Disease Severity Research Articles

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 < 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.

Multidisciplinary management of gastroesophageal reflux disease: an italian retrospective study

Abstract Background Millions of individuals are affected by gastroesophageal reflux disease (GERD) that causes significant discomfort negatively affecting patients’ overall quality of life. For a collaborative approach of continuous improvement in public health we wanted to know the real-world perspectives in the multidisciplinary and multimodal management pathway. Methods We aimed to interview a sample of gastroenterologists (GE), primary care physicians (GP), and otolaryngologists (ENT) to investigate the management of the intake and treatment of patients reporting symptoms of GERD. Symptoms were divided into typical and extraesophageal, and their severity and impact on quality of life was explored with the GERD Impact Scale (GSI) and Reflux Symptom Index (RSI). Results A total of 6211 patients were analyzed of whom with typical symptoms were 53.5%, while those with extraesophageal symptoms were 46.5%. The latter were more frequently reported by ENT patients (53.6%, p < 0.0001). GSI was highest in patients followed by GE (9 points) and GP (9 points) than ENT specialists (8 points), while the RSI was higher in the ENT group (14.3 ± 6.93) than in the groups of GP and GE, respectively (10.36 ± 6.36 and 10.81 ± 7.30, p < 0.0001). Chest pain had the greatest negative impact on quality of life (p < 0.0001). Of the 3,025 patients who used (proton pump inhibitors) PPIs, non-responders had a lower GSI when treated with a combination of adjunctive drug treatments and bioadhesive compounds, compared with single-component drugs. Conclusions The multidisciplinary and multimodal approach to the management pathway of GERD patients reveals variations in patient profiles by physician specialty, directing toward more appropriate and targeted treatments. In addition, the combination of adjunctive drug treatments and bioadhesive compounds appears to be effective in the management of patients refractory to PPIs. Key messages • The presentation of GERD symptoms is different in accordance with the physician’s speciality: the patients with GERD referred to a gastroenterologist had more severe disease and poorer quality of life. • The combination of adjunctive pharmacological treatments and bioadhesive compounds seems to be effective in the management of PPI refractory patients.

Knowing the Antibody Status may influence compliance of health care workers to COVID-19 booster dose

Abstract Background Previous studies showed that the fourth SARS-CoV-2 vaccine dose has a protective effect against infection, as well as against severe disease and death. This study aimed to examine whether knowledge of a high level antibody after the 3rd dose may reduce compliance to the 4th booster dose among health care workers. Methods We conducted a prospective cohort study among health care workers vaccinated with the first three doses at Rambam Healthcare Campus, a tertiary hospital in northern Israel. Participants underwent a serological test before the 4th booster vaccine was offered to all of them, with results provided to participants. The population was divided into two groups: those with antibody below 955 AU/ml, and those with 955 AU/ml and higher, a cutoff found protective in a previous study. Multiple logistic regression was carried out to compare the compliance to the 4th booster between the two groups, adjusted for demographic and clinical variables. Results After adjusting for the confounding variables, the compliance was higher in those with antibody levels below 955 AU/ml (OR = 1.41, P = 0.05, 95% CI 1.10-1.96). In addition, male sex, and age of 60 years and above were also associated with higher vaccination rate (OR = 2.28, P < 0.001, 95% CI 1.64 - 3.17), (OR = 1.14, P = 0.043, 95% CI 1.06 - 1.75), respectively. Conclusions Knowledge of the antibody status may affect compliance with the booster dose. Considering waning immunity over time, reduced compliance may affect the protection of health care workers who declined the 4th dose. Key messages • Knowing the antibody status may affect compliance of health care workers with the booster dose. • Reduced compliance of health care workers may affect their protection.

New advances in RSV: Is prevention attainable?

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection (LRTI), hospitalization, and mortality in infants and young children globally. The greatest burden of severe disease and mortality occurs in low-middle income countries (LMICs), with large and vulnerable childhood populations. The highest rates of RSV-hospitalization occur in healthy-term infants under 3 months of age. Preterm infants, children with chronic lung disease of prematurity, Down's syndrome, congenital heart disease, or immunodeficiency also have a higher risk of severe RSV-LRTI. Early-life RSV-LRTI has also been associated with chronic sequelae, including recurrent LRTI, recurrent wheezing, asthma, and lung function impairment. A RSV pre-fusion (F) maternal vaccine and long-acting monoclonal antibody (nirsevimab) have been licensed for the prevention of RSV-LRTI in infants and young children. Studies show high efficacy and effectiveness particularly for preventing severe RSV-LRTI. Maternal RSV vaccine given at 24-36 weeks of pregnancy was effective in preventing RSV medically attended LRTI and severe RSV-LRTI through 6 months after birth in a phase 3 study conducted in 18 countries over two RSV seasons. Vaccination was safe with no significant difference in adverse events between infants born to mothers who received RSV preF vaccine compared to placebo. A numerical imbalance in preterm births that occurred predominantly in South Africa, unrelated to vaccine timing or gestational age at vaccination and unassociated with mortality, coincided with COVID-19 delta and omicron waves. Nirsevimab, given as a single dose prior or during the RSV season, had high efficacy in preventing RSV-LRTI hospitalization in infants in preterm and in full-term infants, as well as in young children with underlying conditions through 150 days post administration in phase 2 and 3 trials. High effectiveness against hospitalization or severe disease in infants and in at-risk children up to 2 years of age has also been reported in several countries where implementation has occurred. RSV-LRTI is now a preventable disease in infants and young children. Rapid implementation of these highly effective interventions has occurred in many high-income countries, but access remains very limited in LMICs. Access to such RSV preventive interventions is urgently needed for all children to strengthen child health and promote global equity.

