Atrial Fibrillation as a Prognostic Factor for All-Cause Mortality in Patients With Transthyretin Amyloid Cardiomyopathy.

Background: Atrial fibrillation/atrial flutter (AF/AFL) are common manifestations of transthyretin amyloid cardiomyopathy (ATTR-CM) but have not been found to be predictive of mortality. Objectives: This analysis aimed to examine whether baseline or historical AF/AFL at enrollment was prognostic for all-cause mortality. Methods: In the ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial), a 30-month study of tafamidis vs placebo for ATTR-CM, AF/AFL was evaluated as an independent prognostic factor for all-cause mortality using Cox proportional hazards modelling. The impact of AF/AFL on tafamidis efficacy was explored by adding an interaction term for AF/AFL status and treatment. Results: ATTR-ACT enrolled 441 patients with ATTR-CM (median age 75 years; 90% male); 314 (71.2%) had baseline or historical AF/AFL at enrollment. AF/AFL was an independent prognostic factor for all-cause mortality after adjusting for covariates prespecified in the ATTR-ACT model (treatment, genotype, New York Heart Association functional class; HR: 0.550; 95% CI: 0.368-0.821) but not in an expanded stepwise model selection analysis including 23 covariates (blood urea nitrogen and N-terminal pro-B-type natriuretic peptide concentration, 6-minute walk test distance, genotype, treatment, and global longitudinal strain were prognostic [P < 0.01]). The interactions between tafamidis treatment and AF/AFL for all-cause mortality (P = 0.33) and changes in Kansas City Cardiomyopathy Questionnaire Overall Summary score (P = 0.83) and 6-minute walk test distance (P = 0.82) were not significant. Conclusions: In ATTR-ACT, baseline or historical AF/AFL was prognostic for all-cause mortality in analyses with limited adjustment but not after accounting for additional indicators of disease severity. Baseline or historical AF/AFL did not impact the efficacy of tafamidis treatment. (Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy [ATTR-ACT]; NCT01994889).

Cathepsin B in cardiovascular disease: Underlying mechanisms and therapeutic strategies.

Cathepsin B (CTSB) is a member of the cysteine protease family, primarily responsible for degrading unnecessary organelles and proteins within the acidic milieu of lysosomes to facilitate recycling. Recent research has revealed that CTSB plays a multifaceted role beyond its function as a proteolytic enzyme in lysosomes. Importantly, recent data suggest that CTSB has significant impacts on different cardiac pathological conditions, such as atherosclerosis (AS), myocardial infarction, hypertension, heart failure and cardiomyopathy. Especially in the context of AS, preclinical models and clinical sample imaging data indicate that the cathepsin activity-based probe can reliably image CTSB activity in foam cells and atherosclerotic plaques; concurrently, it allows synchronous diagnostic and therapeutic interventions. However, our knowledge of CTSB in cardiovascular disease is still in the early stage. This paper aims to provide a comprehensive review of the significance of CTSB in cardiovascular physiology and pathology, with the objective of laying a theoretical groundwork for the development of drugs targeting CTSB.

Hyperactivation of ATF4/TGF-ß1 signaling contributes to the progressive cardiac fibrosis in Arrhythmogenic cardiomyopathy caused by DSG2 Variant.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy characterized with progressive cardiac fibrosis and heart failure. However, the exact mechanism driving the progression of cardiac fibrosis and heart failure in ACM remains elusive. This study aims to investigate the underlying mechanisms of progressive cardiac fibrosis in ACM caused by newly identified Desmoglein-2 (DSG2) variation. METHODS: We identified homozygous DSG2F531C variant in a family with 8 ACM patients using whole-exome sequencing and generated Dsg2F536C knock-in mice. Neonatal and adult mouse ventricular myocytes isolated from Dsg2F536C knock-in mice were used. We performed functional, transcriptomic and mass spectrometry analyses to evaluate the mechanisms of ACM caused by DSG2F531C variant. RESULTS: All eight patients with ACM were homozygous for DSG2F531C variant. Dsg2F536C/F536C mice displayed cardiac enlargement, dysfunction, and progressive cardiac fibrosis in both ventricles. Mechanistic investigations revealed that the variant DSG2-F536C protein underwent misfolding, leading to its recognition by BiP within the endoplasmic reticulum, which triggered endoplasmic reticulum stress, activated the PERK-ATF4 signaling pathway and increased ATF4 levels in cardiomyocytes. Increased ATF4 facilitated the expression of TGF-ß1 in cardiomyocytes, thereby activating cardiac fibroblasts through paracrine signaling and ultimately promoting cardiac fibrosis in Dsg2F536C/F536C mice. Notably, inhibition of the PERK-ATF4 signaling attenuated progressive cardiac fibrosis and cardiac systolic dysfunction in Dsg2F536C/F536C mice. CONCLUSIONS: Hyperactivation of the ATF4/TGF-ß1 signaling in cardiomyocytes emerges as a novel mechanism underlying progressive cardiac fibrosis in ACM. Targeting the ATF4/TGF-ß1 signaling may be a novel therapeutic target for managing ACM.

