Left Ventricular Internal Diameter Research Articles

Overexpression of triadin in adipose tissue causes cardiac dysfunction

Abstract Introduction As a member of the protein complex that regulates the ryanodine receptor (RyR) , triadin plays a critical role in intracellular calcium homeostasis. Our previous results demonstrate that the NAD-dependent deacetylase sirtuin-1 (SIRT1) downregulates the expression of triadin isoform Trisk 51 in adipose tissue. A transgenic mouse model with adipose tissue selective overexpression of Trisk 51 (Adipo-TRDN) was established. Aim The present study is designed to investigate the role of SIRT1-triadin signalling in the development of dilated cardiomyopathy/heart failure with reduced ejection fraction. Methods Wild type (WT) littermates, Adipo-TRDN without or with human SIRT1 overexpressed in adipose tissue (Adipo-TRDN/SIRT1) were used for this study. All mice were provided with standard chow diet, normal drinking water and kept in a 12/12 light-dark cycle. Echocardiography was performed in 30 weeks old male mice using Visual Sonics Vevo 2100 Imaging System to measure systolic and diastolic function using B-mode, M-mode, Color Doppler and Tissue Doppler parameters. Results Systolic cardiac impairment was present in the Adipo-TRDN mice compared with their littermate controls. Left ventricular internal diameter during systole (LVID, s) was increased in Adipo-TRDN compared with WT littermates (3.0031 vs. 2.1878 mm, p-value: 0.0059). Changes in the Left ventricular anterior wall thickness (LVAW) during systole and diastole were found to be non-significant (1.6180 vs. 1.3530 mm, 1.1443 vs. 1.0455mm). Although fractional shortening (FS %) differences were non-significant (27.64% vs. 34.83%), there was a significant reduction in ejection fraction (EF %) in Adipo-TRDN mice compared with their WT controls (49.41% vs. 64.73%, p-value: 0.0472). No differences were found in the Left ventricular mass (LV) (106.80 vs.84.10 mg). Left ventricular volume during systole (LV Vol; s) was also significantly enhanced in Adipo-TRDN compared with their WT controls (35.25 vs.16.30 μL, p-value: 0.0047). Overexpression of human SIRT1 lead to partial improvement in the pathogenesis of dilated cardiomyopathy in Adipo-TRDN mice. Ejection fraction and fractional shortening were both increased in the Adipo-TRDN/SIRT1 compared with Adipo-TRDN mice (70.70% vs. 49.41%, p-value: 0.0017, 39.60% vs. 27.64% p-value: 0.0151). LV mass and LV Vol;s were reduced in the Adipo-TRDN/SIRT1 compared with Adipo-TRDN mice (75.83 vs. 106.80 mg, p-value: 0.0543) (14.02 vs. 35.25 μL, p-value: 0.0005). LVID (s), LVAW (d) and LVAW (s) were also reduced in Adipo-TRDN/SIRT1 compared with Adipo- TRDN mice (2.1641 vs. 3.0031mm, p-value: 0.0041, 0.8728 vs. 1.1443, p-value: 0.0319, 1.2369 vs. 1.6180mm, p-value: 0.0018). Conclusion Development of dilated cardiomyopathy induced by adipocyte specific overexpression of Triadin is partially prevented by adipose SIRT1.

Deep learning in echocardiography: real-time measurements of left ventricular wall thickness and chamber dimensions in the parasternal long-axis view

Abstract Background Accurate measurements of left ventricular (LV) wall thickness and chamber dimensions in the parasternal long-axis view (PLAX) are essential in the standard echocardiographic examination. Manual assessments introduce variability, and conducting the numerous measurements required for a comprehensive echocardiographic assessment is time-consuming. Therefore, there is potential for improving workflow. Purpose To develop a novel deep learning (DL)-based method for fully automated, real-time measurements of LV wall thickness and chamber dimensions while scanning the patient, and to validate its performance in an unselected prospective cohort. Methods PLAX recordings from 207 subjects were annotated to train DL networks for cardiac segmentation, timing of end-systole and end-diastole, measurements of LV wall thickness and chamber dimensions. The application presents results from three consecutive cardiac cycles in real-time to the operator for review (Figure 1). Agreement and correlation with reference measurements were evaluated, and the combined acquisition and measurement times for both the novel- and reference methods were recorded. Results Feasibility for real-time measurements in PLAX was 98%, with one patient excluded due to poor acoustic window. Agreement with reference measurements was good for interventricular septal diameter (IVSd) (bias - 0.7 mm, limits of agreement (LoA) -4.38 to 2.94 mm), posterior wall thickness (PWd) (bias 0.8 mm, LoA -2.32 to 3.84 mm) and left ventricular internal diastolic diameter (LVIDd) (bias 0.0 mm, LoA -7.0 to 6.9 mm, Figure 2A). Strong correlations were found for IVSd (R=0.84), PWd (R=0.66) and LVIDd (R=0.85), all significant (p <0.001). The average time for acquiring PLAX images was 53 ± 22 seconds, with an additional 42 ± 11 seconds for reference analysis, totaling 94 ± 27 seconds to complete reference PLAX measurements. In contrast, the real-time application took only 59 ± 34 seconds to obtain the same measurements (Figure 2B), resulting in a mean time reduction of 36 seconds (95% CI 24-47 seconds). Conclusion This novel DL-based method for fully automated, real-time analysis of key metrics in PLAX is time-efficient, feasible, and yields measurements in good agreement with manual reference. This method has the potential to substantially improve efficiency and precision of PLAX assessment in clinical practice.

Cardiac dilation, energy stress and ventricular remodeling: insights from prolonged voluntary exercise in male mice with TAC-induced HFpEF.

