Background: A mouse model of myocardial ischemia-reperfusion (I/R) is widely used to study myocardial ischemia-reperfusion injury (I/RI). However, few studies focus on the direct comparison of the extent of pathological events resulting from variant durations of ischemia and reperfusion process.Methods: A mouse model of I/RI was established by ligation and perfusion of the left anterior descending coronary artery (LAD), and the dynamic changes were recorded by electrocardiogram at different stages of I/R. Subsequently, reperfusion duration was used as a variable to directly compare the phenotypes of different myocardial injury degrees induced by 3 h, 6 h and 24 h reperfusion from myocardial infarct size, myocardial apoptosis, myocardial enzyme, and inflammatory cytokine levels.Results: All mice subjected to myocardial I/R surgery showed obvious myocardial infarction, extensive myocardial apoptosis, dynamic changes in serum myocardial enzyme and inflammatory cytokines, at least for the first 24 h of reperfusion. The infarct size and apoptosis rates gradually increased with the extension of reperfusion time. The peaks of serum myocardial enzyme and inflammatory cytokines occurred at 6 h and 3 h of reperfusion, respectively. We also established I/R mice models with 30 and 60 mins of ischemia. After 21 days of remodeling, longer periods of ischemia increased the degree of fibrosis and reduced cardiac function.Conclusions: In summary, we conclude that reperfusion durations of 3 h, 6 h, and 24 h induces different injury phenotypes in ischemia-reperfusion mouse model. At the same time, the ischemia duration before reperfusion also affects the degree of cardiac remodeling. Myocardial infarction (MI) occurs when the blood supply to the heart is interrupted, and causes damage and possible death of the heart tissue . Timely In vivo studies in mice, the degree of myocardial fibrosis and scar area are important indexes to evaluate cardiac function after I/RI in mice.Inflammatory damage has been shown to be a characteristic pathologic process in myocardial I/RI and it is also one of the reasons for the aggravation of myocardial injury and the enlargement of myocardial infarction area , 12. MorIn the present study, we evaluated the different response to different durations of ischemia and reperfusion in mice, and analyzed the effects of different ischemia and reperfusion times on myocardial injury, inflammatory response, myocardial apoptosis, myocardial fibrosis, and cardiac function. Our study may provide a clear approach to the construction of mice myocardial I/RI models for researchers, so that they can choose the appropriate timing, combination, and determine the schedule of end point of the experiment.Focusing on a mouse model of myocardial I/RI, a total of 70 mice were used in this study. Except for the deaths caused by technical accidents during I/R surgery and prolonged pathological cardiac remodeling, 21 mice were used for cardiac TTC staining analysis, 16 mice were sacrificed for collection of myocardial tissue and blood samples, and 15 mice were subjected to echocardiography to measure cardiac function and myocardial tissue section preparation for histopathology.The flow chart of the experimental protocols in the study is given in To evaluate the outcomes of different reperfusion times on myocardial infarction, we measured the ischemic area  and the infarct (INF) area in each group by TTC and Evans blue double-staining . There wDetection of myocardial apoptosis by TUNEL staining and western blot analyses for apoptosis markers were performed on the myocardial tissue. As shown in In addition to infarct and TUNEL staining, we evaluated serum myocardial enzyme as marker of ischemic myocardial injury. The variations in enzyme levels following reperfusion are shown in interleukin 6 (IL-6) and interleukin-1β (IL-1β) levels constantly rose at the beginning of reperfusion and reached a maximum concentration after 3 h. The content of inflammatory factors decreased gradually with the extension of reperfusion time, but still remained higher than the normal level at least after 24 h of reperfusion. Furthermore, the western blot results also confirmed that the expression of anti-inflammatory cytokines IL-10 in myocardial tissue was decreased with the extension of reperfusion time, while the expression level of Toll-like receptor 4 (TLR4) was on the contrary . Subsequently, reperfusion duration was used as a variable to directly compare the phenotypes of different myocardial injury degrees induced by 3 h, 6 h and 24 h reperfusion from four aspects: myocardial infarct size, myocardial apoptosis, myocardial enzyme levels and inflammatory cytokines levels. All mice subjected to I/R surgery showed obvious myocardial infarction and extensive myocardial apoptosis, and the infarct size and apoptosis rates gradually increased with the extension of reperfusion time, at least for the first 24 h of reperfusion. The enlargement of infarct size with increasing duration of reperfusion after 30 mins of MI as seen in this study may, at least in part, be due to increased apoptotic cell death.During myocardial ischemia, the integrity of the cell membranes is damaged, causing myocardial enzyme to be released into the peripheral blood , 27. TheA number of studies supported that the inflammatory response is one of the major mechanisms involved and plays a pivotal role in the pathogenesis of myocardial I/RI , 30. It 2S therapy enhances phosphorylation and nuclear localization of nuclear factor erythroid 2-related factor 2 (NRF2), leading to the expression of NRF2-targeted downstream anti-oxidative stress genes, thus protecting cardiac tissue against I/R injury [Among the recognized mechanisms of myocardial ischemia-reperfusion injury, oxidative stress also has become an area of increasing interest and research focus . ImbalanR injury . MoreoveR injury –42. TherThe degree and time of myocardial remodeling after injury in mice depended on the time of LAD ligation and the use of reperfusion protocol . BecauseThe finding that myocardial infarction size increases with the reperfusion time extension is controversial, but several previously published studies are in accordance with this finding , 45. OurAll male C57BL/6 J mice aged 8–10 weeks were purchased from GemPharmatech Co. Ltd.,  and raised at the specific pathogen-free laboratory animal facility of West China Hospital, Sichuan University . All efforts were made to minimize suffering in animals. At the end of the experiment, mice were anaesthetized with 2% isoflurane and euthanized by cervical dislocation.All mice were anaesthetized in the chamber at 2% isoflurane, under sterile conditions. Myocardial ischemia-reperfusion injury was induced by ligation of the left anterior descending artery (LAD) by a 7-0 silk suture for 30 mins or 60 mins followed by reperfusion for 3 h, 6 h and 24 h (acute I/R injury) or 21 days (I/R remodeling). Sham-operated mice were treated with the same surgery without tying the left anterior descending coronary artery. Electrocardiography was performed to evaluate the successful generation of the MI model. After that, mice were sacrificed at various time points, and myocardial tissue was collected for further analysis.Electrocardiogram (ECG) was performed immediately after MI surgery. All mice were anaesthetized with isoflurane, carefully positioned on the ECG recording platform. Surface lead II ECG was obtained. After electrode setup and system adjustment were accomplished, the next 1 min of ECG recordings were analyzed by LabChart 8.2.3 . In this experiment, three stages of ECG were recorded: before operation, myocardial ischemia and reperfusion.The infarct size was determined by TTC staining. 3 h, 6 h and 24 h after reperfusion, the LAD was re-ligated at the same location, 1 mL Evan’s Blue (Sigma) was injected via the aorta to visualize the area at risk (AAR). Then the hearts were immediately stored at -20° C for 30 min followed by slicing 2 mm thick from the apex of the heart to the aorta. The sections were then stained with 1% TTC for 20 min at 37° C. To assess surgery homogeneity, area at risk/left ventricle weight (AAR/LV) was calculated. The infarct size/area at risk (INF/AAR) was calculated to evaluate the myocardial infarction severity.TUNEL BrightRed Apoptosis Detection Kit  was used to perform TUNEL staining on 5 μm frozen heart sections according to the manufacturer’s protocol after α-Actinin-Cy3 antibody. All sections and glass bottom plates were examined by confocal microscope . TUNEL positive and α-actinin positive nuclei were counted for cardiomyocyte TUNEL positive.Myocardial tissue and cell suspension was lysed by RIPA lysis buffer . BCA Protein Assay Kit  was adopted to determine protein concentrations. After equal quantities, total proteins were separated in SDS-PAGE gel , and the bands were transferred onto PVDF membranes . After blocked with 5% skimmed milk and washed with tris-buffered saline containing 0.1% tween-20 (TBST), protein bands were blotted with primary antibodies at 4° C overnight. After washing with TBST, protein bands were blotted with HRP conjugated secondary antibody and monitored using ECL buffer . Quantifications of western blotting were measured with Fusioncapt advance software. Antibody information: Bax , Bcl2 , Cleaved-caspase3 , IL-10 , TLR4 , α-SMA , MMP-9 , Collagen I , GAPDH . HRP-conjugated secondary antibody .ELISA was performed to measure the levels of myocardial enzyme and inflammatory cytokine in mice serum. Quantitative measurement of LDH, CK, CK-MB, IL-6, TNF-α and IL-1β was performed in serum supernatants using LDH ELISA Kit , CK ELISA Kit , CK-MB ELISA Kit , IL-6 ELISA Kit , TNF-α ELISA Kit , and IL-1β ELISA Kit (88-7013-22) respectively, according to manufacturer’s manuals.All mice underwent transthoracic echocardiography under 1.5% isoflurane anaesthesia. The cardiac function  were detected by Vivid7 Dimension system  with a 30 MHz central frequency scan head and measured from M-mode images taken from the parasternal short-axis view at papillary muscle level.Mice myocardial tissue was fixed in 4% paraformaldehyde followed by embedded with paraffin. Pieces of heart embedded in paraffin were cut into 5 μm sections and mounted on glass slides. After dewaxing and dehydrating with xylene and ethanol, the sections were stained successively with hematoxylin and eosin staining, iron hematoxylin staining, ponceau acid magenta, phosphomolybdate staining, and aniline blue dyeing. Images were acquired using a bright field microscope . Myocardial infarct scar area was analyzed by ImageJ.P < 0.05 was considered to be statistically different. Analyses were performed using GraphPad Prism 8.Data from the mouse and cell model were expressed as mean ± SD. Significant differences were assessed by One-way ANOVA followed by Tukey post hoc test which was used for statistical comparisons between multiple groups. A value of


