Poor Prognosis Research Articles

Coronary microvascular dysfunction as assessed by cardiac MRI and its association with aerobic exercise capacity in dilated cardiomyopathy

Abstract Background Dilated cardiomyopathy (DCM) has a poor prognosis. Aerobic exercise capacity (peak VO2) is an independent predictor of mortality but the central mechanisms contributing to exercise intolerance in DCM are unknown. Purpose To characterise myocardial perfusion reserve (MPR) and determine if cardiovascular magnetic resonance (CMR) measures of structure, function and microvascular function are associated with aerobic exercise capacity in DCM. Methods Single centre, prospective, case-control comparison of adults with DCM and matched controls. Adenosine-stress perfusion CMR to assess cardiac structure, function and quantitative perfusion, and cardiopulmonary exercise testing (CPET) to determine peak VO2, was performed. Controls were propensity matched based on age, sex, body mass index and diabetes status, and between group comparison was adjusted for other key clinical characteristics (CMR: ethnicity and systolic blood pressure; CPET: ethnicity, systolic blood pressure, smoking history and lung disease). Comparison of perfusion in segments with and without late gadolinium enhancement was performed using mixed effects linear regression taking into account individual patient segmental perfusion. Pre-specified multivariable linear regression, including key clinical and cardiac variables, was undertaken in patients with DCM to identify independent associations with percentage predicted peak VO2, which incorporates age, sex, height and weight. Results Sixty-six patients with DCM (median age 61 years, 71% male) were matched to 66 controls (median age 59 years, 71% male). The DCM group had greater left ventricular (LV) end-diastolic and end-systolic volumes, lower systolic and diastolic function, and had more focal and diffuse fibrosis compared to controls (Table 1). There was lower rest (0.58±0.14 versus 0.65±0.17 mL/min/g; P=0.033) and stress (1.53±0.49 versus 2.01±0.60 mL/g/min; P<0.001) myocardial blood flow, and lower MPR (2.69±0.84 versus 3.15±0.84 mL/g/min; P=0.002) in the DCM group. In DCM patients, mixed effects linear regression demonstrated lower rest (adjusted mean 0.54(95% CI 0.50-0.57) versus 0.58(0.55-0.62) mL/g/min; P<0.001) and stress MBF (1.38(1.25-1.51) versus 1.55(1.43-1.67) mL/g/min; P<0.001) in segments with LGE compared to segments without LGE, but there was no difference in MPR (2.71(2.47-2.96) versus 2.76(2.55-2.97) mL/g/min; P=0.496). DCM patients had markedly lower peak VO2 (19.8±5.5 versus 25.2±7.3 mL/kg/min; P<0.001). Multivariable linear regression demonstrated that LV ejection fraction, extracellular volume fraction and MPR, but not LV mass, were independently associated with percentage predicted peak VO2 in DCM (R squared=0.531, P<0.001; Table 2). Conclusions DCM patients have lower rest and stress myocardial blood flow and lower MPR compared to controls. In DCM, MPR, LV ejection fraction and fibrosis are independently associated with aerobic exercise capacity.

A novel risk score model of lactate metabolism for predicting outcomes and immune signatures in acute myeloid leukemia

Acute myeloid leukemia (AML) is a malignant tumor with high recurrence and refractory rates and low survival rates. Increased glycolysis is characteristic of metabolism in AML blast cells and is also associated with chemotherapy resistance. The purpose of this study was to use gene expression and clinical information from The Cancer Genome Atlas (TCGA) database to identify subtypes of AML associated with lactate metabolism. Two different subtypes linked to lactate metabolism, each with specific immunological features and consequences for prognosis, were identified in this study. Using the TCGA and International Cancer Genome Consortium (GEO) cohorts, a prognostic model composed of genes (LMNA, RETN and HK1) for the prognostic value of the lactate metabolism-related risk score prognostic model was created and validated, suggesting possible therapeutic uses. Additionally, the diagnostic value of the prognostic model genes was explored. LMNA and HK1 were ultimately identified as hub genes, and their roles in AML were determined through immune infiltration, GeneMANIA, GSEA, methylation analysis and single-cell analysis. LMNA was upregulated in AML associating with a poor prognosis while HK1 was downregulated in AML associating with a favorable prognosis. The findings underscore the noteworthy impact of genes linked to lactate metabolism in AML and illustrate the possible therapeutic usefulness of the lactate metabolism-related risk score and the hub lactate metabolism-related genes in guiding AML patients’ treatment choices.

Integrated analysis of bulk and single-cell RNA sequencing reveals the impact of nicotinamide and tryptophan metabolism on glioma prognosis and immunotherapy sensitivity