Exercise in heart failure with preserved ejection fraction (HFpEF) remains a hot topic, although current treatment strategies have not been shown to improve the long-term prognosis of HFpEF. Previous studies have mostly focused on the roles of endurance training, the mechanisms underlying long-term voluntary exercise have not been elucidated. The purpose of the present analysis was to evaluate alterations in cardiac function in HFpEF mice (HFpEF-Sed) after 6 weeks of voluntary running (HFpEF-Ex), investigate mechanisms, and compare the effects with fluoxetine (HFpEF-FLX). We found that voluntary exercise, instead of fluoxetine intervention, significantly improved left ventricular end-diastolic internal diameter (LVIDd) and the rate of change in anterior wall thickness (ATW) in HFpEF mice. The exercise capacity of HFpEF-Sed mice was significantly reduced, but prolonged voluntary running significantly reversed the expression of myocardial BNP, TNF-α, and IL-6, α-MHC, and β-MHC in HFpEF-Sed mice, along with myocardial fiber disorders accompanied by massive inflammatory cell infiltrates. Importantly, myocardial Complex III and Complex V, Mfn2, Drp1, p62, and LC3 II/I expression in HFpEF-Sed mice were all significantly different from those of normal mice, whereas voluntary exercise significantly reversed these expressions. These findings strongly suggest that long-term voluntary exercise is effective in avoiding acute and chronic energy stress in HFpEF-Sed mice, which is consistent with the mechanism of current first-line treatment for HFpEF. This notion was further supported by electron microscopy results, which showed no pathological features in cardiomyocyte mitochondrial morphology after prolonged voluntary exercise. Additionally, fluoxetine was found to inhibit depressive-like behavior in HFpEF mice.

The improvement effects of TAVR on cardiac electrical remodeling of patients with severe aortic stenosis

Objectives: To assess the effectiveness of transcatheter aortic valve replacement (TAVR) on electrocardiographic remodeling in patients with severe aortic stenosis (AS), and identify its influencing factors. Methods: A cohort study was conducted on patients with a confirmed diagnosis of severe AS who successfully underwent TAVR at the Second Affiliated Hospital of Dalian Medical University between June 2018 and March 2023. Data, including standard 15-lead electrocardiograms and echocardiograms, were collected before the operation, 1 week after the operation, and 3 months after the operation. The average degree of ST-segment depression in the lateral wall leads of the electrocardiograms, and the amplitude of the T-wave were measured and calculated. The changes of electrocardiograms indexes were observed, and Spearman correlation analysis was used to explore the correlation between each index of electrocardiograms and each index of echocardiography. Multiple linear regression analysis was used to determine the influencing factors of the improvement of electrocardiographic remodeling in patients with severe AS after TAVR. Results: A total of 33 patients with severe AS, aged (73±9) years, were included in the study. Among them there were 15 (45%) males. The degree of ST-segment depression, supra-aortic flow velocity, peak transaortic pressure, and mean transaortic pressure exhibited significant improvement at 1 week post-TAVR (all P<0.05). Similarly, significant improvements in T-wave hypoplasia or inversion, left ventricular mass, and left ventricular mass index were observed at 3 months post-TAVR (all P<0.05). The degree of ST-segment depression was found to be correlated with supra-aortic flow velocity, peak transaortic pressure, and mean transaortic pressure (all P<0.05). Additionally, a correlation was observed between T-wave amplitude and left ventricular mass, left ventricular mass index, left ventricular end-diastolic internal diameter, and left ventricular ejection fraction (all P<0.05). Multiple linear regression analysis revealed that supra-aortic flow velocity was an independent influencing factor of the level of ST-segment depression (β=-0.156, P=0.007), while left ventricular mass index was identified as an independent influencing factor of T-wave amplitude (β=-2.007, P=0.001). Conclusion: The improvement in electrocardiographic remodeling could be observed after TAVR in patients with severe AS, which may be due to enhanced cardiac perfusion and regression of left ventricular hypertrophy subsequent to aortic valve opening.

Cardiac function and coronary plaque development following masculinizing gender-affirming hormone therapy: A prospective cohort study.

Myocardial dysfunction and the presence of calcified and non-calcified coronary plaques are predictors of cardiovascular disease. Masculinizing gender-affirming hormone therapy may increase cardiovascular risk, highlighting the need for prospective studies to evaluate cardiovascular outcomes during gender-affirming hormone therapy. To evaluate changes in cardiac morphology, systolic and diastolic function, and development of coronary plaques after masculinizing gender-affirming hormone therapy. Prospective study including 47 transmasculine persons (gender-affirming hormone therapy-naïve, TransM_TN, n=15 and gender-affirming hormone therapy-ongoing, TransM_TO, n=32). Included persons were evaluated at study inclusion and after one year of masculinizing gender-affirming hormone therapy. At baseline, the median age of TransM_TN was 22 years (interquartile range 19-28 years) and TransM_TO 26 years (interquartile range 24-37 years) with a median gender-affirming hormone therapy duration of 4 years (interquartile range 2-5 years). Cardiac morphology including left ventricular wall thickness, volume, and mass, as well as left ventricular systolic and diastolic function was evaluated using echocardiography. Coronary artery calcifications and non-calcified coronary plaque were assessed using coronary computed tomography angiography. Paired and unpaired statistical analyses were performed within and between TransM_TN and TransM_TO groups. In TransM_TN, diastolic function decreased during follow-up with decreased septal and lateral left ventricular relaxation (14-11cm/s, p=0.04 and 18-15cm/s, p=0.02, respectively). No significant changes were observed in cardiac morphology, systolic function, or formation of coronary artery calcifications and non-calcified coronary plaque in TransM_TN or TransM_TO groups. At baseline, left ventricular end-diastolic internal diameter was significantly higher in TransM_TO compared to TransM_TN, 4.6cm (interquartile range 4.3-5.0cm) versus 4.4cm (interquartile range 4.2-4.6cm), p<0.05. Other baseline cardiac outcomes were comparable between TransM_TN and TransM_TO. Diastolic function declined after the initiation of masculinizing gender-affirming hormone therapy and individuals on long-term masculinizing gender-affirming hormone therapy had larger left ventricular dimensions compared to individuals before gender-affirming hormone therapy initiation. Cardiac morphology, systolic function, and coronary plaque formation remained stable during masculinizing gender-affirming hormone therapy.