To analyze regional variations in T2 and T2* relaxation times in wrist joint cartilage and the triangular fibrocartilage complex (TFCC) at 3 and 7 T and to compare values between field strengths.t-tests were used to compare T2 and T2* values between field strengths and between different ROIs. Spearman’s rank correlation was calculated to assess correlations between T2 and T2* time values at 3 and 7 T.Twenty-five healthy controls and 25 patients with chronic wrist pain were examined at 3 and 7 T on the same day using T2- and T2*-weighted sequences. Six different regions of interest (ROIs) were evaluated for cartilage and 3 ROIs were evaluated at the TFCC based on manual segmentation. Paired p ≤ 0.045), with one exception: at the distal lunate, no significant differences in T2 values were observed between field strengths. T2* values differed significantly between 3 and 7 T for all ROIs of the TFCC (p ≤ 0.001). Spearman’s rank correlation between 3 and 7 T ranged from 0.03 to 0.62 for T2 values and from 0.01 to 0.48 for T2* values. T2 and T2* values for cartilage varied across anatomic locations in healthy controls at both 3 and 7 T.T2 and T2* time values of the cartilage differed significantly between 3 and 7 T for all ROIs (Quantitative results of T2 and T2* mapping at the wrist differ between field strengths, with poor correlation between 3 and 7 T. Local variations in cartilage T2 and T2* values are observed in healthy individuals.T2 and T2* mapping are feasible for compositional imaging of the TFCC and the cartilage at the wrist at both 3 and 7 T, but the clinical interpretation remains challenging due to differences between field strengths and variations between anatomic locations.•Field strength and anatomic locations influence T2 and T2* values at the wrist.•T2 and T2* values have a poor correlation between 3 and 7 T.•Local reference values are needed for each anatomic location for reliable interpretation.The online version contains supplementary material available at 10.1186/s41747-023-00394-1. The wrist is one of the most challenging anatomic areas to examine by magnetic resonance imaging (MRI) due to the small size of tissues including the thin articular cartilage at multiple locations and the triangular fibrocartilage complex (TFCC) with its complex anatomy . DetectiConventional MRI usually depicts morphologic degenerative changes at the cartilage and the TFCC only at advanced stages of disease . In cont1+) distribution and chemical shift artifacts, which may also affect compositional imaging such as T2 and T2* mapping [However, at 3 T, T2 mapping data for the cartilage or TFCC at the wrist are limited to a few feasibility studies , 10, 11. mapping , 16. In  mapping , 18. KnoWe hypothesized that T2 and T2* values differ between field strengths, but show excellent correlation, and that T2 and T2* time values show significant variability between different anatomic locations in healthy articular cartilage and in different regions of interest (ROIs) of the TFCC at the same field strength. Hence, the aims of this study were (1) to compare T2 and T2* values obtained at 3 and 7 T for articular cartilage and the TFCC at different anatomic locations in healthy controls and patients with chronic wrist pain; (2) to assess the correlation of T2 and T2* values between field strengths; and (3) to compare T2 and T2* values of articular cartilage and the TFCC in healthy controls at 3 and 7 T to determine whether these values vary with anatomic location.Participants were prospectively enrolled between July 2018 and June 2019 after providing written informed consent. The study sample consists of 25 patients and 25 healthy volunteers  and 7 T  with dedicated wrist coils on the same day. All participants underwent 3-T MRI first. For all measurements at 3 T, a 16-channel receive hand–wrist radiofrequency coil was used. For excitation, the integrated body coil was used. For 7-T MRI, a 1-channel transmit/16-channel receive wrist radiofrequency coil  was employed. The transmit part consists of a separate quadrature birdcage coil. At 7 T, a coronal multi-echo spin-echo T2-weighted sequence  and multi-echo gradient-echo T2*-weighted sequence  were acquired.syngo MapIt  [At 3 T, protocols with image acquisition times comparable to those used at 7 T were applied: a coronal multi-echo spin-echo T2-weighted sequence  and a coronal multi-echo gradient-echo T2*-weighted sequence . Detailed MRI parameters are provided in Supplementary Table SAll images were blinded for the whole assessment and were evaluated by a radiologist (R.H.) with eight years of experience in musculoskeletal MRI and a special interest in wrist imaging. T2 and T2* maps were assessed by placing ROIs at nine anatomic locations. Six of these ROIs were placed in the cartilage of the distal radius, in the proximal scaphoid, in the proximal radial lunate and ulnar lunate, in the distal radioulnar joint, and in between the distal lunate and proximal capitate . Three RThe imaging evaluation for T2 and T2* at 3 T and 7 T was repeated by a second radiologist (E.B.) with four years of experience in musculoskeletal MRI. This second evaluation was performed independently from the first reading for 10 randomly chosen study participants  to determine inter-reader reliability. The second radiologist was blinded to the imaging evaluation of the first reading.t-tests, supported by qq-plot check, were used to compare T2 and T2* values for different anatomic locations at 3 T or 7 T. Paired t-tests were also employed for the comparison of T2 and T2* values between 3 and 7 T. The use of paired t-tests was supported by checking the normal distribution through qq-plots for the paired differences of measurements. The correlation of T2 and T2* values between 3 and 7 T was determined by calculating Spearman’s rank correlation to account for outliers. Intraclass correlation was used to calculate the interobserver reliability. Values less than 0.50 indicate poor reliability, values between 0.50 and 0.75 indicate moderate reliability, values between 0.75 and 0.90 indicate good reliability, and values greater than 0.90 indicate excellent reliability [p lower than 0.05 were considered to indicate a statistically significant difference.Statistical analysis was performed by a biostatistician (C.G.) using R software version 4.2.2. The Wilcoxon rank-sum test was used to evaluate differences in age between patients with chronic wrist pain and healthy controls. Paired iability . Values p = 0.003). Figures A total of 27 healthy controls and 36 patients with chronic wrist pain were screened for study inclusion. Two healthy controls and eight patients were excluded prior to the study due to contraindications for MRI, lack of consent, or medical history. Three participants with chronic wrist pain did not complete 7-T MRI due to claustrophobia. Overall, 25 healthy controls (13 women) and 25 patients 14 men) with chronic wrist pain completed the study. The healthy controls  were younger than the patients with chronic wrist pain  at the distal radioulnar joint to 44.2 ± 7.2 at the distal lunate and proximal capitate and from 23.5 ± 5.9 ms to 29.3 ± 8.0 ms at the TFCC. T2* values at the cartilage of controls ranged from 14.2 ± 1.6 ms at the radius to 19.7 ± 3.3 ms at the distal lunate and proximal capitate and from 10.1 ± 1.2 ms to 11.3 ± 2.0 at the TFCC.At 7 T, T2 values at the cartilage of controls ranged from 40.6 ± 15.3 ms at the distal radioulnar joint to 48.8 ± 9.8 ms at the radius and from 26.7 ± 10.7 ms to 31.7 ± 16.8 ms at the TFCC. T2* values at the cartilage of controls ranged from 8.6 ± 2.1 ms at the radius to 11.9 ± 3.0 ms at the ulnar lunate and from 6.2 ± 1.9 ms to 6.4 ± 1.4 at the TFCC. T2 and T2* values of all assessed anatomic locations and for patients with chronic wrist pain are provided in Table versus 46.3 ± 13.0 ms, p = 0.254). At the TFCC, the only significant difference between field strengths observed for T2 values was for the apical attachment of the TFCC in patients . T2* values differed significantly between 3 and 7 T in every anatomic location of the TFCC  and 11/15 comparisons at 7 T  showed significant differences for T2 time values. At the TFCC, T2 values showed significant differences between anatomic locations in 3/3 comparisons at 3 T , while no differences were observed at 7 T .The comparison of T2 and T2* values between pairs of anatomic locations (separated into cartilage and TFCC) for healthy controls is presented in Table p-values from < 0.001 to 0.031) and in 8/15 comparisons at 7 T . At the TFCC, T2* values differed significantly between anatomic locations in 3/3 comparisons at 3 T . No differences were revealed for the same comparison at 7 T .For T2* values of cartilage, significant differences were seen in 10/15 comparisons at 3 T  being higher than 0.75, indicating good reliability. No systematic differences in reliability between 3- and 7-T MRI were observed. Supplementary Table SIn our comparative study, we found that T2 and T2* values of the cartilage and T2* values of the TFCC differed significantly between 3 and 7 T. Overall, the correlation for T2 and T2* values between field strengths was poor for both cartilage and the TFCC. Most T2 and T2* values of articular cartilage varied between anatomic locations in healthy volunteers at both 3 T and 7 T. At 3 T, this was also true for the TFCC, whereas no differences were observed between anatomic locations of the TFCC at 7 T.To our knowledge, no previous studies have assessed T2 or T2* mapping techniques of the wrist at 7-T MRI, despite potential benefits related to its inherently high contrast-to-noise and signal-to-noise ratios compared to lower field strengths . FurtherCompositional MRI techniques such as T2 and T2* mapping enable noninvasive tissue quantification and thereby provide information about structural changes and tissues’ molecular status , 8, 21. 1+) has an influence on the measured T2 relaxation times [1+ is typically more inhomogeneous at 7 T than at 3 T, which might explain the larger standard deviations of the measured T2 relaxation times [Our observed differences in T2 and T2* values between 3 and 7 T support the findings of previously published studies. Although T2 and T2* relaxation times typically decrease with increasing field strength, we observed an increase in T2 relaxation times at higher magnetic field strength . A similon times . B1+ is on times . In a pron times . In addion times  reportedIn vivo and ex vivo studies have shown a strong magic angle effect on T2 values of cartilage with changes of more than 200%, especially in the deeper layers of cartilage [Beyond differences in field strengths, coil design and pulse sequences causing alterations in T2 and T2* values intra-individual variations between different anatomic locations must also be considered , 35, 36.artilage , 41. OurHowever, at the TFCC, significant regional differences occurred at 3 T, but not at 7 T, for both T2 and T2*. The variation in T2 and T2* values between different anatomic locations in healthy controls suggests that single regional values must be interpreted cautiously. It also emphasizes the need to implement local reference values for each anatomic location, which need to be ascertained on the deployed hardware using the respective sequence protocol . Due to Like any quantitative imaging technique, compositional MRI of cartilage requires careful attention to detail across the acquisition and analysis pipeline to ensure that values obtained are accurate, reproducible, and interpretable. Previous studies have shown marked variability across vendors, radiofrequency coils, and pulse sequences , 42–45. 1+ inhomogeneities might have contributed to the variation in measured T2 times.Our study has some limitations: first, the small number of study participants with missing reference standard providing a final diagnosis in the case of the included patients. Further, the uniqueness of the study population limits the generalization of our data and the transferability to other wrist conditions. Second, due to ethical considerations, we cannot provide any histological correlation that objectively validates the MRI findings. Third, the sequences we used for 7-T MRI were optimized and adapted from standard sequences used at 3 T so that measurement times were comparable between field strengths. For T2* mapping at 7 T, we had to use shorter echo times due to the increased susceptibility artifacts at longer echo times. This might also have affected the results. Fourth, the coil design geometry used was different for 3 T and 7 T; thus, the wrist position was slightly different during image acquisition. Moreover, at 7 T, BIn conclusion, T2 and T2* mapping are feasible for compositional imaging of the TFCC and the cartilage at the wrist at both 3 T and 7 T. As observed in other joints, quantitative T2 and T2* time values differ between field strengths. Further, T2 and T2* times vary between anatomic locations and do not show a strong correlation between 3 and 7 T, which may be of high importance for valid imaging interpretation and emphasizes the need to establish reference values for healthy individuals for every anatomic location.Additional file 1: Table S1. Table S2.