BackgroundNicotinamide and tryptophan metabolism play important roles in regulating tumor synthesis metabolism and signal transduction functions. However, their comprehensive impact on the prognosis and the tumor immune microenvironment of glioma is still unclear. The purpose of this study was to investigate the association of nicotinamide and tryptophan metabolism with prognosis and immune status of gliomas and to develop relevant models for predicting prognosis and sensitivity to immunotherapy in gliomas.MethodsBulk and single-cell transcriptome data from TCGA, CGGA and GSE159416 were obtained for this study. Gliomas were classified based on nicotinamide and tryptophan metabolism, and PPI network associated with differentially expressed genes was established. The core genes were identified and the risk model was established by machine learning techniques, including univariate Cox regression and LASSO regression. Then the risk model was validated with data from the CGGA. Finally, the effects of genes in the risk model on the biological behavior of gliomas were verified by in vitro experiments.ResultsThe high nicotinamide and tryptophan metabolism is associated with poor prognosis and high levels of immune cell infiltration in glioma. Seven of the core genes related to nicotinamide and tryptophan metabolism were used to construct a risk model, and the model has good predictive ability for prognosis, immune microenvironment, and response to immune checkpoint therapy of glioma. We also confirmed that high expression of TGFBI can lead to an increased level of migration, invasion, and EMT of glioma cells, and the aforementioned effect of TGFBI can be reduced by FAK inhibitor PF-573,228.ConclusionsOur study evaluated the effects of nicotinamide and tryptophan metabolism on the prognosis and tumor immune microenvironment of glioma, which can help predict the prognosis and sensitivity to immunotherapy of glioma.

Angiotensin-II receptor type 1 and endothelin-1 receptor type A agonistic autoantibodies in patients with STEMI: new kids on the block

Abstract Background The Prognosis after ST-elevation myocardial infarction (STEMI) remains poor. Angiotensin-II and endothelin-1 contribute to adverse prognosis after STEMI through molecular mechanisms that lead to myocardial inflammation, fibrosis and, ultimately, adverse myocardial remodeling. Functional autoantibodies against angiotensin II type 1 (AT1R-AAs) and endothelin-1 type A (ETAR-AAs) receptors bind to the same receptors as natural ligands, eliciting similar (and amplified) responses. In patients with STEMI, AT1R-AAs and ETAR-AAs have been associated with a higher risk of developing microvascular obstruction and left ventricular remodeling. Both microvascular obstruction and left ventricular remodeling are associated with a poor prognosis. Purpose To assess the prognostic role of AT1R-AAs and ETAR-AAs after STEMI. Methods Consecutive STEMI patients who underwent primary percutaneous coronary intervention within 12 h after pain onset were enrolled in this prospective study. The levels of AT1R-AAs and ETAR ETAR-AAs at the time of hospital admission were measured using an enzyme-linked immunosorbent assay (ELISA) in all patients. The incidence of major adverse cardiovascular events (MACE, defined as a composite of cardiovascular mortality, myocardial re-infarction, and hospitalizations for heart failure) during follow-up was the primary outcome. Autoantibody seropositivity was defined according to ELISA’s kit manufacturer’s instructions (levels > 10 U/mL). Results Two hundred patients with STEMI were enrolled. The baseline characteristics of the patients are shown in Table 1. Of these, 110 (55%) were seronegative for both autoantibodies, 44 (22%) were seropositive for one autoantibody (but not both), and 46 (23%) were seropositive for both autoantibodies. The incidence of MACE over a 14-month median follow-up was higher in patients with double (31%) and single (25%) seropositivity than in seronegative patients (13%, p=0.009 and p=0.06, respectively). Survival free from MACE was significantly different across the different degrees of autoantibody seropositivity (Figure 1). In the multivariable Cox regression analysis, adjusted for the variables that were significant in the univariate analysis (highlighted in bold in Table 1), double seropositivity was independently associated with an increased risk of MACE (hazard ratio 2.386, 95 % CI 1.471-3.864, p<0.001). Conclusions The degree of seropositivity for AT1R-AAs and ETAR-AAs is associated with an increased risk of MACE after STEMI. Our findings provide valuable mechanistic insights into the pathophysiology of STEMI and pave the way for future therapies focused on the improvement of long-term prognosis after acute coronary syndromes.

Early left atrial changes in patients with systemic sclerosis by two-dimensional speckle tracking echocardiography

Abstract Background Systemic Sclerosis (SSc) is an autoimmune disease that affects multiple organs 1. Primary myocardial involvement is not uncommon in SSc, with poor prognosis when symptomatic2-4. Pulmonary hypertension and right-sided affection of the heart are well-studied in SSC. Changes in the function of the left atrium (LA) in patients with SSc are early signs of left-sided affection of the heart, which has not yet been well investigated. Two-dimensional (2D) speckle tracking echocardiography (STE) is useful for detecting these early changes. Aim To assess the LA strain parameters in patients with SSC by 2D STE compared to age and sex-matched healthy subjects. Methods This study analyzed prospectively collected data from 30 consecutive SSc patients, excluding those with systemic hypertension and diabetes mellitus and a control group including 30 healthy female volunteers with a mean age of 35.6±7.7. Most SSC patients were females (28/30), with a mean age of 39±10.8. After obtaining informed consent, all participants underwent clinical evaluation and transthoracic echocardiography, including strain analysis. Results Left atrial reservoir (38.1±3.8 % vs. 45.33.7 %; p<0.001), conduit (21.82.7 % vs. 25.73.2 %; p<0.001), and contractile (16.23 % vs. 19.6±2 %; p<0.001) strain parameters were significantly reduced in the SSc population than the healthy controls. The LA stiffness index was also significantly higher in SSc patients (0.186±0.042 vs 0.138±0.018; p<0.001). The total emptying fraction (59.9±7 % vs. 64.73 %; p=0.003), expansion index (160.945.8 % vs. 185.224.1%; p=0.007), and passive emptying fraction (37.37.4 % vs. 40.7±8.5%; p=0.012) were significantly lower in SSc patients compared to the controls. However, the active emptying fraction showed no significant difference between the 2 groups. LA maximal volume was similar between the 2 groups. Conclusion Patients with systemic sclerosis demonstrate reduced LA phasic function even without LA enlargement, as compared to healthy individuals, based on 2D speckle-tracking echocardiography (STE).