Small Extracellular Vesicles from Young Healthy Human Plasma Inhibit Cardiac Fibrosis After Myocardial Infarction via miR-664a-3p Targeting SMAD4.

Cardiac fibrosis, a key contributor to ventricular pathologic remodeling and heart failure, currently lacks effective therapeutic approaches. Small extracellular vesicles from young healthy human plasma (Young-sEVs) were characterized via protein marker, transmission electron microscopy, and nanoparticle tracking analysis, then applied in cellular models and mouse models of cardiac fibrosis. Western blotting and qRT-PCR were used to identify protective signaling pathways in cardiac fibroblasts (CFs). Young-sEVs significantly inhibited cardiac fibrosis and subsequent cardiac dysfunction post-myocardial infarction (MI) in mice. The main findings included that echocardiographic assessments four weeks post-MI indicated that Young-sEVs improved left ventricular ejection fraction (LVEF) and fractional shortening (LVFS), and reduced left ventricular internal diameter in diastole (LVIDd) and systole (LVIDs). Treatment with Young-sEVs also decreased Masson-positive fibroblast areas and collagen synthesis in cardiac tissue. However, sEVs from the old control group did not achieve the above effect. Consistent with in vivo results, Young-sEVs could also inhibit the proliferation, migration, and collagen synthesis of CFs in the TGF-β1-induced cellular fibrosis model. High-throughput microRNA (miRNA) sequencing and qRT-PCR analysis revealed that miR-664a-3p was abundant in Young-sEVs. The high expression of miR-664a-3p significantly inhibited the proliferation, migration, and collagen synthesis of TGF-β1-induced CFs. However, suppressing the expression of miR-664a-3p in Young-sEVs eliminated their therapeutic effect on cardiac fibrosis in mice. Further studies confirmed SMAD4 as a direct downstream target of miR-664a-3p, whose overexpression could reverse the anti-fibrotic effects of miR-664a-3p. In summary, these findings firstly revealed that Young-sEVs could directly bind to the 3'-untranslated region of SMAD4 mRNA through miR-664a-3p, thereby inhibiting the TGF-β/SMAD4 signaling pathway to protect heart from fibrosis and improve cardiac function. Considering the ease of obtaining plasma-derived sEVs, our study offers a promising therapeutic strategy for heart failure, with the potential for rapid clinical translation in the near future.

Pericardial Abnormalities Seen on Echocardiography in The Jos University Teaching Hospital

Introduction: A 2-D Echocardiographic manifestations of pericardial disease that are not mutually exclusive were pericardial effusion or pericardial thickening. A significant number of pericardial disease cases however are without this classical features. Methodology: In a retrospective review of pericardial echocardiography in a teaching Hospital compare the two pericardial disease syndromes. Comparism in terms of cor-morbidity and cardiac functions were carried out. Both subjective and objective assessment of echo parameters were considered for analysis. Results: A 1414retrospective records were reviewed and 169 (10%) were seen to have either pericardial effusion 91 (5.6%), thickening 78 (4.8%) or both 6 (0.3%). There was a slight female dominance and lower mean age compared to those without echo pericardial disease findings. Pericardial effusive subjectively were seen to be associated with more cor-morbidities and complications and objectively had echo parameters indicating poor cardiac functional state. Aorta, left atrium, left ventricular internal diameter in diastole and E/A ratio were statistically different. Conclusions: Routine echocardiography assessing pericardial diseases was observer dependent and pericardial effusion had a less favourable outcome than thickened pericardium.

A Novel Preclinical Murine Model of Systemic Lupus Erythematosus-Like Cardiovascular Disease.

Systemic lupus erythematosus (SLE) affects nine women to every man worldwide, and these patients are at greater risk for cardiovascular disease (CVD) morbidity and mortality. Clinical studies have demonstrated that patients with SLE are more likely to develop CVD, including cardiac and vascular dysfunction. Although many preclinical models of SLE are available, including treatment with Toll-like receptor (TLR) 7/8 agonists, a consistent preclinical model of SLE-like CVD with systemic, cardiac, renal, and cerebral endothelial activation and cardiac dysfunction has yet to be described. Here, we hypothesize that acceleration of SLE with the TLR7/8 agonist resiquimod (R848) will promote cardiac and endothelial activation with subsequent end-stage organ damage in the SLE-prone B6.Nba2 mouse model. Female and male SLE-prone B6.Nba2 mice were treated with R848 or acetone, administered topically twice weekly over a four-week period, to accelerate the development of SLE-like pathophysiology. Echocardiography was performed at baseline, 4 weeks, and 16 weeks. At 16 weeks, tissues were harvested, weighed, and analyzed by histology, immunofluorescence, real-time quantitative polymerase chain reaction, and enzyme-linked immunosorbent assays. We found that female R848-treated mice had increased serum anti-Smith and immunoglobulin G complex deposition in the kidney, heart, and brain consistent with SLE-like etiology. Tissue analysis revealed significant enlargement of the spleen in both female and male R848-treated mice, with only cardiac and renal enlargement in females compared to their respective controls. Echocardiographic imaging revealed left ventricular wall thickening by 4 weeks that was followed by a progressive increase in left ventricular internal diameters and subsequent decrease in ejection fraction over the 16-week time course in female mice. We found that circulating levels of soluble vascular adhesion molecule-1 and soluble intracellular adhesion molecule-1 were increased in both female and male R848-treated mice, whereas cardiac and renal fibrosis were significantly increased in only female R848-treated mice. Our data demonstrate that R848 treatment of SLE-prone B6.Nba2 mice is a novel preclinical model to study the sex-dependent pathophysiologic mechanisms of SLE-like CVD.