B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-pro BNP) are cardiac biomarkers that are released in response to increased ventricular and atrial wall stress. Aortic stenosis (AS) leads to hemodynamic changes and left ventricular hypertrophy and may be associated with natriuretic peptide levels. Several studies have shown that increased natriuretic peptide levels are correlated with AS severity and can predict the need for intervention. It can be useful in risk stratification, monitoring follow-up, and predicting cardiovascular outcomes of patients with severe AS. This paper aims to summarize the evidence of the role of BNP and NT-pro BNP in AS, before and after intervention. Biomarkers are measurable laboratory indicators that could be helpful in the diagnosis or in the therapeutic decision of certain diseases. Several biomarkers have been studied in aortic stenosis, but B-type natriuretic peptide (BNP) is currently the only biomarker that is supported by valvular heart disease guidelines recommendations . BNP is AS is the most prevalent valve heart disease in the general population aged over 65 years, mainly in developed countries . During The role of natriuretic peptides as cardiac biomarkers in congestive heart failure (HF), as well as the prognostic value in patients with HF, is well recognized . BNP levDespite this, the relative importance of BNP and its utility as a cardiac biomarker in aortic stenosis is currently under discussion. This paper aims to summarize the evidence of the role of BNP and NT pro-BNP in aortic stenosis, before and after interventions, highlighting a comprehensive analysis of their diagnostic and prognostic significance, which thus sets this paper apart from other reviews in the field. Boolean searches on PubMed, Medline, and Google Scholar included terms related to BNP or NT-pro BNP with terms for aortic stenosis and aortic valve replacement. The data analysis focused on randomized controlled trials, meta-analyses, and cohort studies conducted between 1995 and 2023. A total of 60 papers were reviewed excluding review articles and others less relevant to the topic.The first studies published correlating BNP levels to severe AS demonstrated that increased natriuretic peptide levels are correlated with the mean pressure gradient, peak velocity, peak transaortic gradient pressure, aortic valve area, and functional status (NYHA symptom class) –13. Qi eIn 2004, Weber et al.  found a Other studies have identified a progressive increase in BNP and NT-pro BNP values with decreasing aortic valve area but included a large increase in patients with LVEF <50%, which may emphasize the association between natriuretic peptide levels and cardiac function , 17.These findings suggest that BNP is related to AS severity and could be useful to monitor asymptomatic patients .The onset of symptoms is a critical point in the natural history of AS and is a hallmark for the recommendation of AVR. In some patients, the development of symptoms related to severe AS, such as exertional dyspnea, is unclear, non-specific, and often difficult to be evaluated clinically .The use of BNP as a biomarker reflecting early decompensation in asymptomatic patients had been demonstrated previously in several studies –16. GerbThe optimal timing of intervention in asymptomatic patients with severe AS remains a challenge in clinical decision-making, and monitoring BNP levels may be helpful in this context. However, measurements of BNP do not substitute clinical and echocardiographic evaluation of these patients.In asymptomatic patients, the relationship between classical parameters of AS severity, in cases of normal flow and high gradient, with elevated natriuretic peptide levels and poor prognosis is well established. In contrast, the association of biomarkers and prognosis for other AS categories remains unexplored. Results from a cohort study with specific subgroups of AS showed that patients with normal flow and low gradient who had lower BNP levels exhibited the best prognosis. While patients with true low flow and low gradient who had higher BNP levels displayed the worse outcome, with more LV remodeling and increased global LV afterload, similar to those patients with normal flow and high gradient . ResultsMoreover, the prognostic value of natriuretic peptides combined with high-sensitivity troponin T (hs-TnT) could be enhanced in LFLG-AS patients who had either preserved or reduced LV ejection fraction. Elevations of both BNP and hs-TnT were associated with a significantly higher risk of cardiovascular mortality in this group . FurtherStudies correlating natriuretic peptides and biomarkers, such as troponin or imaging modalities, e.g., LV global longitudinal strain (LV-GLS), can provide synergistic risk stratification, independent of symptoms, risk factors, and other severe echo parameters in critical patients with AS. After aortic valve replacement, reversal of LV remodeling with regression of myocardial hypertrophy was observed, leading to an improvement in LV-GLS and decreased NT-pro BNP levels. However, more prospective studies are needed before natriuretic peptides can be used routinely to determine valve intervention timing , 24.Mixed aortic valve disease (MAVD) is defined as an association between AS and aortic regurgitation (AR). In patients with moderate-to-severe MAVD, high BNP levels were correlated with worse LV-GLS, higher LV-mass index, elevated left atrial volume index, and higher prevalence of moderate or greater tricuspid regurgitation, which are significantly associated with critical clinical outcomes. Previous studies demonstrated worse outcomes in patients with moderate MAVD when compared to those with either moderate AS or AR alone .p < 0.001)  . In addi< 0.001)  identifi< 0.001) .Pedrazzini et al.  showed aThe relationship between AS and sudden death is well-recognized . PreviouThe plasma level of pre-procedure BNP has also been linked with the left ventricle mass index after surgical AVR in early and late evaluation, and this is closely related to unfavorable outcomes and worsening of symptoms in the post-procedure follow-up . The stuImportantly, Clavel et al.  showed iThus, ESC/EACTS and AHA/ACC guidelines recommend intervention in patients with asymptomatic AS and BNP levels >3 ×  normal, as a class IIB recommendation , 35–37.Recent evidence in studies on transcatheter AVR (TAVR) showed superiority in primary outcomes compared to conventional surgical AVR in most scenarios . In factNatriuretic peptide values were also evaluated in patients submitted to TAVR and were related to prognosis , 40. HigPost-TAVR BNP value also has clinical and prognostic correlation. BNP values after discharge were analyzed in patients included in the OCEAN-TAVI multicenter registry in order to evaluate prognosis and correlations with the patient profile and procedure . The cutVarious factors can lead to misinterpretation, either overestimating or underestimating BNP value. For instance, renal dysfunction, advanced age, female sex, atrial fibrillation, inflammation, hyperthyroidism, and the use of sacubitril/valsartan can cause an overestimation of BNP levels. On the other hand, certain factors including obesity, the immediate period following acute coronary syndrome onset, and the presence of pericardial effusion can result in an underestimation of BNP levels . Thus, iBNP is a prognostic marker in asymptomatic patients with severe AS, and values above the 3 ×  normal level may help indicate intervention , 35–37.