Comparing predictive risk to actual presence of coronary atherosclerosis on coronary computed tomography angiography: a retrospective cohort analysis

Abstract Background There is limited data supporting the ability of cardiovascular risk scores (CVRS) to accurately predict asymptomatic coronary artery disease (CAD). Purpose To examine the predictive accuracy of CVRS in detecting presence and extent of atherosclerosis, determined by coronary computed tomography angiography (CCTA). Methods Asymptomatic individuals without known CAD, undergoing a screening CCTA with available CVRS data, were examined retrospectively. Natural language processing of the CCTA report data extracted the coronary artery calcium score (CACS) and the extent and severity of coronary plaque (low, moderate, or extensive, using a modified CAD-RADS 2.0 classification). Normal was defined as both zero plaque and zero CACS. CVRS was categorized as high (>15%), moderate (10-15%), low (1-9%) and "zero" (<1%) risk. Results 828 individuals (median age 58.6, IQR=52.0, 65.3 years, 57% male) met inclusion criteria, and a zero, low, moderate, and high CVRS was identified in 13, 483, 113 and 219 individuals, respectively. Any degree of atherosclerosis was found in 548 scans (67% male). However, of the 137 males and 68 females with extensive atherosclerosis, 47 (34%) and 38 (56%) respectively had a low CVRS classification. Overall, 23% of males and 31% of females had CAD predicted by CVRS, with little to no agreement between CVRS and atherosclerosis burden (Cohen’s kappa: males, κ=0.149; females, κ=0.096). Conclusions In asymptomatic individuals without known CAD, CVRS does not reliably predict the presence and extent of CAD, and severe disease may be present in apparently low CVRS.Graphical AbstractFigure

Artificial intelligence to assist the echocardiographic identification of transthyretin cardiac amyloidosis

Abstract Introduction Transthyretin cardiac amyloidosis (ATTR-CM) is a severe disease, and treatments are most effective when initiated at early stage. Echocardiography is the main tool for screening patients with suspected ATTR-CM or populations at high risk of ATTR-CM. Suspicion of ATTR-CM triggers a dedicated confirmatory evaluation. Echocardiographic diagnosis is however difficult to implement in a non-expert cardiologist workflow. An algorithm to assist the identification of potential cases would be helpful to assist clinicians. Objective To develop an algorithm using artificial intelligence (AI) to assist the identification of potential ATTR-CM cases using routine transthoracic echocardiography. Methods In this non-interventional, monocentric case-control study, a dedicated database, comprising confirmed ATTR-CM patients and a control group, was built. We trained and validated a deep learning model based on Convolutional Neural Network from transthoracic echocardiography video loops. Results A total of 4394 patients were included in the database: 208 in the ATTR-CM group (76% males, mean age 69±10 years old, 90% hereditary ATTR-CM with NAC I score in 77%) and 4186 in the control group (59% male, mean age 62±16 years). After training the model to identify potential ATTR-CM, the ROC curve AUC was 0.97, accuracy was 94.7%, precision was 87.3%, and recall 84.4%. After selecting a subgroup of 130 pairs of matched ATTR-CM/controls based on age, sex, and wall thickness, the algorithm performance remained robust (AUC 0.99, accuracy 99.4%, precision 100%, recall 98.3%). Conclusion and Perspectives: Diagnosis of ATTR-CM by echocardiography can be assisted by an algorithm using AI. The algorithm remains effective in distinguishing ATTR-CM from other causes of left ventricular hypertrophy. External validation of this tool is underway.ROC curveAssisted classification

Characterizing disease burden and health care resource utilization in patients with hypertrophic cardiomyopathy: a nationwide real-world study in Finland