EVALUATION OF THE RELATIONSHIP BETWEEN IRON LOAD, AGE, AND CARDIAC FUNCTION IN CHILDREN AND YOUNG ADULTS WITH THALASSEMIA MAJOR: A PULSED-WAVE DOPPLER AND TISSUE DOPPLER IMAGING STUDY

Objective: To determine the structural and functional cardiac differences in children and young adults with thalassemia major (TM) compared to healthy subjects using pulsed-wave Doppler and tissue Doppler imaging methods and determine the relationship between iron overload and these differences. Materials and Methods: We analyzed the data of pediatric and young adult TM patients (n = 44) aged 4–22 years and an age- and gender-matched control group (n = 40) in our hospital data system between Oct.01.2023 and Oct.01.2024. Height, weight, body mass index (BMI), systolic–diastolic blood pressure measurements, complete blood count, ferritin, cardiac T2* magnetic resonance imaging (MRI) values, and echocardiography results were recorded. In addition to comparisons between the two groups, correlation analysis was performed between ferritin–cardiac T2* MRI results and echocardiographic parameters and age in TM patients. Results: Our study showed growth retardation (low height standard deviation score (SDS), low weight SDS and low BMI SDS), dilatation of the left cavities (high left ventricular internal diameter end diastole (LVIDd)), increased left ventricular muscle mass (high left ventricular mass index (LVMI)), cardiac distinctive diastolic (restrictive pattern: left ventricular (LV) peak early diastolic flow (E)/peak late diastolic flow (A) and E/early diastolic myocardial peak flow (E') high), and subclinical systolic (LV peak systolic flow low and LV Tei index high) dysfunction. In addition, iron load (ferritin and cardiac T2* MRI) was correlated with LVMI, and cardiac diastolic and systolic function indicators. As age increased, ferritin value did not change, but cardiac T2* MRI value decreased and diastolic–systolic parameters worsened. Conclusion: Periodic cardiac T2* MRI and Doppler echocardiography examinations of patients with TM may detect subclinical myocardial dysfunction at an early stage, thus providing a window of opportunity for intervention.

Ershen Zhenwu Decoction Suppresses Myocardial Fibrosis of Chronic Heart Failure with Heart–Kidney Yang Deficiency by Down-Regulating the Ras Homolog Gene Family Member A/Rho-Associated Coiled-Coil Kinases Signaling Pathway

Ethnopharmacological significanceThe therapeutic efficacy of Ershen Zhenwu Decoction (ESZWD)—a famous formulation from Xin’an for patients with chronic heart failure heart–kidney Yang deficiency (CHF-HKYD)—is well established. Still, the underlying molecular mechanism is not clear. Aim of the studyThis study investigated mechanisms by which ESZWD suppresses cardiac pathology, including myocardial fibrosis, in CHF-HKYD model rats and Ang II-stimulated cardiac fibroblasts (CFs). Materials and methodsThe components in ESZWD were analyzed by ultra-high-performance liquid chromatography coupled with Quadrupole Time-Of-Flight mass spectrometry (UHPLC-Q-TOF-MS). CHF-HKYD model was established in the male Sprague–Dawley rats through bilateral thyroidectomy and intraperitoneal administration of 0.02% doxorubicin (DOX), twice weekly for 3 weeks. Subsequently, the CHF-HKYD model rats were randomly categorized into the Model, ESZWD-L (3.96 g/kg/d ESZWD), ESZWD-M (7.92 g/kg/d ESZWD), ESZWD-H (15.84 g/kg/d ESZWD), and Sac/Val (68 mg/kg/d sacubitril/valsartan) groups and treated daily for 4 weeks. As a control, the sham surgery group (Sham) was used. Primary cardiac fibroblasts (CFs) were categorized into Control, Model, ESZWD, and Sac/Val groups. Then, the CFs were stimulated with Ang-II. The ESZWD and Sac/Val groups were incubated with different concentrations of drug-containing sera and their effects on CF viability were assessed via the CCK-8 assay. The ESZWD and Sac/Val groups received drug-containing serum concentrations determined by CCK-8 assay results. The cardioprotective effects of ESZWD were determined using echocardiography, Hematoxylin & Eosin (H&E) staining, Masson staining, and Sirius red staining, and the Enzyme Linked Immunosorbent Assay (ELISA). ESZWD's effects on the Ras Homolog Gene Family Member A (RhoA) / Rho-Associated Coiled-Coil Kinases (ROCKs) signaling pathway and myocardial fibrosis were assessed by Western blotting and Quantitative Real-Time PCR (qRT-PCR) analyses. Immunofluorescence was used to observe fibrotic markers in CFs. ResultsESZWD treatment improved cardiac function in the CHF-HKYD rats by significantly reducing myocardial fibrosis and ventricular remodeling. ESZWD treatment increased the rats' body temperature (Tb) and 24-hour urine volume, left ventricular ejection fraction (LVEF) and LV fractional shortening (LVFS), and decreased LV internal systolic diameter (LVIDs), LV internal diastolic diameter (LVIDd), and heart weight/ body weight (HW/BW) compared to the Model group. In comparison to the model rats, ESZWD treatment decreased serum levels of B-type natriuretic peptide precursor (NT-proBNP), tumor necrosis factor-alpha (TNF-α), interleukin-11 (IL-11), and IL-17A. ESZWD treatment significantly down-regulated the protein and mRNA expression levels of collagen I A1, α-SMA, RhoA, ROCK1, and ROCK2 in the heart tissues of the CHF-HKYD rats and the Ang II-stimulated CFs. ConclusionESZWD significantly improved cardiac function and attenuated myocardial fibrosis and inflammation in the CHF-HKYD rats by inhibiting the RhoA/ROCKs signaling pathway.

