample sizes have estimated a prevalence of TV ranging from 62% to 88%.,,,,In this study, we observed various morphologies of the TV. Although attempts to describe TV variability have previously been made,,,,,,,et al.et al.et al.Several studies have shown that the TV may obstruct the entrance to the CS and prevent its cannulation.,et al.et al.et al.Besides an obstructive TV, other obstacles may prevent successful CS cannulation. A previous study reported that the presence of a prominent VV may be one of the main obstacles to advancing the catheter into a great cardiac vein.It seems reasonable to identify any obstacles preoperatively and prepare accordingly for the coronary venous advancement in case of strong suspicion of complications during CS cannulation. Recently, a computed tomography study was conducted to address this need and to examine whether imaging modalities could be considered in cases of failure of conventional VV intubation. However, the detection rate of VV by computed tomography was significantly lower than that achieved with cadaveric findings. In computed tomography imaging, the VV covered more of the CS lumen in comparison to cadaveric measurements .et al.et al.It should be emphasized that the presence of an obstacle does not rule out the possibility of successful CS catheterization. CS venous angioplasty and stenting have been proposed as promising strategies. Oto The CS may be easily injured during interventional procedures. The reported incidence of coronary sinus rupture or dissection is about 1%.in vivo haemodynamic conditions, which may have caused measurement bias. The dimensions and shape of coronary venous structures may change during the cardiac cycle. In haemodynamic conditions, the behaviour of the TV and VV may cause difficulties that we may have been unable to accurately depict. Second, we studied heart specimens obtained from patients without cardiovascular disease, who are not representative of the patients typically requiring CS cannulation. Therefore, we were unable to assess coronary venous system discrepancies. Third, we performed only an anatomic evaluation, but microscopic correlations were not performed. However, we strongly believe that these limitations have a relatively limited impact on the overall results and conclusions of this study.This study has several limitations. Firstly, it was conducted during autopsies, that is, in the absence of physiologic This study provides unique insight into the anatomy of the CS, which might facilitate successful CS catheterization. We identified six main types of TV. Only 1.1% of the TVs in our sample caused total occlusion of the CSO. However, we found that an obstructive TV can coexist with a VV covering >75% of the CS lumen, which might hinder CS cannulation. Moreover, the CSO area and CS length positively correlated with each other and with the RA transverse and longitudinal diameters. We believe that our findings will help physicians identify patients at risk of difficult CS catheterization.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Conflict of interest: none declared.The data underlying this article will be shared on reasonable request to the corresponding author.


Atrial Fibrillation (AF) and Heart Failure (HF) are closely linked to each other, as each can be either the cause of or the result of the other. Successfully treating one of the two entities means laying the basis for treating the other one as well. Management of patients with AF and HF can be challenging and should primarily adhere to available guidelines. Concerning AF, medication is limited and causes many side effects, leading to low medical adherence. Several smaller studies, summarized in a big meta-analysis, provide evidence that ablation of AF in HF patients is crucial for improving quality of life, reducing HF hospitalizations, and reducing death, provided the LVEF is at least 25% or higher. In advanced HF, alternative treatment options  might still be the better option. Early rhythm control should be taken into consideration, as there is evidence that it is associated with better cardiovascular outcome. Atrial Fibrillation Begets Heart Failure and Vice Versa” [Framingham Heart Study in 2003 showed an increased mortality in patients with congestive heart failure (CHF) who later developed AF  as well as in individuals suffering from AF who subsequently developed HF  [Atrial fibrillation (AF) is the most common cardiac arrhythmia, with rapidly increasing numbers worldwide due to the progressive aging of the population. It is predisposed by several risk factors such as heart failure (HF), ischemic heart disease, high