Relevance of increased negative T waves in apical hypertrophic cardiomyopathy with progressive myocardial damage: Insights from repeat cardiac magnetic resonance studies.

In patients with apical hypertrophic cardiomyopathy (HCM), progressive electrocardiographic changes are observed during long-term follow-up. However, it is difficult to correspond these changes to the specific myocardial changes. Cardiac magnetic resonance (CMR) imaging can elucidate myocardial changes by late gadolinium enhancement. Here, we present the long-term follow-up (>18 years) on a patient with apical HCM, whereupon, precise and continuous changes in the myocardium, causing ST segment and T wave changes on electrocardiography, were observed on CMR images. The combination of electrocardiography and CMR facilitates management of patients with apical HCM because it helps explain and understand the nature of electrocardiography changes over time.

Cardiac amyloidosis: A diagnostic challenge.

Cardiac amyloidosis is indeed a condition characterized by the deposition of amyloid proteins in the myocardium, leading to thickening and stiffening of the heart muscle. These abnormal protein deposits can interfere with the heart's normal functioning and may pose diagnostic challenges due to its varied clinical presentation and resemblance to other heart condition. Here, we present a case of 55-year-old female patient of uncontrolled hypertensions for 15 years. About 15 years ago, she presented with chest pain and was diagnosed with cardiomyopathy (CM) characterized by low left ventricle (LV) function of unknown cause. Despite being on antihypertensive treatment, the patient continued to experience chest heaviness with persistent elevate blood pressure. An echocardiogram revealed increased LV septal wall thickness, valvular thickening, and biatrial dilation. Subsequently, cardiac magnetic resonance imaging (CMR) was performed, which revealed left atrium enlargement and asymmetrical myocardial wall thickening, particularly at the septum. White blood axial image revealed thickened inter atrial septum, while late gadolinium enhancement (LGE) magnetic resonance (LGE MR) images showed patchy LGE at the base relative to the apex of the myocardium, highlighting the base-to-apex gradient, subendocardial pattern enhancement at apical lateral wall, and transmural pattern enhancement of the mid anteroseptal and inferoseptal wall. Additionally, a short axis time to invert T1 scout image of left ventricle displayed an abnormal nulling pattern initially in the myocardium, followed by the blood pool, and finally the spleen. These findings collectively led to the diagnosis of cardiac amyloidosis.

Value of cardiac magnetic resonance feature-tracking in Arrhythmogenic Cardiomyopathy (ACM): A systematic review and meta-analysis.

We aimed to assess the diagnostic performance of Cardiac Magnetic Resonance (CMR) strain parameters in ACM patients to evaluate their diagnostic role. We systematically searched MEDLINE, EMBASE, Scopus, and Web of Science. Of the 146 records, 16 were included. All Right Ventricle (RV) global strains were significantly reduced in ACM patients compared to controls (Standardized Mean Difference (SMD)[95 % Confidence Interval (CI)]: Longitudinal 1.31[0.79,1.83]; Circumferential 0.88[0.34,1.42]; Radial -1.14[-1.78,-0.51]). Similarly, all Left Ventricle (LV) global strains were significantly impaired in ACM compared to healthy controls (SDM [95 %CI]: Longitudinal 0.88[0.48,12.28], Circumferential 0.97[0.72,1.22], Radial -1.24[-1.49,-1.00]). Regarding regional RV strains, longitudinal and circumferential strains were significantly reduced in basal and mid-wall regions, while they were comparable to controls in the apical regions. The RV radial strain was reduced only within the basal region in the ACM group compared to controls. ACM patients exhibited significant impairment of regional LV strains in all regions-basal, mid-wall, and apical-compared to control subjects. Ultimately, despite the limitations of CMR-FT in terms of reproducibility, it is superior to qualitative assessment in detecting wall motion abnormalities. Thus, integrating CMR-FT with ACM diagnostic criteria seems to enhance its diagnostic yield.