Nanocarriers Targeting Circular RNA ADARB1 Boost Radiosensitivity of Nasopharyngeal Carcinoma through Synergically Promoting Ferroptosis.

Nasopharyngeal carcinoma (NPC) is a common malignant tumor of the head and neck, prevalent in regions such as Southern China and Southeast Asia. Radiotherapy serves as the primary clinical treatment for this carcinoma. However, resistance to radiotherapy is a fundamental cause of treatment failure and patient mortality, with the underlying mechanisms yet to be fully elucidated. We identified a recently characterized circular RNA, circADARB1, which is markedly upregulated in NPC tissues and closely associated with poor prognosis and radiotherapy resistance. Both in vitro and in vivo experiments demonstrated that circADARB1 inhibited ferroptosis, thereby inducing radiotherapy resistance in NPC cells. Building on these findings, we synthesized a biomimetic nanomaterial consisting of semiconducting polymer nanoparticles wrapped in cell membranes, designed to deliver both siRNA targeting circADARB1 and iron ions. The application of this nanomaterial not only efficiently suppressed the expression of circADARB1 and boosted intracellular iron concentrations, but also enhanced ferroptosis induced by radiotherapy, improving the radiosensitivity of NPC cells. Furthermore, our study revealed that circADARB1 upregulated the expression of heat shock protein HSP90B1, which repaired misfolded SLC7A11 and GPX4 proteins triggered by radiotherapy, thereby preserving their stability and biological functions. Mechanistically, SLC7A11 facilitated cysteine transportation into cells and glutathione synthesis, while GPX4 employed glutathione to mitigate intracellular lipid peroxidation induced by radiotherapy, shielding cells from oxidative damage and inhibiting ferroptosis, and ultimately leading to radiotherapy resistance in NPC cells. Our investigation elucidates molecular mechanisms with substantial clinical relevance, highlights the promising application prospects of nanotechnology in precision cancer therapy.

Therapeutic targeting of the protein tyrosine kinase-7 in cancer: an overview.

The protein tyrosine kinase-7 (PTK7) is an evolutionarily conserved transmembrane receptor that has emerged as a potential therapeutic target for human tumors. PTK7 is a pseudokinase that is involved in the modulation of the Wnt signaling pathway through interactions with other receptors. These interactions result in targeted gene activation that regulates cell polarity, migration, and proliferation during embryogenesis. Aside of this role during development, PTK7 has been shown as overexpressed in numerous cancers including colon carcinoma, leukemia, neuroblastoma, hepatoma, and ovarian cancer. The activity of PTK7 and the direct correlation with poor prognosis have fostered preclinical investigations and phase I clinical trials, aiming at inhibiting PTK7 and inducing antitumoral effects. In this review, we provide an exhaustive overview of the diverse approaches that use PTK7 as a new molecular target for cancer therapy in different tumor types. We discuss current therapies and future strategies including chimeric antigen receptor-T cells, antibody-drug conjugates, aptamers, based on up-to-date literature and ongoing research progress.

Types of pulmonary hypertension and prognosis in COVID-19: 18-months analysis of BNP-PL national database

Abstract Introduction The COVID-19 pandemic significantly increased mortality in the group of patients (pts) with pulmonary hypertension (PH). However, there is no data whether specific types of this disease, such as PAH associated with connective tissue diseases, were more likely to have a poor prognosis. Aim To assess mortality in the course of COVID-19 among pts diagnosed with PH, treated under the Polish ministry therapeutic program and registered in the national BNP-PL database, according to the type of PH. Methods We analyzed the records of the complete population of Polish pts treated under the National Drug Program of PH (PAH and CTEPH) and registered in the national database of BNP-PL from 01 March 2020 to 31 August 2022. The clinical severity of COVID-19 course and mortality were reviewed. Clinical characteristics of infected and deceased patients were compared in relation to the type of PH. Results The analysis included 143 pts with SARS-CoV-2 infection (mean age 61 ± 15 years; 60% female). Mortality rate was 24% (34/143, including 20 out-of-hospital deaths) vs. 2.6% for estimated in the general population. The highest mortality was observed in the group of pts with idiopathic PAH (33%), slightly lower among pts with connective tissue diseases [CTD] (29%). Patients with congenital heart diseases had a fairly good prognosis [CHD] (81% recovered), and the best survival was recorded in those with CTEPH (84%). CTD and IPAH were found to represent "high-risk" subset with mortality risk ~ 32% vs. ~ 17% in others (p=0.032). Etiologic categories had significant trend for different COVID-19 outcomes according to chi2 test for trend (p=0.039). Conclusions The SARS-CoV-2 infection in pulmonary hypertension pts was related to high mortality, with pts with IPAH had the worst prognosis, folloved by pts with CTD who might already have had lung involvement. Interestingly, the best survival was recorded in one of the oldest group - patients with CTEPH. This may be related to the chronic anticoagulant treatment used in this group, as significant disorders of coagulation pathways have been observed in SARS-CoV-2 infection.