blood pressure, valvular heart disease, sleep apnea, and diabetes, and at the same time increases the risk of developing heart failure of any kind . AF and heart failure co-exist in up to 30%  of patiee Versa” ). When b HR 3.1) . A publi HR 3.1) .arrhythmia induced cardiomyopathy” (AIC) is a special entity of heart failure caused by AF and should particularly be suggested in patients with an oligo- to asymptomatic course and a tendency to high-rate conduction of AF. In contrast to dilated cardiomyopathy (DCM), the following parameters favor the presence of an AIC: progressive dilatation of the left-ventricular end-diastolic diameter (LVEDD), early involvement of the right ventricle, decreased apical strain, and rapid NT-proBNP-decrease after restoring sinus rhythm. Consequently, cardioversion in combination with rhythm control should be attempted in these patients.The so-called tachymyopathy or “Pathophysiologic and cellular mechanisms that try to explain the progression from AF to heart failure, due to AF, include cellular and extracellular remodeling with altered extracellular collagen distribution that contributes to myocardial dilatation and wall-thinning followed by decreased myocardial contractility as well as increased density of collagen fibers, leading to increased myocardial stiffness and diastolic dysfunction. Furthermore, loss of AV synchrony, rapid ventricular response with depletion of myocardial energy stores, increased sympathetic nerve activity, and irregular ventricular response with alternating ventricular preload have been discussed [2+ overload might contribute to initiation and maintenance of AF [iscussed ,7,8,9. Oce of AF .integrated approach to arrhythmia treatment, considering anticoagulation, better symptom control, and cardiovascular risk factor management including HF-treatment (“ABC pathway”) [Therefore, it has been suggested that either achieving and maintaining sinus rhythm (“rhythm control strategy”) or adequate heart rate control (“rate control strategy”) could benefit patients with HF. Recent guidelines on treatment of AF point out the need for an athway”) .The overall management of HF patients with AF is sometimes challenging.Concerning medical treatment strategies for heart rate control in patients with reduced left ventricular ejection fraction (LVEF), beta blockers and/or digoxin are recommended to target a heart rate <100–110 beats per minute (bpm).RACE-II trial [p < 0.001). After 1 and 2 years and at the end of the follow-up period, the resting heart rates in the lenient control group were 86 ± 15, 84 ± 14, and 85 ± 14 beats per minute.Although the number of patients with heart failure was quite small, the II trial  in 2013 AFFIRM [Concerning rhythm control, the large randomized AFFIRM  trial  or a “pace and ablate” concept with biventricular pacing (n= 40 patients) in combination with atrioventricular node (AVN) ablation. They were monitored for both symptomatic and asymptomatic episodes of AF. The composite primary endpoint  favored the PVI group (p < 0.001) within the 6-month observational period, reaching significance in each subgroup. Therefore, the authors concluded that PVI was superior to biventricular pacing combined with AVN ablation in patients with heart failure and drug-refractory AF. The single-center, randomized, controlled CAMTAF [p = 0.015), functional capacity, and heart failure symptoms  compared to medical rate control.Published in 2008, the PABA-CHF  study wad CAMTAF  trial (2AATAC [p= 0.037) was observed in the catheter ablation group as well as fewer unplanned hospitalizations (p < 0.001).The AATAC  study (2CASTLE-AF [n = 184 patients) or catheter ablation (n = 179 patients). All participants had an LVEF of 35% or less, an implanted ICD, and guideline-based HF medication. After a median FU of 37.8 months, the death rate from any cause (p = 0.01) or cardiovascular cause (p = 0.009) and hospitalization for worsening heart failure (p = 0.004) were significantly lower in the ablation group. Interestingly, this was not true for patients with a LVEF of 25% or smaller, where medical therapy seemed to be the better option. This finding was in agreement with the results of the multicenter, open-label, controlled, randomized AMICA [The ASTLE-AF  trial, ped AMICA  study  underwent catheter ablation and were matched to 899 controls. Over a median follow-up of 3.8 years, ablation was associated with a statistically significant reduction in all-cause mortality  with no difference in major bleeding or stroke. A reduced hazard of HF rehospitalization for patients after ablation was observed until approximately 3 years post-ablation, which