A multi-omics atlas of sex-specific differences in obstructive hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease. Women with HCM tend to have a later onset but more severe disease course. However, the underlying pathobiological mechanisms for these differences remain unknown. METHODS: Myectomy samples from 97 patients (53 males/44 females) with symptomatic obstructive HCM and 23 control cardiac tissues were included in this study. RNA-sequencing was performed on all samples. Mass spectrometry-based proteomics and phosphoproteomics was performed on a representative subset of samples. RESULTS: The transcriptome, proteome, and phosphoproteome was similar between sexes and did not separate on PCA plotting. Overall, there were 482 differentially expressed genes (DEGs) between control females and control males while there were only 53 DEGs between HCM females and HCM males. There were 1983 DEGs between HCM females and control females compared to 1064 DEGs between HCM males and control males. Additionally, there was increased transcriptional downregulation of hypertrophy pathways in HCM females and in HCM males. HCM females had 119 differentially expressed proteins compared to control females while HCM males only had 27 compared to control males. Finally, the phosphoproteome showed females had 341 differentially phosphorylated proteins (DPPs) compared to controls while males only had 184. Interestingly, there was hypophosphorylation and inactivation of hypertrophy pathways in females but hyperphosphorylation and activation in males. CONCLUSION: There are subtle, but biologically relevant differences in the multi-omics profile of HCM. This study provides the most comprehensive atlas of sex-specific differences in the transcriptome, proteome, and phosphoproteome present at the time of surgical myectomy for obstructive HCM.

Impact of cardiac conduction disease in patients with cardiac amyloidosis: A national retrospective cohort study.

BACKGROUND: There is a paucity of data regarding the impact of cardiac conduction disease (CD) on clinical outcomes in patients with cardiac amyloidosis (CA). METHODS: The National Inpatient Sample (NIS) was queried to identify all CA admissions and those with CD using ICD-10 codes from 2016 to 2019. We explored baseline characteristics and used multivariate logistic regression to assess the association between CD and several clinical outcomes during index admission; a p-value of <0.05 was significant. Propensity score matching (PSM) was performed to validate our results. RESULTS: A total of 12,185 patients with CA were identified. Of these, 920 (7.6 %) had CD. The median age of the sample was 72 years (IQR: 64-80). After multivariate adjustment and PSM, the presence of CD in CA was associated with higher odds of ventricular arrhythmias (VA) (aOR = 2.97, 95 % CI 1.78-4.96, p < 0.001), syncope (aOR = 3.44, 95 % CI 1.51-7.83, p = 0.003), and cardiovascular implantable electronic device (CIED) implantation (aOR = 12.86, 95 % CI 5.50-30.04, p < 0.001) but not with sudden cardiac arrest (p = 0.092), acute heart failure (p = 0.060), all-cause in-hospital mortality (p = 0.384), and non-routine discharge in patients admitted for CA (p = 0.271). CONCLUSIONS: Although CD was not associated with all-cause in-hospital mortality, there was a significant association with VAs and syncope. Syncope is associated with worse survival in patients with CA. Further studies that prospectively follow patients are needed to determine the true effect of cardiac CD on mortality in patients with CA.

The role of Cardiotrophin-1 and echocardiography in early detection of subclinical diabetic cardiomyopathy in children and adolescents with type 1 diabetes mellitus.