Metabolic syndrome X has been known to be a risk factor for the development of cardiovascular dysfunction. Insulin resistance, diabetes mellitus and serum lipid abnormalities, which are all seen in metabolic syndrome X, have been found to negatively impact heart function, leading to heart failure in particular. Heart failure is a condition resulting when the heart is unable to perform its function of providing sufficient blood flow to meet the body’s requirements. The treatment of heart failure in metabolic syndrome X varies based on the various components of metabolic syndrome X, which include obesity, hyperglycemia, hypertension and dyslipidemia. Obesity is regarded as one of the derangements seen in patients with metabolic syndrome X. It is a significant risk factor in the development of cardiovascular disease, which may eventually lead to heart failure. However, the obesity paradox suggests that obesity provides a higher chance of survival in patients with metabolic syndrome and heart failure. This review article focuses on the pathophysiology of heart failure in patients who already have metabolic syndrome X, as well as the therapeutic management complexity of the two conditions taking into consideration the protective role provided by obesity. Introduction2. Prevalence and incidence3. Morbidity and mortality4. Association of heart failure and metabolic syndrome X5. Pathogenesis of heart failure in metabolic syndrome X patients6. Diagnosis 7.Heart failure’s treatment in metabolic syndrome X8. Prognosis 9. Conclusion1. It is a steadily increasing metabolic abnormality, affecting 34% of the general population and may lead to glucose abnormality and significant cardiovascular complications such as high blood pressure and dyslipidemia that may increase the risk of heart failure, affecting both therapeutics and follow-up management plan2,3. Heart failure (HF) is a chronic, progressive condition in which the heart muscle is incapable of pumping enough blood to meet the body’s needs for blood and oxygen. Heart failure is a major health concern that has been a subject of interest since it was designated as an emerging epidemic in 19974,5. Since then, the total number of cases has evolved and become a major cause of mortality, hospitalization, and health care expenses among patients older than 65 years6. The presence of heart failure along with other comorbidities significantly affects the long-term morbidity and mortality of symptomatic and asymptomatic patients.Metabolic syndrome, also known as insulin resistance syndrome or metabolic syndrome X, is a multifactorial syndrome affecting men more than women, and is mainly influenced by hormonal, genetic, and lifestyle factorsobesity paradox. Obesity has been found to increase short and medium-term prognosis in association with the cardiorespiratory capacity of the patients. Several therapeutic effects including better physical activity and diet resulted in better outcomes in heart failure patients7. To date, the exact mechanism of metabolic syndrome and its association with heart failure and the obesity paradox are still not well understood. In this review article, we aim to highlight current knowledge regarding the impact of metabolic syndrome on heart failure development in relation to the obesity paradox.Moreover, metabolic syndrome may cause obesity, which is an established risk of heart failure, but recently it has been published that such a relationship may result in a better prognosis. This is called the 8. Furthermore, older studies have supported this finding as well, the prevalence was 23.1 % which increased to 27 % in 1999-20009. As per the national cholesterol education program (NCEP) criteria, metabolic syndrome is so common in the US that 43.5% of the total over 50 years of age population have it10.The prevalence of metabolic syndrome has significantly increased over the years. According to the national health and nutrition examination Survey (NHANES), the prevalence has increased from 36.3% in 2011-2012 to 38.2% in 2017-2018 in the USA11. Metabolic syndrome is a risk factor for other cardiovascular conditions as well, which contributes to the increase in their prevalence.The increasing prevalence of metabolic syndrome also leads to a growing prevalence of the global pandemic, heart failure, which affects around 26 million people in the whole world12. Moreover, a study of heart transplant patients showed that 42.3% patients had metabolic syndrome along with ischemic heart disease before the transplant13. One study suggested that the prevalence of metabolic syndrome was 49.5% among 200 coronary artery disease (CAD) patients who had undergone coronary angiography14. The population with an age of more than 50 years in NHANES was divided into two groups depending on the presence of the metabolic syndrome and the group with metabolic syndrome showed the highest prevalence of coronary heart disease (CHD)15.According to a systematic review and meta-analysis that were done in Iran, metabolic syndrome was present in 34.2% of a total of 44,735 cardiovascular patients16. A Japanese study with 3603 patients enrolled with chronic heart failure showed the presence of metabolic syndrome in 49 % of males and 19 % of females, which was higher than double than the general population. Another study with 4762 HF patients had metabolic syndrome prevalence of 41.3%17.Similar to other cardiovascular diseases, the prevalence of the metabolic syndrome is also high in heart failure patients. Various studies have shown similar findings. One single-center study showed that out of 865 patients with indigent heart failure, 40% had metabolic syndrome18. Population studies have shown that metabolic syndrome increases the risk of developing heart failure and this effect is mediated by insulin resistance. However, obesity is a key component in metabolic syndrome and a customary partner of insulin resistance because it is protective in patients with established heart failure, although insulin resistance confers an increased risk of dying from heart failure. This phenomenon is called the "obesity paradox" accounting for the complexity of the heart failure-metabolic syndrome relationship6. Metabolic syndrome has a prevalence in the general population of 27% and is associated with increased mortality. In a cohort of hospitalized patients with heart failure, the prevalence of metabolic syndrome was 68%, exceeding that of the general population. However, unlike the general population, metabolic syndrome is associated with lower mortality in heart failure patients, establishing that mortality was lower in those with metabolic syndrome (44%) compared to those without . Finally, in a fully adjusted model, there was a significantly lower risk of mortality in those with metabolic syndrome 19. Therefore, physicians treating patients with heart failure need to address the present metabolic syndrome epidemic.The presence of comorbidities significantly affects long-term morbidity and mortality of symptomatic and asymptomatic heart failure patients20. Though generally known, the link between obesity and congestive heart failure is still not fully understood. Obstructive sleep apnea and systemic and pulmonary hypertension were thought to be the primary causes of this illness, which was formerly known as "obesity cardiomyopathy”21,22.For more than 50 years, there has been a correlation between obesity and atherosclerotic heart disease. The obesity pandemic has made this aspect of the population's risk for cardiovascular disease more important and evident23. In individuals with heart failure, insulin resistance is very common (up to 60%), and there is a complex pathophysiological interplay between these two disorders since insulin resistance may be both a cause and an effect of heart failure. Similar to heart failure patients, diabetes mellitus is widespread among them, with prevalence rates in hospitalized patients ranging from 10% to 40%24.Several functional, metabolic, and anatomical changes brought on by insulin resistance and diabetes mellitus ultimately lead to heart failure.Numerous studies show that diabetes mellitus and insulin resistance are not the only risk factors for heart failure. They are also associated with a more severe form of left ventricular dysfunction and higher mortality rates than people without diabetes mellitus or insulin resistance or heart failure25. The lipid abnormalities mentioned in the definition of metabolic syndrome include low plasma levels of high-density lipoprotein (HDL) and high plasma levels of triglycerides. Velagaleti et al. found that low HDL plasma levels were linked to a 40% higher risk of developing heart failure over a 26-year follow-up in a population analysis from the Framingham cohort. Consequently, lipid buildup in the heart leads to heart failure26.Hypertension affects 6 to 10 percent of heart failure patients. According to the model put forth by Vasan and Levy, hypertension is not known to affect LV function in the early stages. A chronic increase in pressure load caused by mechanical stress leads to a rise in the level of cytokines, neurohormones and growth factors which progress to the development of concentric LV hypertrophy, leading to symptomatic heart failure with normal or abnormal LV function27. The homozygous TT genotype of the aminopeptidase M1 (apM1) gene, which was identified in abundance in adipose tissue, was linked to a greater risk of metabolic syndrome. Adiponectin, a protein that resembles collagen, was also encoded by the apM1 gene28. Persistent activation of the sympathetic nervous system and renin-angiotensin-aldosterone system were the processes involved in metabolic syndrome29. Inability to adapt the results of these processes in cardiomyocyte hypertrophy, which, if the problem persists, could cause remodeling and finally result in heart failure30. The association between heart failure and metabolic syndrome has been illustrated in According to Jackson's heart research, visceral obesity is linked to an increased risk of developing heart failure in the black population31.Adipose tissue is classified according to its location: subcutaneous or visceral. However, it was found that visceral adiposity was independently associated with the incidence of hospitalized patients with heart failure with preserved ejection fraction (HFpEF). Obesity and in particular central adiposity directly correlates with increased left ventricular stiffness, which contributes to the diastolic dysfunction in HFpEF. Visceral adipose tissue (VAT), which is stored in the abdominal cavity and accounts for 20% of adipose tissue, is pro-inflammatory and increases cardiovascular risk by promoting metabolic diseases such as diabetes mellitus, dyslipidemia, and hypertension. Obesity-related biomarkers such as adipokines also have prognostic value in heart failure risk but it is unknown if these biomarkers better predict heart failure than anthropometrics and CT-measured adiposity31.Thus, chronic inflammation also plays an important role in heart failure associated with metabolic syndrome. Serum IL-6 and TNF-α levels are high in patients with metabolic syndrome and elevated proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, galectin 3, soluble TNF receptor 1, and soluble TNF receptor 2 can be detected both in heart failure with reduced ejection fraction (HFrEF) and HFpEF. TNF provokes cardiomyocyte hypertrophy and impairs cardiac contractile function. TNF also induces dilation of the left ventricle as a result of extracellular matrix degradation. Several studies have also suggested the role of IL-6 in the progression of heart failure including its interaction with the vasculature and neurohormonal system to promote cardiac HF32. Insulin resistance occurs as a response to multiple stimuli leading to activation of s6 kinase. The response induced myocardial hypertrophy, cardiac fibrosis, impaired