the authors called the “protective effect of catheter ablation”.In 2020, Samuel et al. provided a study  on catheEAST-AFNET-4 [p = 0.005). Serious adverse events related to rhythm control therapy occurred in 4.9% (early rhythm control) and 1.4% of the patients assigned to usual care. During follow-up, symptoms and left ventricular function at 2 years did not differ significantly between the groups.Although not designed as an HF study, the international, investigator-initiated, parallel-group, open, blinded outcome assessment -AFNET-4  trial . Again, potential toxic effects and poor efficacy of AADs failed to reduce hard endpoints. In contrast, catheter ablation for rhythm control of AF was associated with significantly lower all-cause mortality , similar rate of stroke, fewer rehospitalizations , greater improvement in LVEF and quality of life, and lower arrhythmia recurrence in patients with HF  and a growing number of patients, in particular with HF and preserved ejection fraction (HFpEF). Studies should be blinded for the procedure (sham arm) and focus on patient selection, appropriate timing for ablation, and long-term outcomes.Summing up these data, there is good evidence now that sinus rhythm might be beneficial in symptomatic AF patients with HF, as long as rhythm control is achieved by catheter ablation and not by AADs alone. An exception seems to be patients with severely reduced ejection fraction , where medical therapy proved to be the better option, as well as in older people with advanced HF, very large atria, severe symptoms, and advanced frailty. The optimal timing for catheter ablation must be individualized, based on patients’ preferences, the underlying cause of HF, LVEF, and tolerance of AADs. Data from EAST-AFNET-4 suggest that early rhythm control is associated with better cardiovascular outcomes. In patients with tachycardia-induced HF (“tachymyopathy”), especially in those with oligo- or asymptomatic heartrate exacerbations, AF ablation should be considered early due to a high risk of progressive HF caused by recurrent high rate episodes.A recent (2021) AHA scientific statement  on manag2020 ESC Guidelines for the diagnosis and management of atrial fibrillation [2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement [on catheter and surgical ablation of atrial fibrillation and provide a Class IIa (LOE: B) recommendation to consider AF ablation in selected patients with HFrEF to improve survival and reduce HF hospitalizations as well as in patients with symptomatic paroxysmal AF episodes. The 2019 AHA/ACC/HRS focused update [of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation provides a Class IIb (LOE: B) indication for catheter ablation in selected patients with symptomatic AF and HF with reduced LVEF to potentially lower mortality rate and reduce hospitalization for HF , showintatement  on cathed update  of the 2n for HF . They fopace and ablate strategy with pacemaker implantation and AV node ablation should be considered. In HF patients, a device for cardiac resynchronization therapy (CRT) should be the first choice for this concept. New pacing concepts such as conduction system pacing  might provide new therapeutic avenues here but must be validated first by randomized trials in this indication.In the case of highly symptomatic AF, refractory to medication, and/or catheter ablation, the option of a To conclude, heart failure and atrial fibrillation are closely tied to each other and each can be either a source of or a result of the other. Management of these patients can be challenging and should primarily adhere to available guidelines. HF therapy consists mainly of HF medication, supplemented by device therapy , if indicated. Concerning AF, medication is limited and causes many side effects, leading to low medical adherence. There is sufficient evidence available now indicating that ablation of AF in HF patients is crucial for improving quality of life, reducing HF hospitalizations, and reducing death, as mentioned above, provided the LVEF is at least 25% or higher. For those with very low LVEF, alternative treatment options  might still be the better option. Data from EAST-AFNET-4 suggest that early rhythm control is associated with lower cardiovascular outcomes.As HF and AF have the potential to cause each other, successfully treating one of the two entities means laying the basis for treating the other one as well. Appropriate patient selection and timing for the different therapeutic strategies seem crucial. Future randomized controlled studies will have to focus on emerging disease entities, in particular patients with HFpEF.