Atherosclerotic renal artery stenosis, mediating biomarkers, and risk of cardiac among individuals with hypertension: A real-world study

BackgroundAtherosclerotic renal artery stenosis (ARAS) is commonly associated with cardiovascular diseases(CVD). Patients with ARAS typically present with cardiac structural and functional abnormalities, and the differences in cardiac structure and function compared to hypertensive patients without ARAS remain to be explored. MethodsA total of 499 hypertensive patients were included, of whom 134 had ARAS and 365 had no renal artery stenosis (RAS). Parameters about cardiac function and structure detected by echocardiography and other clinical data are collected. Univariate and multivariate binary logistic regression and mediation analysis were performed on the collected data. ResultsCompared to hypertensive patients without ARAS, those with ARAS had significantly increased left ventricular (LV) internal diameter (LVIDd), posterior wall thickness (PWTd), LV geometric abnormalities, diastolic dysfunction, and a higher prevalence of LV hypertrophy (LVH). After adjustment, ARAS was significantly associated with LV diastolic dysfunction (LVDF) (OR = 1.12, 95 %CI = 1.03–1.3), LVIDd (OR = 1.07, 95 %CI = 1.02–1.13), LV geometry (OR = 1.24, 95 %CI = 1.12–1.36), PWTd (OR = 1.2, 95 %CI = 1.09–1.31), and LV mass index (OR = 1.31, 95 %CI = 1.18–1.47). Mediation analysis identified hypersensitive C-reactive protein (Hs-CRP) and serum creatinine (Scr) as significant mediators, accounting for 10.80 % to 59.54 % of the ARAS impact on LV abnormalities. ConclusionARAS appears to be an independent risk factor for abnormalities in cardiac function and structure, potentially mediated by Hs-CRP and Scr. Hypertensive patients with ARAS demonstrate a higher prevalence of left ventricular hypertrophy (LVH) and diastolic dysfunction, underscoring the importance of vigilant monitoring in this population.

Abstract 4125252: Pre-Hematopoietic Stem Cell Transplantation Echocardiographic Indices and Post-Transplant Cardiovascular Outcomes

Introduction: Hematopoietic stem cell transplantation (HSCT) is associated with adverse cardiovascular (CV) events including the development of heart failure (HF) and arrythmias. While transthoracic echocardiogram (TTE) is routinely obtained prior to HSCT, its role in predicting the incidence of HSCT related CV events is poorly understood. Methods: We used data from the Cardiovascular Registry in Bone Marrow Transplantation (CARE-BMT) study, a multicenter observational study of adult patients (aged ≥18 years) who underwent autologous/allogeneic HSCT for malignant or nonmalignant bone marrow disorders at the University of Michigan Health System (UMHS) and Rush University Medical Center from 2008-2019. In this analysis, we included patients from UMHS with a baseline TTE. Data on pre-HSCT TTE parameters and post-HSCT CV outcomes were collected through manual chart review. Left ventricular (LV) function and dimensions were categorized into normal, mildly abnormal, and moderately/severely abnormal based on American Society of Echocardiography guidelines. The primary outcomes were new-onset HF and atrial fibrillation/flutter post-HSCT. Analyses were conducted using a Fine-Gray model adjusted for the pre-HSCT CARE-BMT CV risk score. Results: Of the 2071 patients (mean age at HSCT 55.5 + 12.9 years; 59.5% male) with a pre-HSCT TTE (median 25 days pre-HSCT), 116 (5.6%) and 128 (6.2%) patients experienced HF and atrial fibrillation/flutter, respectively, over a median period of 2.2 years. Greater abnormalities in left ventricular internal diameter at end-diastole (LVIDd) and end-systole (LVIDs) were linearly associated with a higher risk of HF (P-trend 0.018 and 0.004, respectively) (Table). Similarly, moderately/severely abnormal LVIDd was associated with a 2.41-fold (95% CI: 1.07, 5.43) increase in risk of atrial fibrillation/flutter (Table). Pre-HSCT ejection fraction (EF) was not associated with either endpoint. Conclusion: LV dilation, even when mild, was notably associated with increased risk of developing new HF or atrial arrythmias post-HSCT, regardless of EF. Whether evidence of LV dilation should prompt the initiation of guideline directed medical therapy to minimize the risk of incident HF warrants further study.

Systems Pharmacology to Explore the Potential Mechanism of Ginseng Against Heart Failure.

The aim of this study is to elucidate the pharmacological mechanism underlying the effects of Ginseng Radix et Rhizoma (ginseng) in heart failure (HF), providing a theoretical foundation for its clinical application. The potential mechanism of ginseng in the context of HF was investigated using systems pharmacology that combined network pharmacology, Gene Expression Omnibus (GEO) analysis, molecular docking, and experimental verification. Network pharmacology was employed to identify drug-disease targets. Core gene targets were subsequently subjected to enrichment analysis by integrating network pharmacology with GEO. Molecular docking was utilized to predict the binding affinities between identified targets and ginseng compounds. Furthermore, the therapeutic efficacy of ginseng was validated in an isoproterenol (ISO)-induced rat model of HF. The modulation of key signaling pathways by ginseng was confirmed through Western blot analysis. A total of 154 potential targets of ginseng in the treatment of HF were identified through network pharmacology analysis. The analysis of GSE71613 revealed that the PI3K-Akt pathway, reactive oxygen species, oxidative phosphorylation, MAPK signaling, and Ras signaling pathways are predominantly associated with patients with HF. By integrating the findings from network pharmacology and GEO analysis, ginsenoside Rg1 and ginsenoside Rb3 were identified as the potential components in ginseng, while FN1 and PRKAA2 were recognized as key targets involved in the PI3K-AKT and AMPK pathways, respectively. Molecular docking analysis revealed a strong affinity between the potential components and the identified core targets. In vivo experiments indicated that the extract of ginseng (EPG) significantly ameliorated ISO-induced cardiac dysfunction by improving cardiac parameters such as cardiac left ventricular internal systolic diameter, left ventricular end-diastolic volume, left ventricular end systolic volume, and left ventricular ejection fraction, while also reducing malondialdehyde production. In addition, EPG was found to enhance superoxide dismutase activity and ATP levels, while concurrently reducing the levels of interleukin (IL)-1β, IL-6, and TNF-α. The extract also reduced myocardial oxygen consumption, inflammatory cell infiltration, and the number of damaged myocardial fibers. Moreover, EPG was observed to upregulate the expression of p-PI3K, p-AKT, p-AMPK, and Bcl-2, while downregulating the expression of p-NFκB, TGF-β, and Bax. The therapeutic effects of ginseng on HF are primarily mediated through the PI3K-Akt and AMPK pathways. Ginsenoside Rg1 and ginsenoside Rb3 have been identified as potential therapeutic agents for HF.