myocardial-endothelial signaling, and death of myocardial and endothelial cells. A study correlated a higher risk of heart failure incidence was related to a higher fasting insulin level. Prolonged Insulin resistance by the body can cause an increase in left atrial size, left ventricular mass, and alterations in transmitral velocity33. Hyperinsulinemia resulting from insulin resistance, along with an increase in adipokine levels and alterations of baroreceptor heart rate reflex are some key factors that give rise to chronic activation of the sympathetic autonomic nervous system. This leads to peripheral vasoconstriction and tachycardia. Although the metabolic demand of the heart increases in sympathetic stimulation, the metabolic supply to the tissues is decreased due to the transition from glycolysis pathway to fatty acid oxidation. The development of hypertrophy of cardiac myocytes results as a compensatory mechanism and failure to address the condition can thereby proceed to heart failure31 ailure31 .34.There is a paradoxical relationship between obesity and heart failure, especially in those with BMI 30-35. The mechanism of this still remains unclear, however, the increased lean mass that obese individuals have could play a critical role in improving long-term outcomes. Excess lean mass allows a higher cardiorespiratory fitness, which in turn improves heart failure prognosis; furthermore, the exact mechanism is unknown35.The diagnosis of heart failure begins with a thorough assessment of the patient's history and physical. Classic signs and symptoms of heart failure, such as dyspnea, dyspnea on exertion, orthopnea, peripheral edema, pathologic S3 and S4 heart sounds, crackles/rales at the lung bases, and jugular venous distention raise clinical suspicion of heart failure. It is of note that the history and physical examination provide low specificity and sensitivity to the diagnosis of heart failure36. HFpEF on the other hand, displays a normal 12 lead ECG, though the presence of atrial fibrillation or paced rhythm increases the probability that HFpEF is present. A normal ECG makes left ventricle systolic dysfunction unlikely with a 98% negative predictive value37.Electrocardiography (ECG), Chest X-ray, and Laboratory evaluation are initial diagnostic evaluations for patients who are suspected to have heart failure. ECG is particularly useful in patients that have HFrEF. These patients have significant ECG abnormalities, and the ECG provides high sensitivity and limited specificity for identifying HFrEF in these patients38-40. Cardiomegaly, Kerley-B lines, pleural effusion, and cephalization of the pulmonary vessels are findings suggestive of heart failure. Redistribution and cardiomegaly are the best predictors of increased preload and reduced ejection fraction, but neither is sufficient to definitively diagnose heart failure. alveolar edema, interstitial edema, and cephalization all have high specificity for HFrEF, but only cardiomegaly had a sensitivity of over 50 percent39. Chest X-rays are more limited in providing diagnostic value for patients with HFpEF where the sensitivity of cardiomegaly is 24 percent and pleural effusion is only 9 percent41.Chest radiographs are useful especially for patients presenting with dyspnea because they can provide information that helps differentiate heart failure from a primary pulmonary disease42. BNP or NT-proBNP levels have sensitivities of 93 percent and a specificity of 74 and 65 percent respectively for the diagnosis of heart failure36.It is recommended that the clinician obtain a complete blood count, urinalysis, serum electrolytes, blood urea nitrogen, serum creatinine, glucose, fasting lipid panel, liver function test, iron studies, assays for BNP or NT-proBNP, and thyroid-stimulating hormone levels for patients who are suspected to have heart failure. These laboratory studies provide essential information with regard to patients’ comorbidities, treatment approach, and potential causes or confounders of heart failure. In the context of the correct clinical presentation, BNP or NT-proBNP levels provide immense value to the diagnosis of heart failure, but should not be used in isolation to diagnose or exclude heart failure35 , a measure of heart function collected by echocardiography, is used to diagnose and categorize heart failure into either HFpEF or HFrEF. If the LVEF is less than 50 percent, the patient is diagnosed with HFrEF, and if the LVEF is over or equal to 50 percent then the patient is diagnosed with HFpEF. While echocardiography is essential to the diagnosis of heart failure, it alone does not establish or exclude heart failure. Thus, a conclusive diagnosis cannot be made without considering the signs, symptoms, clinical features, laboratory values, chest radiography, and ECG of the patient being evaluated35 .44.Metabolic syndrome X is diagnosed when the patient has central obesity with two or more of the following; raised triglycerides or specific treatment for this lipid abnormality, reduced HDL cholesterol or specific treatment for this lipid abnormality, raised blood pressure or treatment of previously diagnosed hypertension, and raised fasting plasma glucose or previously diagnosed type 2 diabetes. Metabolic Syndrome X is the most dangerous heart attack risk factor as patients with metabolic syndrome X are three times as likely to have a heart attack or stroke compared to people without the syndrome. It is imperative to diagnose and identify individuals with metabolic syndrome early, so that lifestyle interventions and treatment may prevent the development of diabetes mellitus and/or cardiovascular diseaseThe treatment for heart failure in metabolic syndrome X is multifactorial and mainly targets the different components of metabolic syndrome X: obesity, hyperglycemia, hypertension, and dyslipidemia. These components can be treated using lifestyle modifications or pharmaceutical agents.45. Lifestyle modifications like weight loss, exercise, or dietary changes can be beneficial in managing both heart failure and metabolic syndrome X. For example, aerobic exercise has been shown to have anti-hypertensive effects since it decreases systolic and diastolic blood pressure. Furthermore, it also decreases fasting blood glucose, triglycerides, and low-density protein concentrations. On the other hand, combined exercise has been shown to decrease diastolic blood pressure with minor improvements in high-density lipoprotein levels43. Moreover, a low carbohydrate, low fat, or Mediterranean diet helps improve the different components of metabolic syndrome X46. Yet, it is important to note that all of the above treatment options not only have a favorable effect on weight loss, but also on central obesity. It is essential to mention that even though obesity paradox exists, where obese and overweight patients with heart failure have a better prognosis than average weighted people with heart failure, there is little known about it. Therefore, the most acceptable and widely used therapy protocol still remains weight loss.According to current guidelines, in patients with metabolic syndrome X and heart failure, the blood pressure should be less than 130/80 mmHg, cholesterol should be less than 100 mg/dL, and glycosylated hemoglobin levels should be less than 7 percent47. For patients with insulin resistance, medications like thiazolidinediones (TZDs), alpha-glucosidase inhibitors, and sulfonylureas have been effective. Interestingly, both metformin and TZDs have been shown to reduce levels of inflammatory markers like PAI-I and hs-CRP48. This is important because according to some studies, there is a possible correlation between inflammatory cytokines, heart failure, and metabolic syndrome X18. Therefore, both of these medications may prove to be beneficial in this regard too.The pharmaceutical approach, much like lifestyle modifications, also targets the individual components of metabolic syndrome X. For hyperglycemia, the drug of choice is metformin. It is known to be a cardioprotective drug that is associated with better survival in patients with heart failure and diabetes mellitus. Moreover, it is safe to use in patients with diabetes mellitus and HFrEF, whereas insulin had a negative impact31.Angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) are the mainstay of therapy for hypertension because they are cardioprotective drugs that can be used to treat patients with HFrEF. However, it is important to recognize that inotropic calcium channel blockers are contraindicated in this patient population. Furthermore, B-blockers, hydralazine, diuretics, and amlodipine can be used to treat systolic HF45. Hence to effectively treat heart failure in metabolic syndrome X, it is crucial to target the underlying components of metabolic syndrome using either lifestyle changes or medications.For the treatment of dyslipidemia, the medication of choice is statins. Statins, like atorvastatin and simvastatin, have been associated with a reduction in HF-related hospitalizations in patients with pre-existing heart failure. But it is important to recognize that rosuvastatin, also a statin drug, has not been associated with decreasing cardiovascular events7.Clinicians have long known that there is a direct correlation between patients with metabolic X and an increased risk of cardiovascular morbidity. The counterintuitive association between obesity and a declining prevalence of heart failure still raises questions. The paradox that overweight and obese people with established heart failure had a better short- and medium-term prognosis than leaner patients was well-documented in many epidemiologic studies in large heart failure cohorts. This association and the degree of cardiorespiratory fitness were related49. Research has revealed that BMI (Body Mass Index) is ineffective at differentiating between metabolically healthy and unhealthy obesity and hence cannot be extrapolated to quantify the risk of cardiovascular morbidity50.Although sternal infections, supraventricular arrhythmias, and bleedings are more common, moderate obesity has not been demonstrated to be associated with perioperative morbidity and death51.Although there is no doubt that weight loss enhances heart structure and function and lessens heart failure symptoms, no significant research has been done on how weight loss affects clinical events in heart failure. As a result, there are no recommendations for individuals with heart failure regarding the ideal body composition52.Metabolically healthy obesity (MHO) and the "fat but fit" phenomena are terms used to describe patients who have been given an obese diagnosis based on BMI but who also have higher Cardiorespiratory fitness (CRF) and few metabolic abnormalities. Finally, we suggest that obese patients who present with an excess of body fat but no metabolic abnormalities should still be considered a population that is "at risk" and as such, they should be advised on how to change their lifestyle to improve their CRF and stop the onset of other cardiovascular disease risk factors like diabetes mellitus and impaired fasting glucose. This is known as primary preventionThe connection between heart failure and metabolic syndrome X is succinctly summarized in this study, with a focus on the pathophysiology, risk factors, diagnosis, therapy, and prognosis of the illness. It is well established that metabolic syndrome X is associated with an increased risk of cardiovascular morbidity and mortality. Therefore, the treatment of metabolic syndrome X remains to be a challenge in patients with heart failure. We have also mentioned the “obesity paradox” which explains that obesity can be a positive prognostic factor. Since it is not still well understood, the Obesity Paradox provides a gray area for future researchers as it can dramatically alter the course of treatment for heart failure in association with metabolic syndrome X.