Abstract Background Hypertrophic cardiomyopathy (HCM) is an often hereditary myocardial disease with an estimated prevalence of 1:500 in the general population. Purpose This study aimed to investigate healthcare resource utilization (HCRU) and associated costs in patients diagnosed with HCM (and the associated subtypes: obstructive or non-obstructive) in a nationwide cohort in Finland. Methods This retrospective, registry-based cohort study included all Finnish patients diagnosed with HCM between 2000 and 2021, who were 12+ years old at the time of diagnosis, as identified from the national care registers for healthcare. HCRU data were collected between 2014 and 2021 from the Finnish national care registers for health care and the social insurance institution. Data pertaining to New York Heart Association (NYHA) classification were collected from three Finnish university hospitals. Results The study cohort comprised 5,834 patients with an HCM diagnosis; obstructive HCM accounted for 34% of cases. Mean per patient-year costs were €6638, 95% confidence interval (CI) €6472-€7415, and €6112, 95% CI €5957-€6560 for those with obstructive and non-obstructive HCM respectively. All-cause hospitalizations at specialized care were the most prominent cost associated with patients with obstructive and non-obstructive HCM equating to 46.3% and 46.1% of the total cost respectively (Fig 1.). Comorbidity burden, as measured by Charlson comorbidity index (CCI) score, was greater in patients with the obstructive than non-obstructive phenotype of the disease (CCI ≥4: 2.2 and 1.8, p<0.01, respectively). The highest utilization of invasive procedures was found for patients with NYHA class III-IV. Conclusion This population-based study, utilizing real-world data, provides novel insights into HCRU and related costs among Finnish patients with HCM (and associated subtypes). HCRU appears to be primarily driven by hospitalizations at specialized care. Furthermore, the data indicate that patients with obstructive HCM are likely to have a more severe disease, with higher comorbidity burden and requiring more invasive procedures than patients with the non-obstructive form of the disease. However, there were no statistically significant differences in health care costs between those with obstructive and non-obstructive HCM.

Impaired right ventricular strain is associated with worse prognosis in patients with liver cirrhosis

Abstract Introduction Cirrhotic cardiomyopathy is a complication of liver cirrhosis accounting for significant morbidity and associated with reduced patient survival. It is characterized by reduced afterload, increased cardiac output, and diastolic dysfunction. However, there are limited data regarding the prognostic significance of right ventricular (RV) mechanics. Novel echocardiographic techniques such as speckle tracking echocardiography can detect subclinical myocardial dysfunction early in the course of non-ischemic myocardiopathies. Purpose To investigate the prognostic role of RV free wall strain (RVFWS) in patients with liver cirrhosis. Methods We prospectively enrolled 70 patients with liver cirrhosis in stable clinical condition. Patients with coronary artery disease, valvular heart disease, ongoing alcohol consumption or poor acoustic window were excluded from the study. Transthoracic echocardiography was performed and RVFWS was calculated from RV focused 4-chamber views using a dedicated software. Since RVFWS was as expected negative in all patients, absolute values were used for all calculations. Clinical and laboratory examination was also performed in all patients and the Model for End-Stage Liver Disease (MELD) score a widely used tool for assessing liver disease severity was calculated. All-cause mortality at 24 months was the primary endpoint and was available in all patients. Results Mean RVFWS in the cohort was 27.4±6.3% and using a lower normal limit of 20%, reduced RVFWS was detected in six patients. According to the Spearman coefficient analysis, RVFWS was correlated with MELD (rho=0.274, p=0.023) indicating increased values in patients with more advanced liver disease. According to the univariate Cox-regression proportion hazard models RVFWS as a continuous variable was not significantly correlated with worse two year survival (HR: 1.01 (0.95-1.08, p=0.658). Interestingly, among conventional echocardiographic parameters basal RV diameter (p=0.004) and right atrial end-systolic area (p=0.008) were associated with increased risk for the primary endpoint. The association of the primary endpoint with other parameters of RV systolic function was also not statistically significant. The Multivatiate Cox Regression survival analysis, which incorporated age, sex, MELD, hemoglobin, systolic blood pressure and cardiac output, showed that among echocardiographic parameters for the evaluation of the RV, only RVFWS showed a tendency to be associated with worse survival (p=0.062). When patients were stratified into tertiles according to RVFWS values, those in the first tertile (with lower absolute RVFWS values) had significantly increased hazard for the primary endpoint (HR: 5.82, 2.18-15.8, P<0.001) (figure 1). Conclusions RVFWS values are within normal limits in most patients with liver cirrhosis. When adjusted for the severity of the liver disease, reduced RVFWS values are associated with worse prognosis in cirrhotics.

Correlation between LDL/HDL-cholesterol ratio and long term prognosis after acute coronary syndrome and severity of coronary artery disease