Echocardiographic Assessment in Patients with Vascular Ehlers-Danlos Syndrome: Insights from an Unexplored Field.

Vascular Ehlers-Danlos syndrome (vEDS) is an inherited connective tissue disorder characterized by arterial fragility. Celiprolol is a β1-adrenoceptor antagonist with partial β2 agonist activity that has been shown to reduce rates of vascular events in this setting, though the underlying mechanisms are not yet fully understood. Moreover, very few echocardiographic data are available in patients with vEDS. To perform a comprehensive echocardiographic assessment of a cohort of patients with vEDS with or without celiprolol therapy compared with healthy subjects. Twenty patients with genetically confirmed diagnosis of vEDS followed at our Institution (University Hospital of Brescia, Italy) were divided into two groups according to whether or not they were on celiprolol therapy at the maximum recommended dose (400mg daily) for at least 12 months. Both groups were compared to 10 healthy individuals matched for sex, age, body mass index (BMI), and office blood pressure (BP) values. Each participant underwent transthoracic echocardiography with tissue Doppler analysis (TDI) for a comprehensive evaluation of cardiac structure and function. Mean age was 35 years and mean BMI was 21.6 kg/m2. Female sex was prevalent (60%). Left ventricular (LV) internal diameter values tended to be lower in patients with untreated vEDS than in healthy controls (4.33 vs 4.74cm, respectively), though this difference was not statistically significant. Similar data were observed for LV mass index (56.9 vs 68.6 g/m2), stroke volume (56.6 vs 71.6 mL), and E/A ratio (1.26 vs 1.66), whereas an opposite trend was observed for e' lateral (13.2 vs 12.2cm/s). No statistically significant difference was found between groups in terms of other parameters of LV mass, systolic and diastolic function. A normal LV geometry was found in all the cases. Indices of mechano-energetic efficiency and ventricular-arterial coupling were also similar between groups. No patient presented with aortic root dilation, mitral valve prolapse, valve insufficiency of more than mild degree, or valve stenosis of any degree. Our study suggests that patients with vEDS have normal cardiac mass and geometry, as well as normal systolic and diastolic function. Celiprolol therapy does not seem to significantly influence such aspects. Compared with vascular imaging, less stringent follow-up with echocardiography seems reasonable in this setting. Future studies with prospective design should confirm these aspects.

Endothelial NRG-1 knock-out causes left ventricle dilation in the presence and absence of angiotensin II administration

Abstract Introduction Neuregulin-1 (NRG-1) is a growth factor derived from endothelial cells and belongs to the epidermal growth factor (EGF) family. While NRG-1 is expressed by various cell types, including epithelial cells, glial cells, neurons, and myocytes, the primary source of NRG-1 is considered to be the endothelium. NRG-1 exerts its effects through the EGF receptors ERBB2, ERBB3, and ERBB4. Upon ligand binding, these receptors dimerize and become phosphorylated, leading to downstream signaling that impacts tissue proliferation, differentiation, and survival. The biological role of NRG-1 is intricate due to its isoforms and differential expression across distinct tissue types. In our study, we investigated the impact of endothelial NRG-1 knock-out (KO) on the heart, both in the presence and absence of angiotensin II (ANGII) treatment. ANGII serves as a trigger for NRG-1 upregulation. Methods C57BL/6N-VE-cad-cre-ERT2 mice were crossbred with C57BL/6N-NRG F/F mice, enabling endothelial-specific NRG-1 knockout (KO) using a tamoxifen-inducible promoter. At eight weeks of age, C57BL/6N-VE-cad-cre-ERT2-NRG F/F mice received tamoxifen (1 mg) or vehicle injections for nine consecutive days intraperitoneally (i.p.) to induce the KO. Two days after injection, osmotic minipumps were subcutaneously implanted, releasing a stable dose of angiotensin II (ANGII) at a rate of 400 ng·kg·min⁻¹ for a four-week period. Sham operations served as controls (SHAM). In the final week of treatment, high-frequency ultrasound imaging was performed to assess cardiac function and dimensions. After four weeks of ANGII treatment, mice were sacrificed, and organs were weighed and harvested for further molecular analysis. Results High-frequency ultrasound revealed left ventricle dilation in the absence of endothelial NRG-1, both in ANGII-treated and SHAM-treated mice. This was demonstrated by a significant increase in systolic and diastolic left ventricle internal diameter (LVID) in the endothelial NRG-1 KO groups compared to their respective controls. Additionally, systolic and diastolic LV volume (LV-vol) was significantly increased in the endothelial NRG-1 KO groups, regardless of ANGII treatment. Notably, there was no difference in LVID and LV-vol between SHAM and ANGII-treated groups in the presence of endothelial NRG-1, indicating that LV dilation is primarily due to the absence of endothelial NRG-1 rather than ANGII. Furthermore, heart weights of the endothelial NRG-1 KO mice were significantly increased compared to the control groups, as shown in Figure 1. Conclusion Our study demonstrates that endothelial NRG-1 KO leads to LV dilation, suggesting a crucial role for endothelial-secreted NRG-1 in maintaining normal LV function in adulthood. Further research is needed to fully understand the precise role of NRG-1 in LV homeostasis.