Acute myocardialinfarction is the most common cause of CS (7-10%),3. Various conditionseventually lead to CS, most commonly valvular regurgitation, ischemic and non-ischemiccardiomyopathy, pericardial disease, and arrhythmia. The American Heart Associationemphasizes the importance of early monitoring and initial stabilization prior toinvasive management. A variety ofmechanical circulatory support (MCS) devices have been introduced with the goal ofproviding hemodynamic support and improving outcomes. The basic concept is that supportand decompression of the ventricle lead to reduced myocardial stress and consumption ofoxygen while increasing end-organ perfusion. Venoarterial extracorporeal membraneoxygenation (VA-ECMO) offers immediate circulatory support and concomitant gas exchangefor patients with left and right ventricular failure,4. Despite the recognizedadvances of VA-ECMO (Cardiogenic shock (CS) is a complex, multifactorial, and highly morbid conditionrequiring interdisciplinary expertise and state-of-the-art management. Despite advancesin therapeutic options, CS’ 30-day mortality remains high, around 40-50% in contemporaryrandomized trials. CS is caused by impaired myocardial contractility, resulting inreduced cardiac output, end-organ hypoperfusion, and hypoxia. The inability to meet thebody’s metabolic demands due to diminished cardiac output leads to insufficient tissueperfusion VA-ECMO , there a. Despiteadvances in therapeutic options for CS, the outcome and quality of life of thesepatients rely on multidisciplinary efforts, from technology and engineering of thedevice to surgical and intensive care expertise. Establishment of standardized protocolsand the shock team’s multidisciplinary cooperation and shared decision-making, includingevaluation of timing and strategy to escalate or de-escalate MCS, are the primary aimsof care.VA-ECMO offers temporary bridge-to-recovery with restoration of normal cardiac function,bridge-to-bridge with implantation of temporary VAD, or bridge-to-destination with moredurable left VAD  or cardi. In terms of VAD,the Impella CP® 5.0 and 5.5, intra-aortic balloon pump, TandemHeart®,HeartMate 3™, and Impella RP® provide possible options for these patients.Although VA-ECMO offers bridging to durable left VAD or HTx, the possibility of fullcardiac recovery must be considered with daily cardiorespiratory tests evaluating thepossibility of weaning.Institutional protocols and algorithms are fundamental to add more surveillance andimprove outcomes for these patients. In case of impossibility of left ventricularrecovery with intensification of VA-ECMO, referral to the VAD team must be considered,if the metabolic conditions are resolved and neurological assessment shows no diffuselesionsex-vivo heart perfusion are developing advances in HTx surgery thatmay allow for organ procurement from greater distances and prevention of earlytransplant failure,9. Some centers in Australia and Europe have pioneeredHTx after cardiac death in response to the critical demand for donor hearts. The optimal timing to refer thepatient for HTx remains unclear. Due to the many challenges and importance of shareddecision-making, a shock-team is essential. It is crucial to define standard protocolsand regularly educate the multidisciplinary team.If VAD therapy proves to be ineffective, it is crucial to involve the HTx team,especially when transplant requirements are met and no contraindications for HTx arise.Orthotopic HTx is an effective alternative for patients requiring long-term support.Aiming for HTx after VA-ECMO is not straightforward; it is critical that protocols andinstitutions are well-connected with a national or international organization managingorgan donation. The scarcity of donors, primary graft dysfunction, and othercomplications following transplantation are limiting factors of this procedure. At thesame time, donation after circulatory arrest, hypothermic preservation, andIn conclusion, recent developments in MCS technology have caused a paradigm shift in CScare with current consensus advocating for early use of VA-ECMO in refractory CS.VA-ECMO has progressed to the point where skilled practitioners initiate the devicewithin minutes, providing complete cardiorespiratory support. After initial diagnosis,hemodynamic stabilization of the patient is essential. The decision-making to progressto more durable devices or HTx requires interdisciplinary teamwork by means of a shockteam consisting of both HTx and VAD participants. There is a scarcity of current data ontrends, results, and exit strategies of patients undergoing VA-ECMO for CS. Numerousoptions for escalating or de-escalating MCS exist, but determining the exact timingremains a challenging and crucial task. Further studies, protocols, and definitions ofcriteria are necessary to propose algorithms for improved patient management.


This study aimed to identify time parameters predicting favourable CRT response. A total of 38 patients with ischemic cardiomyopathy, qualified for CRT implantation, were enrolled in the study. A 15% reduction in indexed end-systolic volume after 6 months was a criterion for a positive response to CRT. We evaluated QRS duration, measured from a standard ECG before and after CRT implantation and obtained from mapping with NOGA XP system (AEMM); and the delay, measured with the implanted device algorithm (DCD) and its change after 6 months (ΔDCD); and selected delay parameters between the left and right ventricles based on AEMM data. A total of 24 patients presented with a positive response to CRT versus 9 non-responders. After CRT implantation, we observed differences between responders and non-responders group in the reduction of QRS duration (31 ms vs. 16 ms), duration of paced QRS (123 ms vs. 142 ms), and the change of ΔDCDMaximum (4.9 ms vs. 0.44 ms) and ΔDCDMean (7.7 ms vs. 0.9 ms). The difference in selected parameters obtained during AEMM in both groups was related to interventricular delay (40.3 ms vs. 18.6 ms). Concerning local activation time and left ventricular activation time, we analysed the delays in individual left ventricular segments. Predominant activation delay of the posterior wall middle segment was associated with a better response to CRT. Some AEMM parameters, paced QRS time of less than 120 ms and reduction of QRS duration greater than 20 ms predict the response to CRT. ΔDCD is associated with favourable electrical and structural remodelling.Clinical trial registration: SUM No. KNW/0022/KB1/17/15. Conduction disturbances underlie the dyssynchrony of cardiac contraction and cause haemodynamic consequences that lead to unfavourable remodeling2. Cardiac resynchronization therapy (CRT) restores the desired sequence of heart contraction, improves quality of life, reduces severity of symptoms, and decreases morbidity and mortality, but in approximately 30% of patients it fails to produce the expected hemodynamic and clinical effects3. The reasons for the lack of response to CRT are still being investigated, and efforts are being made to identify predictive parameters to identify those patients who may benefit from biventricular pacing. The present study attempts to evaluate parameters that determine the distribution of electrical stimulation in the heart before and after implantation of a cardiac resynchronization system. The study also evaluates changes in some of them 6 months after implantation. Thus, this study aimed to identify the time parameters that may predict the response to CRT.Heart failure has one of the highest morbidity and mortality rates globally. It is estimated that approximately 2% of the population suffers from symptomatic heart failure, and this percentage increases with ageBetween April 2014 and July 2017, 38 patient—9 women (24%) and 29 men (76%), aged 49 to 76 years (mean age 65.6 ± SD 5.7)—with sinus rhythm, left bundle branch block (LBBB), ischemic cardiomyopathy, and with ESC class I and II indications for CRT implantation were included in the study. Participants with the following factors were excluded from the study: acute coronary syndrome less than 3 months prior to study inclusion, coronary artery disease requiring revascularization, previously implanted pacemaker or cardioverter-defibrillator, aortic valve calcification or left ventricle (LV) thrombus, chronic kidney disease, pregnancy or lactation, active neoplastic disease, viral infection, hemorrhagic diathesis, allergy to contrast solution, current participation in another study, or life expectancy less than 6 months. All methods were performed in accordance with the relevant guidelines and regulations. The investigation conforms to the principles outlined in the Declaration of Helsinki. The project was approved by the Bioethics Committee of the Medical University of Silesia and registered under number KNW/0022/KB1/17/15. All patients signed the informed consent form. All patients underwent echocardiography with Phillips iE 33 and Cx 50 devices. Anatomo-electromechanical mapping (AEMM) was performed in each patient using the NOGA XP system. Unipolar and bipolar left ventricular electrical potentials (273 ± 47 recorded and mapped points per each patient), as well as time and mechanical parameters, were recorded from each mapped point. Averaged parameter values were analysed in the LV “bull’s-eye” view in 4 basal and intermediate segments  and in 1 apical segment. The resynchronization system implantation procedure was performed in all patients with the right ventricular lead positioned in the RV apex and the left ventricular lead positioned in the target lateral or posterolateral cardiac vein, avoiding the apical region. The function of the resynchronization system was confirmed four weeks after the procedure. Echocardiography and clinical evaluation were repeated 6 months after the implantation. The excitation propagation delay parameters were analysed based on three independent measurements.The QRS duration (QRSd) and the paced QRS (QRSp) were measured from the standard ECG recording at 50 mm/s, based on the QRS duration in V1–V6 leads at baseline and after 6 months of pacing and the difference was calculated between the native QRS (QRSd) and the paced (QRSp) complexes—ΔQRS.The QRS complex time from the ECGs was obtained during NOGA electromechanical mapping (QRSn) in leads V1–V6 using individual optimal signal gain, which allowed precise detection