Abstract Introduction Dyslipidaemia is an important correctable risk factor for coronary artery disease (CAD). Many studies have confirmed that the lower the low-density lipoprotein cholesterol (LDL-C) levels are, the lower is the CAD morbidity and mortality rates (1). However, many patients who achieved low levels of LDL-C still experience a major adverse cardiovascular event (MACE) because of the other residual risk factors. Therefore, there is a constant need for better stratification of patients who are at higher risk for novel MACE following their first acute coronary syndrome (ACS). Evidence increasingly suggests that the ratio of LDL-C/HDL-C might be a new and better marker of cardiovascular disease, as it simultaneously evaluates the levels of both LDL-C and HDL-C (2). Purpose The aim of this study was to investigate the prediction value of LDL-C/HDL-C ratio for long term prognosis after ACS as well as its correlation with CAD severity. Methods We included patients hospitalized at out centre with ACS from January 2017 to January 2024. Demographic data, data on LDL-C and HDL-C levels on admission and calculated Syntax score were used. Syntax score is a comprehensive angiographic scoring system which determines complexity by using coronary anatomy and lesion characteristics (3). Follow-up data were collected either by clinical follow-up visits or by telephone interviews. The MACE was defined as the composite of cardiovascular death, acute coronary syndrome and need for elective or urgent percutaneous or surgical revascularization. Results This registry-based study included 2471 patients with ACS, median age of 64 (interquartile range 56-73) years, 31% female. Total of 1099 patients (44%) had non-ST elevation ACS and 1372 (54%) had ST elevation myocardial infarction (STEMI). Median Syntax score was 13 (IQR 7-20.5), with 1494 (61%) patients having low Syntax score (≤16), 508 (21%) patients medium (16-22), and 448 (18%) high score (>22), respectively. Median follow up was 17 (3-27) months. LDL-C/HDL-C ratio correlated significantly with cardiovascular death, with weak coefficient (2.94 vs. 2.54 p<0.001; rho=0.102, p<.0001), however did not correlate with MACE (2.88 vs. 2.92, p=0.188, rho=0.06, p=0.77). This remained identical when tested for patients with STEMI and non-STE ACS. In addition, LDL-C/HDL-C ratio did not correlate with CAD severity as assessed with Syntax score (low 2.92 vs. medium 2.83 vs. high 2.86, p=0.597; rho=0.4, p=0.09). Conclusion Our data suggest that LDL-C/HDL-C ratio cannot be used as a relevant predictor of post-ACS long-term MACE or cardiovascular death, nor it can be correlated with CAD severity. Further studies are needed to establish the real value of LDL-C/HDL-C ratio as a post-ACS predictor.

Improvement of gastric disease and ridden horse pain ethogram scores with diet adaptation in sport horses.

Gastric disease is highly prevalent in sport horses and may lead to poor performance, cause behavioral changes and impact welfare. Assess whether diet affects gastric disease and pain expression during riding, and whether it has an impact on physiological and locomotor variables during an exercise test, including jumps. Nine healthy show-jumping Warmbloods trained at the same stable. Prospective observational cohort study. The horses receiving a pelleted diet, high in sugar and starch (>30%), were examined at T0 and after 12 weeks (T12) of changing to a cooked, muesli-type low-starch (11%) diet. Each time, the horses underwent a standardized exercise test (SET) and a ridden pain score (Ridden Horse Pain Ethogram [RHpE]) was calculated by 2 blinded observers. The next day, horses underwent gastroscopy and gastric lesions were scored blindly. Results were analyzed using Wilcoxon and Spearman tests. After 12 weeks of a low starch diet, the Equine Gastric Disease (EGD; 4 [3-5] at T0 vs 1 [0-1] at T12, P < .01) and RHpE scores (6 [3-13] at T0 vs 3 [0-6] at T12, P < .01) improved significantly. Squamous, glandular, and EGD scores were positively correlated with RHpE scores (respectively, r = .747, P < .01; r = .743, P < .01 and r = .867, P < .01). Gastric disease and pain scores correlated positively in ridden horses. A low starch diet significantly decreases the severity of gastric disease and associated pain score during riding in horses. Gastric ulcers may be mitigated and the comfort of equines athletes improved by dietary adjustments.

Association of thyroid hormones with the severity of chronic kidney disease: a cross-sectional observational study at Tabuk, Saudi Arabia

Background The interplay between chronic kidney disease (CKD) and thyroid dysfunction is becoming more evident in the biomedical community. However, the intricacies of their relationship warrant deeper investigation to understand the clinical implications fully. Objective This study aims to systematically evaluate the correlation between thyroid hormone levels, including thyroid-stimulating hormone (TSH), triiodothyronine (T3), and thyroxine (T4), and markers of renal disease severity. These markers include serum creatinine, urea, and parathyroid hormone (PTH) levels in individuals diagnosed with CK). Methods We conducted a cross-sectional observational study involving a cohort of 86 participants with CKD recruited from the renal clinic at King Fahad Hospital in Tabuk. Biochemical parameters, encompassing plasma electrolytes and thyroid hormone concentrations, were quantitatively assessed. These measurements were performed with the aid of a Roche Cobas E411 analyzer. The Pearson correlation coefficient was employed to delineate the strength and direction of the associations between the thyroid function markers and renal disease indicators. Results The statistical analysis highlighted a generally weak correlation between the concentrations of thyroid hormones and the indicators of renal disease severity, with Pearson correlation coefficients between −0.319 and 0.815. Critically, no significant correlation was found between creatinine and thyroid hormones (TSH, T3, T4), nor was any substantial correlation between urea and thyroid hormones. Conversely, a robust positive correlation was noted between the levels of parathyroid hormone and serum creatinine (r = 0.718, p &lt; 0.001). Conclusion The data suggests that thyroid hormone levels have a minimal correlation with the severity of renal disease markers. In contrast, the pronounced correlation between PTH and creatinine underscores the importance of considering PTH as a significant factor in managing and therapeutic intervention of CKD complications. These initial findings catalyze further research to thoroughly investigate the pathophysiological relationships and potential therapeutic targets concerning thyroid dysfunction in patients with renal impairment.