Echocardiographic findings in newborns with inadequate intrauterine growth during pregnancy

Abstract Background Infants born small for gestational age (SGA) or diagnosed with fetal growth restriction (FGR) are at increased risk of neonatal mortality as well as cardiovascular disease later in life. Previous studies based on smaller cohorts (n&amp;lt;200) of newborns with SGA and FGR (n&amp;lt;200) have demonstrated structural and morphological alterations in the heart compared to infants born appropriate for gestational age (AGA). However, to our knowledge no previous study has systematically investigated the effect of SGA and FGR on echocardiographic parameters in the infant heart. Purpose To investigate whether echocardiographic parameters differ among infants born SGA or with FGR, in comparison to infants born AGA. Methods This study is a population-based cohort study of infants (n&amp;gt;25,000) offering postnatal cardiac examination including transthoracic echocardiography (TTE) between 2016-2018. We compared left ventricular (LV) TTE parameters in infants born SGA (birthweight ≥3rd and &amp;lt;10th percentile, n=2,106) and with FGR (birthweight &amp;lt;3rd percentile, n=972) with infants born AGA (birthweight ≥10th and &amp;lt;90th percentile, n=20,468) using a multiple linear regression analysis. We have investigated LV volumes, systolic function, diastolic function, and LV structure. All analyses were adjusted for sex, gestational age at birth, weight, length, and age at cardiac examination. Results Infants born SGA had higher heart rates compared with infants born AGA. Both infants born SGA and infants with FGR had significantly smaller LV dimensions including septal and posterior wall thicknesses (IVSd and LVPWd), and LV internal diameters (LVIDd and LVIDs). Infants born SGA had smaller end-diastolic and end-systolic volumes compared with infants born AGA (Table 1). Infants born SGA or with FGR had significantly higher mitral valve early peak velocities, compared with infants born AGA, and infants born SGA showed increased mitral valve atrial peak velocities indicating altered diastolic function (Table 1). Conclusion Infants born with inadequate intrauterine growth had smaller LV dimensions compared with infants born AGA, even when adjusting for infant size and age. Infants born SGA and with FGR both exhibited altered diastolic function. Longitudinal studies of children with inadequate intrauterine growth are needed to determine the impact on adult cardiac health.

Left atrial parameters predict incident atrial fibrillation and flutter in patients with heart failure with reduced ejection fraction

Abstract Background Left atrial (LA) function parameters have shown prognostic value in relation to incidence of atrial fibrillation in the general population, but this remains to be investigated in patients with heart failure with reduced ejection fraction (HFrEF). Purpose This study aimed to investigate the relationship between LA function parameters and the risk of incident atrial fibrillation/atrial flutter (AF/AFL) in patients with HFrEF. Methods Subjects free of AF/AFL were retrospectively included from a HF clinic and followed using the Danish National Patient Registry. Cox proportional hazards regression was used to assess the prognostic value of LA function parameters. These included LA ejection fraction (LAEF), peak atrial longitudinal strain (PALS), peak atrial contractile strain (PACS) and LA conduit strain (LACS). In addition, multivariable Cox regression was performed to adjust for demographic and echocardiographic parameters, including LA volume index (LAVi). The LA function parameters that remained significant in adjusted analysis were examined using cubic splines, and cutoff values corresponding to a hazard ratio (HR) equal to 1 were derived from these. Results The total study population consisted of 435 subjects with a left ventricular ejection fraction (LVEF) ≤45% (mean age 65.6±11.7 years, male sex 70.1%) free from AF/AFL at baseline. During a median follow-up of 11.4 years [IQR: 10.8, 14.2], 111 (25.5%) developed AF/AFL. Subjects who met the outcome were generally older (69.0±8.8 years vs. 64.4±12.4, p&amp;lt;0.001), had lower baseline heart rate, and a higher prevalence of moderate or severe valve disease (12.6% vs. 3.1%, p&amp;lt;0.001). They also had higher LV mass index and LV internal diastolic diameter index, but similar LVEF. These subjects had larger LAVi (30 ml/m2 [IQR: 24, 38] vs. 26 ml/m2 [IQR: 20, 32], p&amp;lt;0.001), while LAEF (33±14.8% vs. 39±14.9%, p&amp;lt;0.001), PALS (20.3% [IQR: 16.2, 26.5] vs. 23.2% [IQR: 18.6, 29.6], p=0.001), and PACS (9.7% [IQR: 6.9, 13.5] vs. 12.0% [IQR: 7.8, 16.4], p=0.004) were all significantly lower. LACS was similar between groups. In univariable Cox regression, all LA parameters were significant predictors of the AF/AFL (LAEF: HR 0.98 per 1% increase, 95% CI 0.96-0.99, p=0.0002, PALS: HR 0.96 per 1% increase, 95% CI 0.94–0.98, p=0.0008, PACS: HR 0.95 per 1%, 95% CI 0.93–0.98, p=0.0024, LACS: HR 0.96, 95% per 1% increase CI 0.92–0.998, p=0.039. In adjusted analysis, however, only LAEF (HR 0.98, 95% CI 0.976-0.995, p=0.0087) and PACS (HR 0.96, 95% CI 0.993–0.999, p=0.044) remained significant. Splines were constructed for LAEF and PACS (Figure 1), and a cutoff for increased risk of AF/AFL at 38% for LAEF and 12% for PACS, respectively, were derived (Figure 2). Conclusion LAEF and PACS are associated with risk of incident AF/AFL in patients with HFrEF, independent of clinical and echocardiographic risk factors. Our results suggest an increased risk of AF/AFL at LAEF below 38% and PACS below 12%.Figure 1 SplinesFigure 2 Cumulative incident curves

Left ventricular late diastolic strain rate predicts cardiovascular mortality in patients with heart failure with reduced ejection fraction