This case describes a 74-year-old male who was hospitalized with hyponatremia and worsening systolic and new diastolic heart failure. Workup showed low voltage QRS complexes on electrocardiogram and new diastolic dysfunction on echocardiogram. Because of this clinical scenario amyloidosis was suspected. ATTR amyloidosis was confirmed without doing an invasive endocardial biopsy by the use of immunofixation studies and Technetium 99 PYPm scan, and abdominal fat pad biopsy. The types and manifestations of amyloidosis in general and cardiac amyloidosis, in particular, are reviewed as well as the diagnostic test available to the clinician to confirm this diagnosis. Amyloidosis describes a variety of clinical entities caused when one of many precursor proteins with unstable tertiary structure misfolds and aggregates as insoluble amyloid fibrils . These fA 74-year-old male presented from an outside hospital (OSH) for nausea, vomiting, dizziness, and hyponatremia. He had a significant past medical history of paroxysmal atrial fibrillation, CHADSVASC 4, chronic heart failure with a reduced ejection fraction of 35-40%, coronary artery disease with recent left heart catheterization showing non-obstructive coronary artery disease. On the way to the OSH, he was found to be in atrial fibrillation with a rapid ventricular response which spontaneously resolved upon arrival. A chest X-ray was reported to show vascular congestion and cardiomegaly. The patient was given 1L normal saline and transferred to our hospital.On admission, he complained of paroxysmal palpitations, shortness of breath at rest, worse with exertion, and orthopnea for several weeks. His medication included amiodarone 200 mg three times a week, aspirin 81 mg once a day, carvedilol 6.25 mg twice a day, furosemide 40 mg twice a day, lisinopril 2.5 mg once a day, and spironolactone 25 mg once a day. Significant findings on physical exam were a Body Mass Index of 21, jugular venous distention (JVD) 8 cm above the sternal angle, with bilateral basilar crackles, no abnormal heart sounds, and no lower extremity edema. Vitals included a mean arterial pressure of 79-89 mmHg. Pertinent blood work is shown in Table Admission chest X-ray is shown in Figure The electrocardiogram is shown in Figure A previous EKG two years prior showed normal sinus rhythm, right bundle branch block, and a first-degree AV block.A transthoracic echocardiogram (TTE) done on admission showed a left ventricular (LV) ejection fraction (EF) of 25-30% along with severe concentric left ventricular hypertrophy, diastolic dysfunction, a mildly dilated right ventricle, moderate right ventricular (RV) hypertrophy, moderately reduced right ventricular systolic function with an estimated right ventricular systolic pressure (RVSP) of 30-35 mmHg, bi-atrial enlargement, moderate tricuspid regurgitation, mild pulmonic insufficiency, and trace pericardial effusion. A TTE done two years prior showed moderately reduced left ventricular systolic function with an EF of 35-40% with normal-sized atria and ventricles, but no diastolic dysfunction.During the patient’s hospital stay, aggressive diuresis was initiated with furosemide 40 IV BID. Heart rate control was achieved with metoprolol. In addition, the patient’s previous outpatient medications were restarted with the resolution of the patient’s hypervolemic signs on exam, although sodium levels remained in the low 120’s throughout the patient’s hospital course. The presence and persistence of hyponatremia were thought to be due to worsening systolic and diastolic heart failure. The resultant decreased perfusion of the kidney causes activation of the renin-angiotensin system and anti-diuretic hormone (ADH) secretion. This can mimic the syndrome of inappropriate ADH (SIADH) with increased urine sodium, decreased serum osmolality, and increased urine sodium concentration. SIADH was discounted as the cause for the hyponatremia as it is usually accompanied by a euvolemic state and our patient was clearly hypervolemic. Because of the severe left ventricular concentric hypertrophy on echocardiogram, bi-atrial enlargement and low voltage QRS on EKG, ATTR cardiac amyloidosis was suspected. Immunofixation was negative and the Kappa/Lambda ratio was