Natriuretic peptides, kidney function and clinical outcomes in heart failure with mildly reduced or preserved ejection fraction: pooled data from the I-PRESERVE, TOPCAT, PARAGON and DELIVER trials

Abstract Background The prognostic utility of N-terminal pro-B-type (NT-proBNP) in patients with heart failure and chronic kidney disease (CKD) is incompletely understood since elevations in NT-proBNP could be related either to decreased clearance by the kidney or to increased severity of structural heart disease. Purpose We sought to assess the association of NT-proBNP with cardiovascular and mortality outcomes in patients with heart failure and mildly reduced or preserved ejection fraction, stratified by baseline kidney function. Methods We conducted a pooled analysis of individual participants with NT-proBNP and estimated glomerular filtration rate (eGFR) measured at baseline in the I-PRESERVE, TOPCAT (Americas region), PARAGON and DELIVER trials. We evaluated the relationship between NT-proBNP and kidney function using piecewise linear regression. Using multivariable Cox and Poisson regression models, we assessed the association of NT-proBNP with clinical outcomes across different levels of eGFR (≥60, 45-&amp;lt;60 and &amp;lt;45 mL/min/1.73m2). The primary outcome was hospitalisation for heart failure or cardiovascular death. Results Among 14,831 participants (mean age 72.1 years, 50.3% female, mean eGFR 63.3 mL/min/1.73m2 and median NT-proBNP 840 pg/mL) followed for a median 33.5 months, there were 3,092 primary outcomes, 2,184 heart failure hospitalisations, 1,465 cardiovascular and 1,049 non-cardiovascular deaths. Participants in lower eGFR categories were more likely to be older, female, and have atrial fibrillation and diabetes (all p&amp;lt;0.001). NT-proBNP levels increased by 9%, 8%, and 23% per 10 mL/min/1.73m2 lower eGFR in patients with baseline eGFR ≥60, 45-60, and &amp;lt;45 mL/min/1.73m2, respectively (P for non-linearity &amp;lt;0.001). For any given NT-proBNP concentration, participants with eGFR &amp;lt;45 mL/min/1.73m2 were at highest risk (Figure 1). Each doubling in NT-proBNP was associated with a 37% relative increase in the primary outcome (HR 1.37, 95% CI 1.34-1.41), consistent across different eGFR categories (P-interaction=0.42). Association between NT-proBNP and other clinical outcomes were also consistent across different levels of kidney function (all P-interaction&amp;gt;0.3; Figure 1). Equivalent risk for the primary outcome was apparent at NT-proBNP levels approximately 2.5- to 3.5-fold lower in patients eGFR &amp;lt;45 mL/min/1.73m2, compared to those with eGFR ≥60 mL/min/1.73m2. (Figure 2). Conclusion NTproBNP is a potent predictor of risk in patients with heart failure with mildly reduced or preserved ejection fraction across the spectrum of kidney function. However, in patients with reduced kidney function, lower NT-proBNP levels confer absolute risk of cardiovascular outcomes similar to substantially higher NT-proBNP levels in patients with normal kidney function. Accordingly, interpretation of NTproBNP levels should vary according to kidney function, particularly in those with eGFR &amp;lt;45 mL/min/1.73m2.

Inflammation and cholesterol associated residual cardiovascular risk and its dependence on chronic kidney disease in statin treated patients with coronary artery disease

Abstract Background/Aim In statin-treated patients with chronic coronary syndrome (CCS) there is uncertainty about the relative contribution of inflammation and dyslipidaemia to residual cardiovascular risk, particularly in the presence of chronic kidney disease. We thus aimed to evaluate high sensitive C-reactive protein (hsCRP) and low density lipoprotein-cholesterol (LDL-C) as predictors of future events in these patients, stratified by estimated glomerular filtration rate (eGFR). Methods We identified patients with CCS on stable statin treatment from a contemporary all-comers cohort recruited at a large tertiary care center in Germany. We excluded patients with active malignancy, infectious disease or in a post-operative state. Cox regression for major adverse cardiovascular events (MACE, composite of cardiovascular death, myocardial infarction, stroke) and all-cause death was performed adjusting for age, sex, arterial hypertension, diabetes mellitus, active smoking, body mass index and change in the intensity of statin therapy at discharge, with log(hsCRP) or LDL-C as the exposure variables. Interaction with eGFR (&amp;lt; vs. ≥ 60 ml/min/1.73m²) was investigated. Results 937 patients with CCS (mean age 71.1 years, 78.7% male, median hsCRP 2.0 mg/L, median LDL-C 73.0 mg/dl, median eGFR 71.3 ml/min/1.73m²) were followed-up over 4 years, with 101 cases of MACE and 171 cases of all-cause death recorded. The hazard ratios (HR) for MACE per standard deviation (SD) increase were as follows: log(hsCRP) 1.08 (95% confidence interval (CI) 0.87, 1.34; p = 0.48), LDL-C 1.10 (95% CI 0.89, 1.35; p = 0.37). For all-cause death the HRs for log(hsCRP) and LDL-C were 1.60 (95% CI 1.36, 1.88; p &amp;lt;0.001) and 0.88 (95% CI 0.74, 1.04; p = 0.14), respectively. Kaplan-Meier curves stratifying the cohort by median values of LDL-C and hsCRP consistently demonstrated a significantly higher risk of death in the subgroups with elevated hsCRP (Figure 1). Contrastingly for LDL-C, levels below (vs. above) the median were associated with a higher mortality rate. This is in part a reflection of a higher prevalence of high-intensity statin therapy in this subgroup (21.0 vs. 14.2%, p = 0.0081), in turn a reflection of greater severity of coronary artery disease (history of myocardial infarction 43.9 vs. 31.9%, p &amp;lt;0.001). Further confounding by unadjusted for diseases with a catabolic metabolism is possible. Interaction analysis with eGFR revealed that log(hsCRP) was predictive of all-cause mortality both in the presence and absence of chronic kidney disease, whilst lower LDL-C values were found to be predictive only at eGFR &amp;lt;60 ml/min/1.73m² (Table 1). Conclusion Residual inflammation as measured by hsCRP predicts all-cause mortality in statin-treated patients with CCS in this contemporary all-comers cohort, both in the presence and absence of chronic kidney disease. The predictive utility of LDL-C is limited, likely due to confounding e.g. by the intensity of lipid lowering medication.Kaplan-Meier curves (all-cause death)Interaction analysis with eGFR