Abstract Background Left ventricular (LV) strain rate measures provide detailed information regarding LV contraction and filling pressures. These include global systolic strain rate (GSRs), early and late diastolic strain rates (GSRe and GSRa), and ratio of transmitral early filling velocity to GSRe (E/GSRe). Purpose To investigate the prognostic value of strain rate measures with regard to cardiovascular mortality in patients with heart failure with reduced ejection fraction (HFrEF). Methods The study population was retrospectively included from a HF clinic and consisted of patients with LV ejection fraction (LVEF) ≤45%. Echocardiography was obtained within 1 year of referral. The study endpoint was cardiovascular mortality, which was analysed using univariable and adjusted Cox proportional hazards models. Incremental prognostic information was assessed using Harrell’s C-index and continuous net reclassification improvement (NRI). Cubic spline analysis was used to dichotomise variables at a hazard ratio (HR) of 1 for better interpretability. Results The final study population consisted of 1160 patients with HFrEF (mean age 68±11.8 years, 72.7% male, LV ejection fraction (LVEF) 28.6±9.9%). During follow-up (median 10.1 years, IQR: 4.7-13.0), 333 (28.7%) met the outcome. Subjects who met the outcome generally had higher age and prevalence of male sex, a higher burden of comorbidities, and more severely impaired conventional echocardiographic parameters. All four strain rate measures were significantly associated with cardiovascular mortality (GSRs: HR 16.88 95% CI [8.42, 33.84] per 1 s-1 increase, GSRe: HR 0.29 [0.18, 0.47] per 1 s-1 increase, E/GSRe ratio: HR 1.31 [1.22, 1.41] per 1 unit increase, GSRa: HR 0.15 95% CI [0.23, 0.65] per 1 s-1 increase, p&amp;lt;0.0001 for all). However, only GSRa remained an independent predictor in multivariable Cox regression after adjustment for clinical risk factors including sex, age, mean arterial pressure, heart rate, body mass index, cigarette pack years, diabetes mellitus, total cholesterol, ischemic heart disease, and echocardiographic factors including LVEF, global longitudinal strain, tricuspid annular plane systolic excursion, LV mass index, LV internal diameter index, E/e’ ratio and left atrial volume index (HR 0.39 [0.23,0.65], p=0.0003). Furthermore, GSRa provided incremental prognostic information to a model containing all aforementioned parameters (Harrell’s C-index 0.789 vs. 0.792 and continuous NRI 0.158). GSRa was dichotomised at 0.5 s-1, and a Kaplan-Meier curve stratified according to this was plotted (log rank p&amp;lt;0.0001)(Figure 2). Conclusion GSRa is an independent predictor of cardiovascular mortality in patients with HFrEF after multivariable adjustment. GSRa provides incremental prognostic value over conventional echocardiographic measures in risk stratification of HFrEF patients. Our results suggest an increased risk of cardiovascular mortality associated with a GSRa below 0.5 s-1.Figure 1:Spline of HR according to GSRaFigure 2:Kaplan-Meier curve

Performance of the novel ANTWERP score in predicting heart function improvement after atrial fibrillation ablation in Asian patients with heart failure.

Previous research has demonstrated that atrial fibrillation (AF) ablation improves heart function variably among patients. We proposed that the ANTWERP score, which was validated in a European group of patients with low left ventricular ejection fraction (LVEF) who had AF ablation, would be valid in an Asian group as well. The purpose of the study is to examine how well a new scoring system (the ANTWERP score) can predict heart function improvement after atrial fibrillation ablation in Asian patients with heart failure. A retrospective review was conducted on patients (n = 84) undergoing AF ablation between January 2019 and June 2022. Initial diagnoses for impaired LV systolic function were confirmed by echocardiography. Patients meeting the "2021 Universal Definition of HF" criteria for LVEF recovery were classified as "responders." Similarities were observed between responders and nonresponders regarding comorbidities, AF type, and LVEF, except for the left ventricular internal diameter in diastole. A higher percentage of responders had an ANTWERP score ≤2 (87.8%) compared to those with a score >2 (55.6%). LVEF improvement was notably higher in the former group (+14.8% vs. +9.4%, p = .043). Atrial reverse remodeling and recurrent atrial arrhythmia rates were similar across groups. The conclusion of the study was that the ANTWERP score effectively predicted LVEF improvement after atrial fibrillation ablation in the Asian population and that this scoring system could be used to guide clinical decisions and prognosis prediction.

Acute exposure to LPS induces cardiac dysfunction via the activation of the NLRP3 inflammasome

Systemic inflammation contributes to left ventricular (LV) dysfunction, however the role of the NLRP3 inflammasome in LV dysfunction in acute inflammatory conditions is unclear. This study investigated the role of the NLRP3 inflammasome in acute (24 h) cardiac structural and functional changes in vivo and in vitro in lipopolysaccharide (LPS)-induced inflammation. LPS-treated Sprague-Dawley (SD) rats showed increased LPS metabolite abundance in their LVs as measured by atmospheric pressure matrix-assisted laser desorption ionisation (AP-MALDI) mass spectrometry imaging (MSI). Echocardiography and histology showed that in LPS-exposed rats, LV internal diameter was decreased, with evidence of macrophage infiltration and oedema. However, there were no changes in LV wall thickness or collagen volume. Additionally, LPS-exposed rats exhibited impaired LV relaxation, potentially contributing to decreased stroke volume. While global systolic function was preserved, LPS exposure in SD rats resulted in impaired myocardial deformation assessed by speckle-tracking echocardiography. Exposure to LPS resulted in upregulation of the expression of components of the NLRP3 inflammasome in rodents. In vitro LPS exposure resulted in increased gene expression of NLRP3 and downstream cytokines IL-1β and IL-18, antioxidant SOD2, and elevated markers of pyroptosis (GSDMD) which were inhibited by treatment with a NLRP3 antagonist. However, LPS-induced increases in the gene expression of apoptosic markers (BAX/Bcl2) were not impacted by NLRP3 antagonism. These findings suggest that inflammation induced adverse cardiac structural and functional changes is, at least in part, mediated by the NLRP3 inflammasome in acute, high-grade inflammatory states. In addition, in vitro findings suggest that while the NLRP3 inflammasome mediates pyroptotic pathways, regulation of apoptosis that is independent of the inflammasome.