OBJECTIVES: To assess the role of Cardiotrophin-1 (CT-1) and echocardiography in early detection of subclinical Diabetic Cardiomyopathy (DCM) in children with type 1 Diabetes Mellitus (T1D). METHODS: This case-control study included two groups of children and adolescents aged between 7 and 18. Group (1) included forty patients with T1D (duration > 5 years) regularly followed at the children's hospital of Cairo University, and Group (2) included forty age and sex-matched healthy subjects as a control group. The serum level of CT-1 was measured, and conventional echocardiography, tissue Doppler imaging (TDI), and 2D speckle tracking echocardiography were performed. RESULTS: The level of CT-1 in the cases ranged from 11 to 1039.4 pg/ml with a median (IQR) of 19.4 (16.60-25.7) pg/ml, while its level in the control group ranged from 10.8 to 162.6 pg/ml with a median (IQR) of 20.2 (16.2-24.8) pg/ml. CT-1 levels showed no statistically significant difference between cases and controls. Patients had significantly higher mean left ventricle E/E' ratio (p<0.001), lower mean 2D global longitudinal strain (GLS) of the left ventricle (LV) (p<0.001), and lower mean GLS of the right ventricle (RV) (p<0.001) compared to controls. Ofpatients with diabetes, 75 % had LV diastolic dysfunction, 85 % had RV diastolic dysfunction, 97.5 % had LV systolic dysfunction, and 100 % had RV systolic dysfunction. CONCLUSIONS: Non-conventional echocardiography is important for early perception of subclinical DCM in patients with T1D. Cardiotrophin-1 was not specific for early detection of DCM.

Metabolic Adaptation in Heart Failure and the Role of Ketone Bodies as Biomarkers.

PURPOSE OF REVIEW: The development and progression of heart failure is characterized by metabolic and physiologic adaptations allowing patients to cope with cardiac insufficiency. This review explores the changes in metabolism in heart failure and the potential role of biomarkers, particularly ketone bodies, in staging and prognosticating heart failure progression. RECENT FINDINGS: Recent insights into myocardial metabolism shed light on the heart's response to stress, highlighting the shift towards reliance on ketone bodies as an alternative fuel source. Elevated blood ketone levels have been shown to correlate with the severity of cardiac dysfunction, emphasizing their potential as prognostic indicators. Furthermore, studies exploring therapeutic interventions targeting specific metabolic pathways offer promise for improving outcomes in heart failure. Ketones have prognostic utility in heart failure, and potentially, an avenue for therapeutic intervention. Challenges remain in deciphering the optimal balance between metabolic support and exacerbating cardiac remodeling. Future research endeavors must address these complexities to advance personalized approaches in managing heart failure.

Functional Status and Quality of Life in Light-Chain Amyloidosis: Advanced Imaging, Longitudinal Changes, and Outcomes.

BACKGROUND: In light-chain (AL) amyloidosis, whether functional status and heart failure-related quality of life (HF-QOL) correlate with cardiomyopathy severity, improve with therapy, and are associated with major adverse cardiac events (MACE) beyond validated scores is not well-known. OBJECTIVES: The authors aimed to: 1) correlate functional status and HF-QOL with cardiomyopathy severity; 2) analyze their longitudinal changes; and 3) assess their independent associations with MACE. METHODS: This study included 106 participants with AL amyloidosis, with 81% having AL cardiomyopathy. Functional status was evaluated using the NYHA functional class, the Karnofsky scale, and the 6-minute walk distance (6MWD), and HF-QOL using the MLWHFQ (Minnesota Living with Heart Failure Questionnaire). Cardiomyopathy severity was assessed by cardiac 18F-florbetapir positron emission tomography/computed tomography, cardiac magnetic resonance, echocardiography, and serum cardiac biomarkers. MACE were defined as all-cause death, heart failure hospitalization, or cardiac transplantation. RESULTS: NYHA functional class, Karnofsky scale, 6MWD, and MLWHFQ were impaired substantially in participants with recently diagnosed AL cardiomyopathy (P < 0.001), and correlated with all markers of cardiomyopathy severity (P ≤ 0.010). NYHA functional class, 6MWD, and MLWHFQ improved at 12 months in participants with cardiomyopathy (P ≤ 0.013). All measures of functional status and HF-QOL were associated with MACE (P ≤ 0.017), independent of Mayo stage for 6MWD and MLWHFQ (P ≤ 0.006). CONCLUSIONS: Functional status and HF-QOL were associated with AL cardiomyopathy severity, improved on therapy within 12 months, and were associated with MACE, independently of Mayo stage for 6MWD and MLWHFQ. They may be validated further in addition to prognostic scores and as surrogate outcomes for future studies.