Hydroxyacid Oxidase 1, a Glutamine Metabolism-Associated Protein, Predicts Poor Patient Outcome in Luminal Breast Cancer

Breast cancer (BC), which remains the most prevalent malignancy among women, is characterised by significant heterogeneity across its molecular subtypes. Oestrogen receptor-positive (ER+) (luminal) BC represents approximately 75% of cases, and despite advancements in treatment there remains around a 40% recurrence rate. Cellular uptake of glutamine is conducted by solute carriers (SLCs), which are significantly associated with outcome in luminal BC. In this study, differential gene expression analysis was carried out using The Cancer Genome Atlas BC dataset. This identified hydroxyacid oxidase 1 (HAO1) as significantly overexpressed in luminal BC with a high expression of SLCs. Extended analysis in the METABRIC (n = 1980) and Breast Cancer Gene-Expression Miner (n = 4421) transcriptomic databases and the Nottingham (n = 952) BC tissue cohort showed a varied survival outcome for HAO1 expression at the genomic, transcriptomic, and proteomic levels. HAO1 copy number (CN) gain (p = 0.002) and high HAO1 protein expression (p = 0.019) were associated with poor prognosis in luminal BC, whereas high HAO1 mRNA expression correlated with better survival outcomes (p = 0.023) suggesting a complex regulatory mechanism affecting HAO1 at different biological levels. Importantly, in luminal BC patients treated with endocrine therapy, high protein expression of HAO1 predicted shorter distant-metastasis free survival (p = 0.042). The knockdown of SLC1A5 and SLC7A5 significantly reduced HAO1 expression in MCF-7 and ZR-751 BC cell lines. Protein analysis confirmed significant associations between HAO1 and SLC7A5 and SLC1A5, emphasising a potential role for the enzyme in glutamine metabolism and its potential as a therapeutic target. This study underscores the prognostic significance of HAO1 in luminal BC and its relationship with patient outcomes.

Transcatheter vs. surgical aortic valve replacement in patients with aortic stenosis and cardiogenic shock.

Patients with aortic stenosis (AS) and cardiogenic shock (CS) are an extremely high-risk population with a poor prognosis in the absence of definitive therapy. We aimed to compare the outcomes of transcatheter aortic valve replacement (TAVR) with those of surgical aortic valve replacement (SAVR) in patients with AS-CS. We queried the Nationwide Readmission Database (2016-21) to identify patients hospitalized for AS-CS who underwent isolated TAVR or SAVR. In-hospital outcomes of TAVR vs. SAVR were compared using multivariable regression and propensity-matching analyses. Ninety-day readmissions were compared using a Cox proportional hazards regression model. A total of 16 161 patients were hospitalized for AS-CS, of whom 6470 (40.0%) underwent isolated TAVR and 9691 (60.0%) underwent isolated SAVR. From 2016 through 2021, the proportion of TAVR increased from 29.5 to 46.5% and the proportion of SAVR correspondingly decreased in AS-CS (Ptrend < 0.01). After adjustment for baseline characteristics, TAVR was associated with lower odds of stroke [adjusted odds ratio (aOR) 0.63, 95% confidence interval (CI) 0.47-0.84], acute kidney injury (aOR 0.80, 95% CI 0.69-0.93), and major bleeding (aOR 0.54, 95% CI 0.40-0.71) and higher odds of vascular complications (aOR 1.56, 95% CI 1.23-1.97) compared with SAVR. In-hospital mortality, myocardial infarction, permanent pacemaker placement, and 90-day all-cause and heart failure readmissions showed similar rates between TAVR and SAVR. However, hospital length of stay was shorter and total costs and non-home discharges were lower with TAVR than with SAVR. This nationwide observational analysis showed that TAVR is increasingly performed in patients with AS-CS and is associated with similar rates of in-hospital mortality and 90-day readmissions but lower rates of in-hospital complications and resource utilization compared with SAVR.

The obesity paradox in patients with hypertrophic cardiomyopathy: A Korean nationwide cohort study

Abstract Background In cardiomyopathies, obesity is known to affect the cardiac remodeling and is associated with a poor prognosis. However, in hypertrophic cardiomyopathy, which is included in the category of heart failure with preserved ejection fraction, the risk of underweight has been suggested, and its impact in practice is controversial. Purpose The aim of this study was to investigate the potential relationship between obesity and cardiovascular outcomes in patients diagnosed with hypertrophic cardiomyopathy. Methods We conducted a retrospective national cohort study from 2013 to 2020 utilizing administrative claims data and health check-up database from the Korean National Health Insurance Service. Patients newly diagnosed with hypertrophic cardiomyopathy from January 2015 to December 2019 were included. Body mass index was stratified into five groups based on the World Health Organization's recommended criteria for Asian populations, and patients were followed until the date of each outcome or the end of the study period. Predefined clinical outcomes included heart failure hospitalization events, fatal arrest events, all-cause death, and composite clinical outcomes. Results A total of 6,361 patients were included in the study, with a mean age was 60 ± 13 years and 32.6% female. During a median follow-up of 3.0 years (interquartile range, 1.8 to 4.3), 921 heart failure hospitalization, 185 fatal arrest, and 340 deaths occurred. The underweight group had higher adjusted hazard ratios for heart failure hospitalization, fatal arrest, all-cause death, and the composite outcome compared to the normal range body mass index group (HR 1.69, 95% CI 1.16-2.47; HR 2.29, 95% CI 1.06-4.93; HR 2.74, 95% CI 1.77-4.24; HR 1.77, 95% CI 1.28-2.45). In addition, the adjusted hazard ratios for the composite outcome were lower in the overweight and obese I group compared to the normal range (HR 0.80, 95% CI 0.68-0.95; HR 0.84, 95% CI 0.72-0.98). Conclusions Among patients with hypertrophic cardiomyopathy, those classified as underweight had an increased risk of heart failure hospitalization, fatal arrest, all-cause death, and composite outcomes compared with normal weight patients, while those classified as overweight and obese had a decreased risk of composite outcomes.