Gender-differences in Polyvascular disease: implications for lipid-lowering management and cardiovascular outcomes

Abstract Background Polyvascular disease (PolyVD) exhibits extensive atherosclerotic disease in multiple vascular beds. Despite lowering LDL-C with a statin, patients with PolyVD still present elevated risks of subsequent atherosclerotic cardiovascular events, suggesting the need to better understand pathophysiology of PolyVD. Female gender has been reported to mitigate severity of atherosclerotic disease and future events’ risks. However, whether this gender-difference exists in patients with PolyVD remains to be fully elucidated yet. Purpose To characterize gender-differences in cardiovascular outcomes in patients with and without PolyVD, respectively. Methods The on-going multi-center registry enroll patients with CAD receiving intravascular imaging-guided PCI. The current study included 679 patients with CAD. PolyVD was defined as the concomitance of other atherosclerotic cardiovascular disease (stroke and/or LEAD). In patients with PolyVD (n=185) and Non-PolyVD (n=494), clinical characteristics and major cardiovascular outcomes (MACE) were compared between men and women, respectively. MACE was defined as a composite of cardiovascular death, non-fatal MI, ischemic stroke, LEAD and coronary revascularization. Results The proportion of women was 21% and 18% in Non-PolyVD and PolyVD subjects, respectively. In patients with non-PolyVD, women were more likely to be older (75 vs. 68 years, p&amp;lt;0.001) and exhibit a lower BMI (22.3 vs. 24.0 kg/m2, p&amp;lt;0.001) with a lower frequency of previous myocardial infarction (13.5 vs. 24.9%, p=0.01). LDL-C levels did not differ between the two groups [102 (76-130) vs. 93 (71-120) mg/dL, p=0.06). However, during the observational period (median=3 years), women were associated with a lower frequency of MACE compared to men (HR=0.31, 95%CI=0.13-0.78, p=0.012, Figure, Table). In patients with PolyVD, BMI, and the frequency of established risk factors and previous myocardial infarction were comparable between men and women. Despite the use of high-intensity statin in over 40% of study subjects (44 vs. 36%, p=0.41), women still exhibited an elevated level of LDL-C [103 (74-122) vs. 82 (64-103) mg/dL, p=0.04]. Furthermore, in contrast to Non-PolyVD patients, similar cardiovascular outcomes were observed in both men and women with PolyVD (Figure). On multivariate analysis adjusting clinical characteristics, women were not a significant factor associated with a reduced risk of MACE (Table). Conclusion 18% of PolyVD were women who presented a higher LDL-C level. While women with Non-PolyVD exhibited better cardiovascular outcomes compared to men, this gender-difference did not exist in patients with PolyVD. Our findings indicate that female PolyVD did not necessarily show better outcomes but similar cardiovascular event’s risks compared to men. Further intensified anti-atherosclerotic managements are required in both men and women with PolyVD.

A Novel Subset of Regulatory T Cells Induced by B Cells Alleviate the Severity of Immunological Diseases.