Characterisation of infantile cardiomyopathy in Alström syndrome using ALMS1 knockout induced pluripotent stem cell derived cardiomyocyte model.

Alström syndrome (AS) is an inherited rare ciliopathy characterised by multi-organ dysfunction and premature cardiovascular disease. This may manifest as an infantile-onset dilated cardiomyopathy with significant associated mortality. An adult-onset restrictive cardiomyopathy may also feature later in life. Loss of function pathogenic variants in ALMS1 have been identified in AS patients, leading to a lack of ALMS1 protein. The biological role of ALMS1 is unknown, particularly in a cardiovascular context. To understand the role of ALMS1 in infantile cardiomyopathy, the reduction of ALMS1 protein seen in AS patients was modelled using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), in which ALMS1 was knocked out. MuscleMotion analysis and calcium optical mapping experiments suggest that ALMS1 knockout (KO) cells have increased contractility, with altered calcium extrusion and impaired calcium handling dynamics compared to wildtype (WT) counterparts. Seahorse metabolic assays showed ALMS1 knockout iPSC-CMs had increased glycolytic and mitochondrial respiration rates, with ALMS1 knockout cells portraying increased energetic demand and respiratory capacity than WT counterparts. Using senescence associated ß-galactosidase (SA-ß gal) staining assay, we identified increased senescence of ALMS1 knockout iPSC-CMs. Overall, this study provides insights into the molecular mechanisms in AS, particularly the role of ALMS1 in infantile cardiomyopathy in AS, using iPSC-CMs as a 'disease in a dish' model to provide insights into multiple aspects of this complex disease.

Atrial Fibrillation in Hypertrophic Cardiomyopathy.

Atrial fibrillation (AF) is common among patients with hypertrophic cardiomyopathy (HCM) with a prevalence greater than 25%. AF in HCM is associated with a high risk of stroke and can be a marker of more advanced cardiomyopathy. Although, it frequently results in cardiac hemodynamic changes which are poorly tolerated, it can be subclinical. Thus, prompt diagnosis and adequate management of AF are essential to minimizing AF-related adverse outcomes in HCM. All HCM patients should be screened for AF regularly, and those with high-risk features should be screened more frequently preferably with extended ambulatory monitoring. Once AF is detected, oral anticoagulation should be initiated. Both general and HCM-specific modifiable risk factors should be addressed and assessment for cardiomyopathy progression should be performed. Although no randomized controlled studies have compared rate versus rhythm control in HCM, early rhythm control could be considered to prevent further LA remodeling.

Ruxolitinib-based senomorphic therapy mitigates cardiomyocyte senescence in septic cardiomyopathy by inhibiting the JAK2/STAT3 signaling pathway.

Background: Cellular senescence has emerged as a pivotal focus in cardiovascular research. This study investigates the previously unrecognized role of cellular senescence in septic cardiomyopathy (SCM) and evaluates senomorphic therapy using ruxolitinib (Rux) as a potential treatment option. Methods: We employed lipopolysaccharide (LPS)-induced neonatal rat cardiomyocytes (NRCMs) and two mouse models-LPS-induced and cecal ligation and puncture (CLP)-induced SCM models-to assess Rux's effects. RNA sequencing, western blotting (WB), quantitative polymerase chain reaction (qPCR), immunofluorescence, immunohistochemistry, senescence-associated ß-galactosidase (SA-ß-gal) assay, and other techniques were utilized to investigate underlying mechanisms. Results: Senescence-associated secretory phenotype (SASP) and cellular senescence markers were markedly elevated in LPS-induced NRCMs and SCM animal models, confirmed by the SA-ß-gal assay. Rux treatment attenuated SASP in vitro and in vivo, alongside downregulation of senescence markers. Moreover, Rux-based senomorphic therapy mitigated mitochondrial-mediated apoptosis, improved cardiac function in SCM mice, restored the balance of antioxidant system, and reduced reactive oxygen species (ROS) levels. Rux treatment restored mitochondrial membrane potential, mitigated mitochondrial morphological damage, and upregulated mitochondrial complex-related gene expression, thereby enhancing mitochondrial function. Additionally, Rux treatment ameliorated SCM-induced mitochondrial dynamic dysfunction and endoplasmic reticulum stress. Mechanistically, Rux inhibited JAK2-STAT3 signaling activation both in vitro and in vivo. Notably, low-dose Rux and ABT263 showed comparable efficacy in mitigating SCM. Conclusions: This study highlighted the potential significance of cellular senescence in SCM pathogenesis and suggested Rux-based senomorphic therapy as a promising therapeutic approach for SCM.