Exploring IRGs as a Biomarker of Pulmonary Hypertension Using Multiple Machine Learning Algorithms

Background: Pulmonary arterial hypertension (PAH) is a severe disease with poor prognosis and high mortality, lacking simple and sensitive diagnostic biomarkers in clinical practice. This study aims to identify novel diagnostic biomarkers for PAH using genomics research. Methods: We conducted a comprehensive analysis of a large transcriptome dataset, including PAH and inflammatory response genes (IRGs), integrated with 113 machine learning models to assess diagnostic potential. We developed a clinical diagnostic model based on hub genes, evaluating their effectiveness through calibration curves, clinical decision curves, and ROC curves. An animal model of PAH was also established to validate hub gene expression patterns. Results: Among the 113 machine learning algorithms, the Lasso + LDA model achieved the highest AUC of 0.741. Differential expression profiles of hub genes CTGF, DDR2, FGFR2, MYH10, and YAP1 were observed between the PAH and normal control groups. A diagnostic model utilizing these hub genes was developed, showing high accuracy with an AUC of 0.87. MYH10 demonstrated the most favorable diagnostic performance with an AUC of 0.8. Animal experiments confirmed the differential expression of CTGF, DDR2, FGFR2, MYH10, and YAP1 between the PAH and control groups (p &lt; 0.05); Conclusions: We successfully established a diagnostic model for PAH using IRGs, demonstrating excellent diagnostic performance. CTGF, DDR2, FGFR2, MYH10, and YAP1 may serve as novel molecular diagnostic markers for PAH.

Impact of global longitudinal strain and anemia for predicting cardiovascular mortality in patients hospitalized for acute heart failure with atrial fibrillation

Abstract Background Iron deficiency is a prognostic factor in heart failure (HF) with reduced ejection fraction (EF). In patients with atrial fibrillation (AF) and HF, left ventricular EF (LVEF) measurements are imprecise due to irregular tachycardia, but it is unclear whether global longitudinal strain (GLS) and anemia assessment are prognostic. Purpose We examined whether GLS and anemia predict cardiovascular death (CD) in patients with acute HF complicated by AF. Methods We retrospectively enrolled patients aged 18 years or older with acute HF complicated by AF who were consecutively admitted to our hospital from January 2014 to December 2018. Exclusion criteria were acute coronary syndromes, no transthoracic echocardiogram performed within 30 days before or after admission, and missing data. All patients were followed up from admission to CD (due to myocardial infarction, HF, stroke or sudden death), or were censored at the date of last contact or 3 years. Anemia was defined as hemoglobin &amp;lt; 12 g/dL in females and hemoglobin &amp;lt; 13 g/dL in males. Patients were divided into four groups according to median GLS and anemia status. Results A total of 320 patients (mean age 79 ± 12 years, 163 females) were included in the analysis. The median duration of AF was 1.2 years; 11% (36/320) had paroxysmal AF. The median brain natriuretic peptide value was 623 pg/ml, and 52% of the patients (165/320) were in New York Heart Association functional class 4. During a median follow-up of 528 days, 24% (77/320) patients were observed with CDs: 2 myocardial infarctions, 51 HF-related deaths, 6 strokes, and 18 sudden cardiac deaths. At the 3-year follow-up, the survival rate by the Kaplan-Meier curve was 89% (95% confidence interval (CI) 76%-95%) in the no anemia group with high GLS (&amp;lt; -10%) and 40% (95% CI 25%-54%) in the anemia group with low GLS (≥ -10%) (p &amp;lt; 0.001, log-rank test). In multivariate Cox regression analysis, GLS (adjusted hazard ratio (aHR) 1.06, 95% CI 1.01-1.14, p = 0.017) and hemoglobin (aHR 0.85, 95% CI 0.76-0.96, p = 0.009) were independent factors for CD, with a significantly increased risk in the anemia group with low GLS compared to the no anemia group with high GLS (aHR 4.11, 95% CI 1.59-10.6, p = 0.004). The results were consistent with no interaction by gender or LVEF 50%. Conclusions Anemic patients with low GLS with AF and HF may have poor prognosis. Prospective studies are needed to determine whether iron supplementation improves prognosis in such patients.

Prognostic Evaluation of Conversion Therapy Following Hepatic Arterial Infusion Chemotherapy or Immunotherapy in Patients with Advanced or Transarterial Chemoembolization Unsuitable Intermediate-Stage Hepatocellular Carcinoma-A retrospective cohort study.