of the QRS complex onset and termination within the isoelectric line.QRS complex measurements.The delay measured by the CRT Toolkit Auto VectSelekt Quartet™ MultiVector Test algorithm—Device Calculated Delay (DCD) between the left and right ventricles available on the Abbott Quadra Assura MP cardioverter-defibrillators used in this project is based on the measuring the beat detection delay between the right ventricular lead and individual rings of the quadripolar left ventricular lead . A test version of native beat delay detection was performed immediately after implantation and after 6 months with assessment of its change—ΔDCD.Intraventricular delay (IVd) is defined as the delay between the earliest recorded QRS excursion in V1 and the earliest left ventricular excitation recorded by the catheter within the left ventricle (LV).Left ventricular electrical activation time (LVEAT) is defined as the time between the earliest and the latest recorded potential within the left ventricle.Total activation time (TAT) is defined as the sum of the interventricular delay time and the left ventricular electrical activation time, reflecting right and left ventricular activation.Local activation time (LAT)—mean and maximum LAT values—represents the time between the earliest activation within the left ventricle and the activation of the corresponding left ventricular segment.Left and right ventricular delays were also measured using parameters obtained with the NOGA XP system (AEMM):In the statistical analysis, the Shapiro–Wilk test was used to assess normality of distribution, the Student's t-test was used for independent samples, and the U-Mann Whitney test was used to compare the groups. Weighted univariate linear regression analysis was used to assess the relationship between selected parameters, and a model based on logistic regression analysis, C statistics and ROC analysis was used in the prediction evaluation.Calculations were performed using MedCalc® statistical software version 20.106-32-bit.Forty patients were eligible for the study, 38 were enrolled, and 33 of them were analyzed Fig. .Figure 1The characteristics of the patient group is shown in Table p = 0.002). The criterion for a positive response to resynchronization therapy was a 15% improvement in LVESVi. Differences between responders (N = 24) and non-responders (N = 9) were also assessed in terms of the parameters studied and their relationship with change in LVESVi after 6 months of biventricular pacing  . There was also a correlation between the percentage of LVESVi reduction and the reduction in QRS complex duration compared to baseline ΔQRS  and after 6 months of follow-up . In ROC analysis, the cut-off criterion for QRSp was ≤ 120 ms , and for ΔQRS > 20 ms .After 6 months of biventricular pacing, a negative correlation with statistical trend was found between the percentage of LVESVi reduction and the duration of stimulated QRSp complex  and the mean delay DCDmean base (p = 0.43). After 6 months, there was a difference in both groups with a correlation between the percentage of LVESVi reduction and the studied differences in the parameters ΔDCDmax  and ΔDCDmean . These relationships are confirmed by the C statistic results: , ΔDCDmean AUC = 0.881, p < 0.001). Regarding the intraventricular delay (IVd), a correlation was found with the percentage of LVESVi reduction after 6 months of biventricular pacing . Furthermore, a correlation was found between the percentage change in LVESVi and left ventricular electrical activation time (LVEAT). In the next stage of the analysis, this parameter showed a different trends in the responder  and non-responder groups . In the LAT analysis, baseline values did not differ between responder and non-responder groups. However, these subgroups also showed an opposite relationship to the LVESVi reduction percentage after 6 months of pacing with LATmax, LATmean, LATsum values. In the next step of the analysis, LAT was evaluated in individual segments for responders and non-responders  shows a clear relationship between the duration of QRS measured during the NOGA procedure and the delay measured by the implanted device algorithm. In the study group, the values of delay measured by NOGA XP system differed between responders and non-responders, and in logistic regression analysis, they were a predictor of response to resynchronization therapy, which was confirmed by ROC analysis with a cut-off point > 34 ms. This result is consistent with the results of Engelas et al.20, indicating a value above 40 ms as the cut-off point of transseptal conduction in predicting response to CRT.The intraventricular conduction delay (IVd) described in an animal model by Strik et al.20. LVEAT prolongation is proportional to baseline left ventricular electrical impulse propagation abnormalities and left ventricular damage. At the baseline, no differences in LVEAT values were observed between responders and non-responders in the study group. In the analysis after 6 months of pacing, an inverse linear relationship was observed between LVEAT and the percentage of LVESVi reduction in the responder group. Analysis of these parameters in the non-responder group showed a different, directly proportional relationship. The behaviour of this parameter reflecting the total excitation time within all LV segments, regardless of location, from the earliest recording of an electrical potential within the LV to the latest one, was explained by the analysis of the maximum, mean, and summed values of the local activation time (LAT). There is a strong correlation between LVEAT and LATmax, as well as LVEAT and LATmean and LVEAT and LATsum. LATmax reflects the time from the earliest beat to the latest segment, whereas LATmean and LATsum reflect global abnormalities in left ventricular electrical impulse transmission. LATmax values between responders and non-responders did not differ from the LVEAT analysis, whereas LATmean and LATsum showed variation in both subgroups. The lack of variation in LATmax is caused by a different location of the segments with the greatest latency, as illustrated in the “bull’s-eye” projection in Fig. The total left ventricular activation time (LVEAT) in AEMM defines the time between the earliest and latest electrical excitation of the left ventricle. There are also noninvasive methods to measure LVEAT based on electrocardiographic recordings21 are also used to identify this area and select the target vessel. As a result, they have beneficial effects on resynchronization. An alternative method of assessing the most delayed segment is to use speckle tracking ultrasound techniques and EnsiteNavX as described by Mafi-Rad et al.23, to obtain the left ventricular lead’s optimal position LAT values of selected segments have predictive values in response to CRT.Identification of the segment with the highest LAT value and the left ventricular lead’s location in this area allows for corrections of delays and improved LV depolarization pattern. Intraoperative techniques using local activation time measured from a guidewire in potentially targeted cardiac vein with intracardiac electrocardiographic recording and the unipolar signal analysis from the guidewire presented by Rials et al.29 and hope for further development of new cardiac pacing techniques on the other.The problem of non-response to resynchronisation therapy affecting approximately 30% of patients with an implanted CRT system remains a complex issue. Claude Bernard, a French medical research physician and physiologist who was awarded the Order of the Legion of Honour, in 1865 said words reflecting the individual patient's relationship to clinical outcomes: "The response of the 'average' patient to a therapy is not necessarily the response of the individual patient standing before the clinician". The predictive parameters of a favourable response to resynchronisation therapy allow us to identify those patients in whom we can expect an improvement after CRT implantation, but does the lack of positive results in this field fully define a non-responder and entitle us to withdraw the patient from this form of therapy? Certainly, by proper qualification based on a reliable assessment of the available broad-spectrum predictive parameters, this decision can be made, especially when we have alternative methods of cardiac resynchronisation using conduction system pacing—bundle-branch pacing (HBP) and left bundle-branch pacing (LBBP) on the one handThe value of this study lay in the use of the highly accurate NOGA XP electro-mechanical mapping system, innovative in the prediction of CRT response, and in the comparison of the obtained results with all parameters available using non-invasive methods. It should be emphasized that electro-mechanical mapping was performed only for the purpose of this study. The main limitation of the study is relatively small group of patients studied: however, due to the invasive nature of the mapping, recruitment to the study was halted when statistically significant correlations occurred.The analysis of time parameters obtained by anatomo-electromechanical mapping (AEMM) can be helpful in identifying patients with a high probability of a positive response to resynchronization therapy, and the values of IVd, LVEAT and LATmean are predictive parameters of response to CRT.The greatest delay in activation of the middle segment of the posterior wall is associated with an increased rate of positive response to resynchronization therapy. In contrast, predominant delays in the basal and middle segments of the anterior wall, as well as in the basal segments of the lateral wall and the septum, are associated with a risk of no response to resynchronization therapy.Stimulated QRS complex time less than 120 ms and a reduction in baseline QRS complex time greater than 20 ms are predictive factors of response to resynchronization therapy. In our prediction model, the value of the reduction in the baseline QRS duration is an independent predictor of positive response to resynchronization therapy among electrocardiographic parameters.Measurements of the delay between right and left ventricular using DCD by the CRT Toolkit Auto VectSelekt MultiVector Test algorithm allow optimal selection of the area with the greatest delay, and changes in the values of these parameters reflect favourable electrical and structural remodeling.