Regulatory T (Treg) cells are crucial for maintaining immune tolerance by suppressing response to self-antigens and harmless antigens to prevent autoimmune diseases and uncontrolled immune responses. Therefore, using Treg cells is considered a therapeutic strategy treating inflammatory diseases. Based on their origin, Treg cells are classified into thymus-derived, peripherally induced, and in vitro induced Treg cells. Our group discovered a novel Treg cell subset, namely, Treg-of-B (Treg/B) cells, generated by culturing CD4+CD25- T cells with B cells, including Peyer's patch B cells, splenic B cells and peritoneal B1a cells, for 3days. Treg/B cells express CD44, OX40 (CD134), cytotoxic T-lymphocyte-associated antigen-4 (CD152), glucocorticoid-induced tumor necrosis factor receptor family-related protein (CD357), interleukin-10 receptor, lymphocyte activation gene-3 (CD223), inducible co-stimulator (CD278), programmed-death 1 (CD279), tumor necrosis factor receptor II, and high levels of IL-10, but not forkhead box protein P3, similar to type 1 Treg (Tr1) cells. However, unlike Tr1 cells, Treg/B cells do not express CD103, CD226, and latency-associated peptide. Treg/B cells have been applied for the treatment of some murine models of inflammatory diseases, including allergic asthma, inflammatory bowel disease, collagen-induced arthritis, gout, psoriasis and primary biliary cholangitis. This review summarizes the current knowledge of Treg/B cells.

Comparison between coronary calcium score and segment involvement score when used in clinical routine

Abstract Data from a nationwide registry on coronary computer tomography angiography. Background The Coronary Artery Calcium Score (CACS) and segment involvement score (SIS) are crucial factors in assessing the severity of coronary artery disease (CAD) and determining the likelihood of future cardiovascular events. However, there are few large multicenter studies comparing the predictive value of CACS and SIS when used in the clinical routine. Objectives To compare CACS and SIS ability to predict cardiovascular outcomes when used in the clinical routine. Methods This retrospective cohort study included patients who underwent Coronary Computed Tomography Angiography (CCTA) for CAD evaluation between 2006-2022 in 29 different centers in Sweden. CACS was calculated using the Agatston method, and SIS was determined based on the number of coronary segments exhibiting plaque. For SIS, patients were categorized into SIS=0, SIS=1, SIS=2, SIS=3, SIS³4, for CACS patients were categorized into CACS=0, CACS=1-9, CACS=10-99, CACS=100-299, CACS³300. Patients were followed regarding the primary outcome of death or myocardial infarction. Multivariable Cox proportional hazards models were used for adjusting for potential confounders. Results A total of 23034 patients underwent CCTA and were followed for up to ten years. Median age (IQR) was 58 (49–67) years, 50% were women, 9% had diabetes mellitus, 42% had hypertension, 25% had hyperlipidemia, 5% had previously known CAD. There were 955 patients (4.1%) with myocardial infarction (MI) and 409 patients (2.2%) died during follow up. There was an increase in cardiovascular events with increasing SIS. When comparing SIS and presence of obstructive stenosis, SIS was a better predictor of outcome (Figure 1). There was also an increase cardiovascular events with increasing CACS (Figure 2). When adjusted for age, sex, risk factors, previous cardiovascular disease and intervention, both SIS and CACS were independently associated with outcome. When SIS and CACS were compared in a receiver operating characteristic curve, CACS had significantly larger AUC than SIS, (0.70[0.67-0.73] vs 0.62[0.60-0.63]). Conclusion Our findings show that both CACS and SIS are important and independent predictors of cardiovascular outcomes thereby offering a valuable tool for personalized risk stratification and management in clinical settings. When used in the clinical routine, CACS appears to be more strongly associated with outcome than SIS.Figure1 Survival SISFigure 2 Survival CACS

COVID-19 impact on childhood vaccination attitudes in pregnant antenatal class attendants in Rome

Abstract Background The COVID-19 pandemic caused a decrease in vaccination rates, impacting vulnerable populations such as pregnant women (PW), who concern about future children’s immunisations. The aim of this study was to assess whether the pandemic led to changes in childhood vaccination attitudes among PW attending antenatal classes at the Fondazione Policlinico Universitario A. Gemelli in Rome. Specifically, it assessed the impact of the pandemic on the perceived usefulness of information sources, their trust in healthcare workers (HCWs) and the National Health Service (NHS), their perception of the risk of infection and severity of vaccine-preventable diseases (VPDs), and their vaccination intentions. Methods A repeated cross-sectional study was conducted across three flu seasons by administering an anonymous questionnaire: one before and two during the pandemic. Intention to vaccinate children was expressed as the percentage of PW who selected each vaccination from the questionnaire. Trust in HCWs and the NHS, and perception of the risk of infection and severity of VPDs were expressed as the percentage of PW who answered “quite” or “very”. For the usefulness of information sources, mean scores were calculated. To assess differences of the three periods a chi-square test was performed (p = 0.05). Results Course attendance surged from 105 to 340. Significant shifts in vaccination intentions were noted: 7.5% and 10% decreases for measles (p = 0.02) and pertussis (p = 0.004), respectively, from 2019-20 to 2020-21. Perceived contagion risk decreased, but perceived disease severity increased. A significant reduction in the proportion of PW suspecting economic interest behind NHS workers promoting vaccination, and an increase in the perceived usefulness of non-institutional websites and of the advice from non-NHS physicians were noted. Conclusions PW’s attitudes towards vaccinations might have been modified by COVID-19 pandemic, regarding risk perception and trust in NHS HCWs. Key messages • Our findings suggests that PW’s attitudes towards childhood vaccinations might be modified by the COVID-19 pandemic, in particular risk perception and trust in NHS healthcare workers. • These findings could help Public Health to develop evidence-based interventions and communication strategies, to maintain vaccine confidence and mitigate potential adverse effects.