Patients with advanced-stage or intermediate-stage hepatocellular carcinoma (HCC) unsuitable for transarterial chemoembolization (TACE) had poor prognoses. Recent advancements in hepatic arterial infusion chemotherapy (HAIC) and immune checkpoint inhibitors (ICIs) have demonstrated higher tumor response rates, which improved overall survival (OS). HAIC achieves an OS rate of approximately 14.5-15.3 months with a 39.1-42.5% tumor response rate. In comparison, ICIs have a 12-14 month OS rate with a 26-33% tumor response rate. Given these promising responses, this study evaluates the efficacy of conversion therapy with curative intent following HAIC or ICIs, focusing on survival outcomes. We retrospectively analyzed 80 patients with advanced or TACE-unsuitable intermediate HCC. Patients completed two HAIC or four ICI cycles, followed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria imaging. Based on demographics, cirrhosis status, Barcelona Clinic Liver Cancer classification (BCLC) stage, treatment responses, and treatment modality, survival impacts were analyzed. OS was compared between HAIC and immunotherapy groups. The effect of conversion therapy with curative intent on survival outcomes was analyzed using a Cox regression model. Among the 80 patients, 26 achieved positive response (CR/PR) with HAIC or ICIs, and 9 of them subsequently underwent conversion therapy with curative intent. Key prognostic factors included Child-Pugh stage B vs. A (HR=2.21, p=0.041), BCLC stage C vs. B (HR=4.38, p=0.011), and elevated AFP levels (HR=5.02, p&lt;0.001). Positive responders saw substantial survival benefits (HR=0.26, p=0.001). Patients undergoing conversion therapy exhibited significantly enhanced survival. Median OS was 13.58 months with standard therapy, while the curative intent surgery group did not reach the median OS (p=0.002). For CR/PR patients, 48-month survival was 75.0% for the curative surgery group versus 38.0% for standard treatment. Conversion therapy with curative intent following HAIC or ICIs might enhances survival in patients with advanced or TACE-unsuitable intermediate-stage HCC.

Clinical impact of transcatheter aortic valve implantation (TAVI) in frail patients: a single-center prospective study

Abstract Introduction Transcatheter aortic valve implantation (TAVI) stands as an effective treatment option for symptomatic severe aortic stenosis, applicable across all surgical risk spectrum. Registries show that up to 60% of these patients exhibit at least one marker of frailty. Frailty has been associated with higher 1-year mortality rates and heightened susceptibility to complications. Conservative treatment, however, has a poor prognosis, with mortality ranging from 30-60% within a year after diagnosis. Objective The primary objective was to assess the clinical impact of TAVI implantation in the frail population. A secondary objective was to assess the occurrence of in-hospital and short-term (30 days) complications. Methods Observational, prospective, single-center study that included all patients with TAVI implantation in our unit in 2023. Frailty was assessed by an interventional cardiologist according to the Rockwood Clinical Frailty Scale (CFS) or Frailty Scale, assigning a score from 1 to 9, with patients being classified as high CFS if they scored ≥5 points or low CFS if &amp;lt;5 points. Results Out of the 298 patients included, 45 (15%) had high CFS vs 253 (85%) with low CFS. Significant differences were found in age (83.3±5.3 years for high CFS vs 79.4±5.8 years for low CFS;p&amp;lt;0.01), gender (60% of females for high CFS vs 43.9% for low CFS;p=0.046) and baseline haemoglobin (12.2±1.5 g/dL for high CFS vs 12.9±1.8 g/dL for low CFS;p=0.008). Other baseline characteristics remained comparable. Patients with high CFS had greater baseline dyspnoea according to the YHA scale (NYHA III-IV 71.1% for high CFS vs 37.9% for low CFS;p&amp;lt;0.001) with greater diuretic use (71.1% for high CFS vs 51% for low CFS;p=0.013). Patients with high CFS had a greater need for a preferential/urgent procedure (p=0.044). There were no differences in the occurrence of complications: stroke (p=0.463), bleeding (p=0.667), vascular complications (p=0.234); except for a higher occurrence of complete AV block (22.3% for high CFS vs 8.7% for low CFS;p=0.024). In-hospital mortality rates showed no differences (0% for high CFS vs 1.6% for low CFS;p=0.396). At 1-month follow-up, there was a significant reduction in NYHA dyspnoea grade within the high CFS group (71.1% NYHA III-IV pre-TAVI vs 2.3% post-TAVI; p&amp;lt;0.001). There was no difference in the incidence of stroke (p=0.375), heart failure readmissions (p=0.734), and vascular complications (p=0.66). There was no difference in all-cause mortality (4.4% for high CFS vs 3.2% for low CFS;p=0.675). Conclusions Highly frail patients undergoing TAVI experience a significant enhancement in functional class compared to their less frail counterparts. While short-term complications parallel those observed in less frail individuals, there is a slightly elevated incidence of pacemaker requirements in this group.NYHA Frail pre and post TAVIComplications

PEDF upregulated in Ngfr-positive cells suppresses proliferation of pulmonary artery smooth muscle cells