Clinical Implications of Left Ventricular Apex Mechanics in Patients with Apical Hypertrophic Cardiomyopathy.

BACKGROUND: Apical hypertrophic cardiomyopathy (ApHCM) is a unique disease with pathological hypertrophy mainly at the left ventricular (LV) apex. Although previous studies have indicated apical dysfunction in ApHCM, how apical mechanics change during disease progression has not been thoroughly examined. We aimed to characterize the mechanics of the LV apex in ApHCM patients at different disease stages and explore the clinical significance of these alterations. METHODS: 104 ApHCM patients were divided into 3 subtypes based on LV apical maximum wall thickness (AMWT) and extent of hypertrophy: relative-type (isolated apical hypertrophy with AMWT <15 mm), pure-type (isolated apical hypertrophy with AMWT ≥15 mm), and mixed-type (both apical and midventricular hypertrophy with AMWT ≥15 mm). Two-dimensional speckle-tracking echocardiography was used to analyze LV segmental strain, global strain, and twist. Comparisons of these parameters were performed among ApHCM subtypes and 30 healthy controls. Logistic regression and Cox proportional hazard regression analyses were employed to explore associations between myocardial mechanics and clinical indicators. A composite outcome of new-onset atrial fibrillation, heart failure hospitalization, myectomy, and all-cause mortality was assessed. RESULTS: Even in relative ApHCM patients, apical longitudinal strain (LS), circumferential strain (CS), and radial strain (RS) were significantly impaired compared to controls (LS: -14.6±4.1% vs.-20.0±1.7%, p=0.001; CS: -19.6±2.5% vs.-25.6±3.7%, p=0.002; RS: 26.6±7.4% vs. 35.6±11.1%, p=0.026), while apical rotation and LV twist remained unchanged. In patients with greater apical hypertrophy (mixed and pure patients), apical LS and RS were more abnormal. Moreover, apical rotation showed significant reductions compared to relative-type patients. After adjusting for clinical and myocardial mechanical parameters, apical rotation was independently associated with NYHA class ≥ II (odds ratio =0.81, 95% confidence interval [CI]: 0.66-0.99, p=0.036) and the composite outcome (hazard ratio =0.82, 95% CI: 0.73-0.91, p=0.001). CONCLUSIONS: Relative ApHCM demonstrates apical dysfunction but sparing of apical rotation, which was abnormal in more extensive phenotypes. LV apex mechanics were closely related to clinical patterns, with apical rotation correlated with both NYHA class ≥ II and clinical events.

Heart-type fatty acid binding protein (H-FABP) as an early biomarker in sepsis-induced cardiomyopathy: a prospective observational study.