within normal limits. These findings and the absence of organomegaly with normal renal function decreased the suspicion for AL amyloidosis. A Technetium pyrophosphate (99 PYPm) scan demonstrated a Grade 3 on the Perugini scale, showing cardiac uptake with greatly reduced or absent bone signal.An abdominal fat pad biopsy was performed which detected a peptide profile consistent with ATTR (transthyretin) type amyloid deposition. Liquid chromatography-mass spectrometry did not detect an amino acid sequence abnormality in the transthyretin protein. This finding was consistent with wild-type amyloidosis rather than hereditary transthyretin-associated amyloidosis. Due to the patient’s severe disease and inability to afford tafamidis, the patient opted for hospice. Amyloidosis is a disease caused by the deposition of insoluble amyloid fibrils in different tissues of the body, which leads to the abnormal functioning of these tissues . ImpropeAmong the different types, ATTR and AL amyloidosis can involve the heart, leading to cardiac amyloidosis . AmyloidThis case was uncommon in the sense that our patient presented with reduced ejection fraction in addition to diastolic dysfunction. Cardiac amyloidosis has historically been associated with a preserved ejection fraction at the time of diagnosis. In fact, reduced ejection fraction <40%) is typically only reported in 30% of wild-type ATTR cardiac amyloidosis (ATTR-CA) cases 0% is typ. Our patCompared to ATTR-CA associated with preserved ejection fraction, patients with ATTR-CA associated with reduced ejection fraction tend to be more symptomatic, New York Heart Association-Functional Class ≥ 3, 61% vs 26%, p<0.001), have mean diastolic dysfunction values that are worse , reduced kidney function , and higher mortality  [On presentation, our patient revealed symptoms and physical exam findings common in heart failures such as orthopnea, elevated JVD, and bilateral crackles. These findings are also commonly found in cardiac amyloidosis patients . AdditioOur patient’s EKG showed low voltage QRS complexes, which is expected in about half of cardiac amyloidosis patients . A pseudCardiac magnetic resonance is another modality that can be used. This provides information on the properties of the myocardial tissue. For example, amyloid deposition in the cardiac interstitium results in myocardial injury. These sites of injury act as areas for gadolinium to accumulate, which causes late gadolinium enhancement . This meA third way to aid in the diagnosis of cardiac amyloidosis involves nuclear imaging, which is the route that was taken with our patient. This approach uses radiotracers, typically Technetium-99m-pyrophosphate (99mTc-PYP) and Technetium-99m and 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD). These nuclear imaging studies show very high specificity and sensitivity, which is why we did not pursue an endomyocardial biopsy to make a diagnosis . Our patLastly, an echocardiogram provides many useful clues in the diagnosis of cardiac amyloidosis. Features of small left ventricle (LV) size with systolic impairment, increased LV wall thickening, bi-atrial enlargement, RV hypertrophy, cardiac valve thickening, and pericardial effusions are all potential findings on echo, many of which were present in our patient . As the Although the echocardiogram provides a useful tool in the diagnosis of the disease, it is not sufficient for diagnosis alone. It also is unable to distinguish ATTR from AL amyloidosis. For this reason, two other tests, a nuclear imaging study and an immunofixation exam, were performed in our patient. ATTR amyloidosis is confirmed with a positive predictive value and specificity of 100% if a nuclear imaging study results in a Perugini Grade 2 or 3 and immunofixation shows the absence of monoclonal proteins . BecauseCardiac amyloidosis is an uncommon cause of new or worsening heart failure. Diagnosis rests on a strong clinical suspicion and electrocardiographic and echocardiologic findings, along with confirmative sereolgic and imaging studies as described above. Previously endomyocardial biopsy was necessary to confirm the diagnosis, but today serologic, imaging, and fat pad biopsy can be used to establish the diagnosis with certainty.