Abstract Background Pulmonary arterial hypertension (PAH) is a disease with poor prognosis that causes right heart failure due to progressive pulmonary artery remodeling. Although existing pulmonary vasodilators contribute to pulmonary artery reverse remodeling by reducing share stress, the development of therapeutic agents that directly target pulmonary vascular remodeling is desired. Nerve growth factor receptor (Ngfr) is involved in the inflammatory reaction and repair process of damaged tissues. We have previously reported that Ngfr-positive cells are increased in the peripheral blood (PB) of PAH patients and are associated with disease progression. We also found that Ngfr inhibited the pathogenetic progression of pulmonary hypertension in a model of hypoxia-induced pulmonary hypertension. However, it remains unclear how Ngfr positive cells are involved in the pathology of PAH. Purpose In this study, we investigate how Ngfr-positive cells affect the pathogenesis of PAH. Methods &amp; Results To evaluate the localization of Ngfr-positive cells in lung tissue, WT mice (C57BL/6) transplanted with bone marrow (BM) of GFP-Tg mice were kept under hypoxia for 3 weeks to create hypoxia-induced pulmonary hypertension (PH) model. Immunostaining of lung tissue sections indicated that double positive cells (Ngfr+GFP+) were present in the interstitial tissue around the small pulmonary artery. To examine the cellular characteristics of Ngfr-positive cells, RNA sequencing of Ngfr-positive and Ngfr-negative cells in PB was performed. Significantly 78 genes were upregulated in Ngfr-positive cells, including 11 secreted proteins. Among these, we focused on pigment epithelium-derived factor (PEDF), a secreted protein involved in angiogenesis. PEDF mRNA expression was decreased in the lung of Ngfr-KO mice compared to WT mice. We next examined the effect of PEDF on pulmonary artery smooth muscle cells (PASMCs). Platelet-derived growth factor (PDGF)-induced cell proliferation of PASMC was inhibited by PEDF stimulation. Furthermore, PEDF stimulation significantly inhibited PDGF-induced mRNA expressions of TNF and MMP9 in PASMCs. Conclusion In this study, we show that PEDF expression is upregulated in Ngfr-positive cells and that PEDF inhibits PDGF-induced hPASMC proliferation, suggesting that NGFR-positive cells may suppress pulmonary vascular remodeling through PEDF-mediated paracrine effects. PEDF might be a new therapeutic target for PH.

Clonal haematopoiesis of indeterminate potential predicts recurrence of atrial arrhythmias after surgical ablation for atrial fibrillation

Abstract Background Clonal haematopoiesis of indeterminate potential (CHIP), characterized by the presence of somatic blood cell clone expanding without other haematological abnormalities, was recently shown to be significantly associated with the development and progression of atrial fibrillation (AF). However, the clinical relevance of CHIP in patients underwent surgical atrial ablation remained unexplored. Aims This study investigated the potential role of CHIP in the recurrence of atrial arrhythmias after surgical ablation in patients with AF. Methods Deep-target sequencing of 74 CHIP (a mean depth of coverage = 4051x) was performed in 132 patients with AF (mean age, 60 years; 75.8% male; mean left atrial diameter, 47mm) who underwent surgical ablation without previous atrial ablation between December 2014 and September 2021. Variant allele fraction (VAF) ≥ 2.0% of any targeted genes indicated the presence of CHIP mutations. The primary outcome is the recurrence of any atrial arrhythmias for &amp;gt;30s after a blanking period of 3 months within a year. The clinical significance of CHIP was determined by multivariable Cox proportional hazards regression. Results A total of 17.4% (23 of 132) patients with AF carried CHIP mutations (DNMT3A, 8.3% and TET2, 3.8%). CHIP prevalence varied among AF types, with paroxysmal, persistent, and long-lasting AF counting for 12.5%, 16.5%, and 36.4%, respectively. During one-year follow-up after blanking period, recurrent atrial arrhythmia was documented in 15 (65.2%) and 37 (33.4%) patients in the CHIP and non-CHIP groups, respectively (p = 0.005 for log-rank test). The association of CHIP with atrial arrhythmias recurrence remained significant after fully adjustment (hazard ratio, [95% confidence interval], 1.92 [1.02-3.63]). Conclusions CHIP mutations with a VAF ≥ 2.0% were identified in 17.4% AF patients undertaken surgical ablation and was associated with poor prognosis. CHIP assessment may be useful in the personalized management of patients who planned to perform surgical ablation for AF.

Association of osteopontin and shrunken pore syndrome with hospitalization for renal failure in acute heart failure patients

Abstract Background Shrunken pore syndrome (SPS) emerges as a distinctive manifestation of glomerular filtration dysfunction mainly manifested by the impairment of moderate-sized molecular filtration, distinguished by a variance in renal filtration between cystatin C and creatinine. SPS exhibits correlations with adverse prognosis of various cardiovascular diseases. A decline in renal function correlates with a poor prognosis among individuals with heart failure (HF). Osteopontin (OPN), a protein involved to bone mineralization, has been linked to deteriorating renal function and heightened risk for adverse outcomes in patients with chronic kidney disease. Purpose To explore if OPN and SPS are associated with hospitalization for renal failure in patients with acute HF. Methods Cystatin C and creatinine were analyzed in 395 hospitalized HF patients, of which 324 also had osteopontin (OPN) analyzed using a proximity extension assay. SPS was calculated using the CKD-EPI Equations for Glomerular Filtration Rate and defined as a cystatin C-based estimated glomerular filtration rate (eGFR) &amp;lt;60% of the creatinine based eGFR. Hospitalization for renal failure was extracted from regional registries using ICD10 codes N17-N19. Logistic and Cox regression models were deployed to explore a) OPN’s association with SPS; b) OPN’s association with hospitalization for renal failure; and c) SPS’s association with hospitalization for renal failure, adjusting for age, sex, systolic blood pressure and use of renin-angiotensin-aldosterone system (RAAS) inhibitors. Results The study population had a mean age of 74.8 (±12.0) years, 32.4% were women and 104 (26.5%) patients presented with SPS (Table 1). During the median follow-up period of 71 (interquartile range 56-88) months, 35 (8.9%) patients were hospitalized for renal failure. OPN was associated with the prevalence of SPS (OR 1.66; 95%CI 1.08-2.27; p=0.002), as well as with higher risk of hospitalization due to renal failure (HR 2.71; 95%CI 1.61-4.56; p&amp;lt;0.001). Further, also prevalent SPS was associated with higher risk of hospitalization due to renal failure (HR 2.44; 95%CI 1.14-5.24; p=0.022). Conclusions Here, we demonstrate that higher OPN levels are associated with a higher prevalence of SPS and an elevated risk of hospitalization due to renal failure among patients with HF. Additionally, the presence of SPS was associated with a higher risk of renal failure-related hospitalizations. These findings highlight the potential utility of OPN and SPS as biomarkers for identifying heart failure patients at risk of renal function decline, underscoring the importance of early risk stratification and targeted interventions in this population.