BACKGROUND: Sepsis-induced cardiomyopathy (SICM) is a common and life-threatening complication of sepsis, significantly contributing to elevated mortality. This study aimed to identify crucial indicators for the prompt and early assessment of SICM. METHODS: Patients diagnosed with sepsis or SICM within 24 h of intensive care unit (ICU) admission were enrolled in this prospective observational study. Patients were assigned to the training set, validation set and external test set. The primary endpoint was 7-day ICU mortality, and the secondary endpoint was 28-day ICU mortality. Three machine learning algorithms were utilized to identify relevant indicators for diagnosing SICM, incorporating 64 indicators including serum biomarkers associated with cardiac, renal, and liver function, lipid metabolism, coagulation, and inflammation. Internal and external validations were performed on the screening results. Patients were then stratified based on the cut-off value of the most diagnostically effective biomarker identified, and their prognostic outcomes were observed and analyzed. RESULTS: A total of 270 patients were included in the training and validation set, and 52 patients were included in the external test set. Age, sex, and comorbidities did not significantly differ between the sepsis and SICM groups (P > 0.05). The support vector machine (SVM) algorithm identified six indicators with an accuracy of 84.5%, the random forest (RF) algorithm identified six indicators with an accuracy of 81.9%, and the logistic regression (LR) algorithm screened out seven indicators. Following rigorous selection, a diagnostic model for sepsis-induced cardiomyopathy was established based on heart-type fatty acid binding protein (H-FABP) (OR 1.308, 95% CI 1.170-1.462, P < 0.001) and retinol-binding protein (RBP) (OR 1.020, 95% CI 1.006-1.034, P < 0.05). H-FABP alone exhibited the highest diagnostic performance in both the internal (AUROC 0.689, P < 0.05) and external sets (AUROC 0.845, P < 0.05). Patients with SICM were further stratified based on an H-FABP diagnostic cut-off value of 8.335 ng/mL. Kaplan-Meier curve analysis demonstrated that elevated H-FABP levels at admission were associated with higher 7-day ICU mortality in patients with SICM (P < 0.05). CONCLUSIONS: This study revealed that H-FABP concentrations measured within 24 h of patient admission could serve as a crucial biomarker for the early and rapid diagnosis and short-term prognostic evaluation of SICM.

Inflammatory cytokine expression in Fabry disease: impact of disease phenotype and alterations under enzyme replacement therapy.

Objectives: The aim of this study is to explore the expression of inflammatory cytokines (ICs) in Fabry disease (FD), the correlation between ICs and FD phenotypes, and the impact of enzyme replacement therapy (ERT) on IC expression. Methods: We recruited 67 FD patients and 44 healthy controls (HCs) and detected concentrations of the following ICs: interferon-γ, interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12P70, IL-17A, IL-17F, IL-22, tumor necrosis factor (TNF)-α, and TNF-ß. We also analyzed the impact of ERT on IC expression in FD patients and the relationship between IC expression and sex, genotype, phenotype, disease burden, and biomarkers. Results: Most ICs were significantly higher in FD patients than in HCs. A number of ICs were positively correlated with clinical aspects, including disease burden (Mainz Severity Score Index [MSSI]) and cardiac and renal markers. IL-8 was higher in the high MSSI (P-adj=0.026*) than in the low MSSI. Conclusions: ICs were upregulated in FD patients, indicating the role of the innate immune process in FD etiology. ERT ameliorated FD-related inflammatory activation, at least to some extent. IC expression was positively correlated with disease burden and clinical markers in FD. Our findings indicated that the inflammatory pathway may be a promising therapeutic target for FD.

Left ventricular volumes and function in successful and failed His-BundLe Pacing. A comparative prospective study.

INTRODUCTION: Initial data suggest that His Bundle Pacing (HBP) could preserve long-term cardiac structure and function better than Right Ventricular Pacing (RVP), but evidence is limited. METHODS: We studied consecutive patients with baseline ejection fraction (EF) ≥ 50% who underwent HBP attempt, either successful (HBP group) or failed (RVP group). Two-dimensional (2D) and three-dimensional (3D) echocardiography were carried out at baseline and after 6 months of ventricular pacing burden > 20%. RESULTS: Among 68 patients, 40 underwent successful HBP, and 28 RVP. The HBP and RVP groups did not differ for age, sex and pacing indication. At baseline, the HBP and RVP groups did not differ for 2D EF (62% vs. 62%), 3D EF (60% vs. 63%), 2D (-19% vs. -19%) and 3D global longitudinal strain (GLS) (-15% vs. -16%). After 6 months, 2D EF (-3.86%) and 3D EF (-5.71%) significantly decreased in the RVP group and did not change in the HBP group (p for interaction .006 and <.001, respectively). 2D GLS (3.08%) and 3D GLS (2.22%) significantly increased in the RVP group, but did not change in the HBP group (p for interaction .013 and <.016, respectively). Pacing induced cardiomyopathy (PICM) (EF drop ≥ 10% and EF < 50%) occurred in 14% (RVP) versus 0% (HBP) of patients (p = .025). CONCLUSIONS: Successful HBP was superior to RVP in preserving LV systolic function despite a high ventricular pacing burden, and was less frequently associated with PICM.