Editorial on the Research TopicMalignant arrhythmias and trigger mechanismsDear readers of this special edition, dear colleagues,Approximately 50% of all events leading to sudden cardiac death worldwide are caused by malignant ventricular arrhythmias, thus depicting a relevant clinical problem to focus on. It was and still is of fundamental importance to grasp and comprehend the respective underlying substrates and mechanisms to develop therapeutic strategies to act against this menace and to enhance our options to avoid patients to endure the consequences of potentially lethal rhythm disturbances. It has taken immense efforts to reach the previously known extent.Where do we come from?The pioneers of clinical electrophysiology laid the pivotal foundations to comprehend extra- and intracardiac appearances of ventricular arrhythmias. Some of these outstanding scientists should be mentioned in this context as pars pro toto. By extensive evaluation, description and interpretation of surface ECG recordings of broad complex tachycardias by Henrick (Hein) Joan Jost Wellens (“Do not panic when confronted with a broad QRS tachycardia. Obtain a 12-lead ECG.”)  in a myocardial infarction canine model, demonstrating that VFT can be increased by rapid median nerve stimulation.Diagnostic and therapeutic algorithms in modern ICDs are designed to detect ventricular arrhythmias precisely as such and apply suitable therapies. Sometimes complex arrhythmias meet sophisticated programmed criteria, leading to conflicts that may result in therapy withhold. You find a respective case report of a patient with short-long-short-sequences and an inhibition of antitachycardiac therapy due to a program feature dealing with VT onset.Ablation therapy is not only an option to cure patients from (monomorphic) ventricular tachycardia. The electrical storm represents an absolutely life threatening ventricular arrhythmia. You are presented an analysis of 160 consecutive patients that underwent a ventricular substrate modulation, proving that this ablative strategy is feasible, safe and effective targeting electrical storm.A seldom, but most challenging clinical situation consists in the occurrence of electrical storm in patients with Brugada syndrome. Treatment procedures are not heterogeneous. Medical therapy (prophylactic as well as emergency drug applications), ICD-implantation and ablation procedures are under investigation and were compiled in an article regarding the management of this particular combination.Meanwhile, Purkinje fibers could be recognized as potential origin of initiation and maintenance of ventricular fibrillation, specifically in patients without endocardiac substrates. Innovative high density mapping tools allow to identify triggers precisely, so that ablative purkinje de-networking could be applied, turning out to be safe, feasible and effective for arrhythmia suppression.We hope you enjoy reading our special edition, assess it as interesting and inspiring, and we wish that you gain detailed information and additional knowledge concerning the topics covered in the individual articles.Kindest regardsReinhard Höltgen, Harilaos Bogossian and Dirk Bandorski


Diabetes mellitus (DM) has been documented among the strongest risk factors for developing heart failure with preserved ejection fraction (HFpEF). The earliest imaging changes in patients with DM are the left atrial (LA) functional and volumetric changes. The aim of this study was to determine the correlation between epicardial fat thickness (EFT) and longitudinal LA reservoir strain (LARS) in patients with type 2 DM (T2DM), as compared with non-diabetic controls.2) in comparison with the non-diabetic ones . On the other hand, a direct association was observed between EFT and the E/e′ ratio, and an inverse correlation was established between EFT and LARS in patients with T2DM . However, regression analysis showed only LV mass index (LVMI) , LAVI , and EFT  were independently correlated with LARS.The study samples in this case-control study comprised of consecutive patients with T2DM (n=64) and matched non-diabetic controls (n=30). An echocardiography was performed on all patients and EFT, volumetric and longitudinal LARS, left ventricular (LV) global longitudinal strain (LVGLS), pulsed-wave Doppler-derived transmitral early (E wave) and late (A wave) diastolic velocities, and tissue-Doppler-derived mitral annular early diastolic (e′) and peak systolic (s') velocities were obtained. The study results demonstrated that the patients with T2DM had thicker EFT (5.96±2.13 vs. 4.10±3.11 mm) and increased LA volume index (LAVI) (43.05± 44.40 vs. 29.10±11.34 ml/mLARS is considered as an important early marker of subclinical cardiac dysfunction. Thickened epicardial fat may be an independent risk factor for decreased LA reservoir strain. Diabetics are especially considered as a high risk group due to having an increased epicardial adipose tissue thickness. Diabetes mellitus (DM) has been documented among the strongest risk factors for developing heart failure with preserved ejection fraction (HFpEF), a sub-type of heart failure (HF), which represents almost half of the total number of patients with symptomatic HF . AdditioThis study was a case-control study including 64 consecutive patients with T2DM with a left ventricular ejection fraction (LVEF) ≥50% and 30 matched non-diabetic controls, who were hospitalized in our hospital due to evidence of ischemia on non-invasive studies and had no apparent CAD on angiogram between 2021 and 2022. This study was conducted according to the Declaration of Helsinki (DoH) ethical principles, and was further approved by the Ethics Committee of Mazandaran University of Medical Sciences, Sari, Iran (ethics code no. IR.MAZUMS.REC.1400.628). All participants also signed an informed consent form. The patients with significant CAD, HF, severe valvular heart disease, valve replacement, an LVEF<50%, left bundle branch block, atrial flutter or fibrillation, cardiomyopathies, neoplastic illnesses, decreased glomerular filtration rate or serum creatinine ≥1.5 mg/dl, and different systemic diseases were excluded from the study. The serum levels of fasting blood sugar (FBS), cholesterol (Chol), triglyceride (TG), low-density lipoprotein (LDL), and hemoglobin A1c (HbA1c) were determined by the blood sample taken after a 10–12 h overnight fasting. Moreover, 2 h post-prandial serum BS was determined by the blood sample acquired 2 h after eating a meal. The ion exchange chromatography method  was used for determining HbA1c level. Body mass index (BMI) was explained as weight in kg divided by height in meters squared. DM was defined according to the guidelines of the American Diabetes Association (ADA), including FBS ≥126 mg/dl 7.0 mmol/L) or 2 h plasma BS during 75 g oral glucose tolerance test (OGTT) ≥200 mg/dl (11.1 mmol/L), or HbA1c ≥6.5% (48 mmol/mol), and included individuals who require to take insulin or oral hypoglycemic medications .0 mmol/L.A transthoracic echocardiography was performed for all patients by the ACUSON SC2000 with a 4V1c transducer  within 24–48 h after hospitalization. All movies and images were stored on a hard disk for further off-line analysis (using the eSie VVI software) by an expert echocardiographer blinded to the patients’data. Epicardial fat was identified as an echo-dense space between the outer wall of the myocardium and the visceral pericardium, anterior to the right ventricular wall in the parasternal long axis view. The point of measurement was vertical to the aortic annulus, and its thickness was measured at the end-systole in an average of three cardiac cycles   grayscale movies were acquired in the apical four-, two-, and three-chamber views  in three cardiac cycles. The peak longitudinal strain values from the basal, mid, and apical segments of the inferoseptal, anterolateral, inferior, anterior, inferolateral, and anteroseptal walls were measured by the tracking of the endocardial and epicardial walls. To identify the LV peak global longitudinal strain (LVGLS), the average value of all 18 myocardial segments was considered . The LA D grayscaIn which, LVIDd, PWT, and SWT indicate the end-diastolic LV internal dimension and posterior and IVS wall thickness, respectively. We also obtained peak velocity of tricuspid regurgitation jet by continuous-Doppler from multiple views . The repThe categorical variables were presented as frequency and percentage. The quantitative variables were expressed as the mean± standard deviation  or median [lower-upper quartile] . Normality was determined by the Shapiro-Wilk test. An independent t-test was used to compare the continuous variables that were normally distributed and the Mann-Whitney U test was used to compare the continuous variables that were non-normally distributed. The categorical variables were compared by Chi-square test and Fisher’s exact test. Moreover, we used a Pearson correlation to find the correlation between different echocardiographic variables in the patients with T2DM and the non-diabetic ones, separately. Multiple linear regression analysis was also conducted on all study population, including the patients with T2DM and the non-diabetic controls to determine the independent correlation between different demographic, laboratory-based, and echocardiographic variables and LARS/-LVGLS. The statistical analyses were performed by the SPSS/PASW  Statistics version 18 . The P value of less than 0.05 signified that the variable was significant. The sample size was determined based on the findings of Evin et al study [2. In total, 71 patients (75.5%) were female, and 23 individuals (24.5%) were male. Moreover, 47 patients (50%) had HLP, 46 people (48.9%) were hypertensive, and 19 individuals (20.2%) were smokers. The demographic variables of the study population are presented in Table This study included 64 patients with T2DM and 30 non-diabetic controls, matched in terms of age and gender, with an LVEF ≥50% and no apparent CAD on angiogram. The mean age of the study population was 55.03±9.86 and their mean BMI was 28.14±3.77 kg/m<23% had worse New York Heart Association (NYHA) functional class and higher pulmonary capillary wedge pressure (PCWP) in comparison with those with a higher value [LAVI represents the long-standing effects of increased LV filling pressures . LARS iser value . LA alsoer value . Previouer value . For thier value . Its thier value . Elevateer value . The corer value .In 2018, Zhao et al conducted a prospective study on 130 people without CAD or atrial fibrillation. Indexed epicardial adipose tissue (EAT) volume was determined by cardiac computed tomography (CT). As well, three-dimensional (3D) volumetric measurements and 2D speckle-tracking echocardiography were performed. The study population were then divided into two groups of large and small EAT volume index. The individuals with larger EAT volume index had significantly impaired LAEF and longitudinal LARS. The total EAT volume index could be thus a predictor of impaired longitudinal LARS and reduced LAEF. They concluded that there was an independent association between EAT volume index and subclinical LA dysfunction . Their fMitral annular motion plays an important role in regulating blood movement in and out of LA. During systole, the mitral annulus descends and transfers more apically. These descending motions can further accelerate LV ejection. In addition, this motion can enlarge LA and increase its compliance, accompanied by a drop in LA pressure and a rise in the pulmonary blood flow during atrial reservoir phase . DelayedDuring the rapid filling phase, LV is relaxed and mitral annulus ascends and gets away from the apex. The resultant drop in the LV pressure then opens the mitral valve and intensifies ventricular filling  . PreviouLARS is considered as an important early marker of subclinical cardiac dysfunction. Thickened epicardial fat may be an independent risk factor for decreased LA reservoir strain. Diabetics are especially considered as a high risk group due to having an increased epicardial adipose tissue thickness.There were some limitations in this study, including the small sample size recruited in a single center. As well, the echocardiography, which is a relatively inexpensive and easily accessible modality, was used to determine EFT. However, measurement of the EFT volume by the CT scan and MRI techniques could lead to more accurate results. Moreover, LA volume and reservoir strain, but not the other components of LA function, were measured in this study. On the other hand, information on patient therapy, time since diabetes diagnosis, and creatinine values were not included for data analysis. In spite of this, the HbA1c level that could be correlated with the mean BS concentration over the past three months was included in this study.