The impact of the 2022 definition of pulmonary hypertension on long-term clinical outcomes in patients with heart failure with preserved ejection fraction

Abstract @ Backgrounds: In recent years, the definitions of pulmonary hypertension (PH) have been revised for early diagnosis and risk stratification of patients with PH. Using the 2015 definitions, the development of a precapillary component of PH in addition to a postcapillary PH was associated with right heart dysfunction and poor prognosis in patients with heart failure (HF) with preserved ejection fraction (HFpEF). However, the prognostic impact of revised definitions of PH in patients with HFpEF has not been fully evaluated. Purpose We investigated the impact of the 2018 and 2022 ESC/ERS definitions of PH on long-term clinical outcomes using data from a prospective, multicenter, observational study of patients with HFpEF (PURSUIT-HFpEF). Methods A total of 250 patients hospitalised with acute HF who underwent right heart catheterisation after initial HF treatment were divided into PH categories according to the 2018 and 2022 definitions: isolated postcapillary PH (Ipc-PH), precapillary PH, combined postcapillary and precapillary PH (Cpc-PH), and unclassified PH. The incidence of the composite endpoint of all-cause death and HF rehospitalisation after discharge was compared across the PH categories. Results The overall prevalence of PH defined as a mPAP &amp;gt; 20 mmHg was 54%. Applying the 2022 definition, 42 patients (17%) were reclassified as either precapillary PH or Cpc-PH, resulting in a significant increase in the propotion of patients classified as having PH with a precapillary component (precapillary PH and Cpc-PH) compared with the 2018 definition (26% vs. 11%, p&amp;lt;0.0001). At a median follow-up of 822 days after discharge, PH with a precapillary component was associated with poor clinical outcomes according to the 2018 definition (Figure 1A), but according to the 2022 definition, clinical outcomes did not differ across the PH categories (Figure 1B). PVR ≥3 Wood units (WU) was a significant prognostic indicator, but there was no significant difference between the PVR 2-3 WU and PVR ≤2 WU categories (Figure 2). Conclusions The 2022 definition showed no association between PH classification and clinical outcomes. In patients with HFpEF, PVR ≥3 WU was identified as the key factor increasing the risk of all-cause death and HF hospitalisation.Figure 1Figure 2

Combined ARNI and SGLT2i impacts on peak tricuspid regurgitant velocity and echocardiographic probability of pulmonary hypertension

Abstract Background In heart failure with reduced ejection fraction (HFrEF), the development of pulmonary hypertension (PH) is associated with poor prognosis. Recent medical advancements have substantially improved both survival rates and HF hospitalization. However, the impact of combining angiotensin receptor neprilysin inhibitor (ARNI) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) on peak tricuspid regurgitant velocity (TRV) and PH echocardiographic probability remains unexplored. Purpose We aimed to evaluate the effect of ARNI alone versus ARNI combined with SGLT2i on peak TRV and PH probability in a real-life population of outpatients with HFrEF. Methods This was an observational monocentric study including patients treated with either ARNI alone or with SGLT2i on top of ARNI. Echocardiographic examinations were performed by fully accredited operators and all parameters were analysed offline by expert operators blinded to clinical data. We performed echocardiographic evaluation in all patients before initiating treatment and at 12 months follow-up. We excluded patients who discontinued ARNI within 6 months of introduction and those who did not complete at least 6 months of follow-up with both drugs. Results 80 HFrEF patients were included, 41 receiving ARNI+SGLT2i and 39 receiving ARNI alone. Baseline mean peak TRV was similar between the two groups (280±44 cm/s and 259±48 cm/s respectively, p=0.09). At follow-up, mean peak TRV was 232±32 cm/s in ARNI+SGLT2i group and 258±45 cm/s in ARNI alone group (p=0.02). The decrease in peak TRV was significant in ARNI+SGLT2i group, p=0.0004 (Table). At baseline the echocardiographic probability of PH was comparable between both groups, p=0.53 (Figure). Nevertheless, during follow-up, the proportion of patients with high probability of PH decreased in the ARNI+SGLT2i group (from 22% to 2%), while in the ARNI alone group it did not change (Figure). Conclusions In HFrEF the combination of ARNI+SGLT2i demonstrates high effectiveness in TRV reduction, downgrading PH probability class. In our population, this evidence is primarily driven by the decrease TRV. These results may suggest the positive effect of SGLT2i on pulmonary vascular remodelling and right heart hemodynamic worth of full investigation in further studies aimed at targeting left-sided PH and its prevention strategies.