Impact of the pullback pressure gradient (PPG) on PCI planning and decision-making

Abstract Background Coronary physiology using a distal measurement of fractional flow reserve (FFR) informs about the severity of coronary artery disease (CAD) and, when used for clinical decision-making about revascularisation, is associated with improved outcomes in patients considered for PCI. A second dimension of coronary physiology is available by performing a pullback maneuver, which aids in assessing the presence and location of focal pressure gradients. Yet, the impact of intracoronary physiology guidance with FFR pullbacks on real-time physician decision-making during PCI is not fully known. Methods This prospective study was performed at 25 sites and enrolled patients with at least one epicardial lesion with FFR ≤ 0.80 planned to be treated by PCI. A standardized physiological assessment with FFR pullbacks and Pullback Pressure Gradient (PPG) calculation was performed. Treatment plans were recorded for each lesion based on angiography alone and following FFR pullbacks. The goal of this study was to assess the procedural impact of physiology guidance in stable patients scheduled for PCI. Results Overall, 993 patients (1044 vessels) underwent complete physiological assessment with FFR and PPG. Decision-making during PCI changed in 47.5% (443/1044) after FFR pullbacks. Decision-making during PCI changed in 32.4% (289/890) after FFR pullbacks. PPG use changed revascularisation decisions in 13.9% (138/993) from PCI to CABG (5%; 50/993), from PCI to CABG in 5% (50/993) and to medical management in 8.9% ( 88/993). The frequency of decision changes was significantly higher in patients with diffuse CAD compared to focal cases (24.8% vs. 44.2%, p &amp;lt; 0.001). Among the subset of 855 patients (involving 880 vessels) who underwent PCI, operators modified decision-making regarding stent length in 22.1% of cases (197 out of 880), with these alterations being more prevalent in patients with diffuse CAD (57.2% vs. 46.3%, p = 0.002). Suboptimal Post-PCI result (FFR &amp;lt; 0.88) was more frequent in cases in which PCI strategy was not adapted based on PPG (55.5% vs. 45.6%, p= 0.016) Importantly, there was no significant change in the overall number of stents per patient after FFR pullbacks. Conclusion A standardized coronary physiological assessment impacted PCI decision-making in one-third of the vessels, with a predominant effect in vessels diffusely diseased. The assessment of the distribution of pressure losses along the coronaries modifies the treatment decision and influences PCI strategy in a significant proportion of patients. These findings provide insights into mechanisms by which coronary physiology might improve PCI outcomes.PCI strategy change based on PPGCumulative change of PCI strategy

Shortened versus standard duration of dual antiplatelet treatment after percutaneous coronary intervention in patients with and without chronic kidney disease: a systematic review and meta-analysis

Abstract Background Impaired renal function is an established risk factor for recurrent cardiac events. The severity of chronic kidney disease (CKD) is related with an increased risk for both ischemic and bleeding complications. As a result, the clinical implications of antithrombotic therapies may be different in patients with CKD as compared to those without. Recently, shortened duration of DAPT, namely one to three months, after percutaneous coronary intervention (PCI) has been proven as a safe and feasible strategy in various different clinical scenarios, like in high-bleeding risk patients, in acute coronary syndromes and complex PCI. However, it remains debatable whether DAPT should be shortened in patients with high ischemic and bleeding risk, such as those with CKD. Purpose The aim of our systematic review and meta-analysis is to explore the safety and efficacy of shortened therapy (1-3 months; S–DAPT) in patients without and without CKD undergoing PCI. Methods Three major databases (MEDLINE, Cochrane Central Register of Controlled Trials, and Scopus) were screened for eligible randomized – controlled trials, or subgroup or post – hoc analyses of them. The studies should compare shortened (S–DAPT) with longer (&amp;gt;3 months) DAPT (L–DAPT) in patients undergoing PCI, and include data on CKD presence. The endpoints were Net Adverse Clinical Events (NACE) and Major Adverse Cardiac Events (MACE) and should be evaluated at 12 months. NACE and MACE were used as per trial defined. The effect of different DAPT regimens was assessed by calculating the risk ratio (RR) with 95% confidence interval (CI) using random-effects model (Mantel-Haenzel). Results A total of eight studies and 56,660 patients were included in our analysis; a notable proportion of patients (9.7%, N=5,466) suffered from CKD. Our analysis showed an overall benefit of S-DAPT in NACE (RR: 0.88, 95%CI: 0.81 – 0.95), which was consistent in patients with and without CKD (p-interaction=0.58). (Figure 1) No significant difference regarding MACE was observed between S-DAPT and L-DAPT (RR: 0.98, 95%CI: 0.90 – 1.06) in both patients with and without CKD (p-interaction=0.19). (Figure 2) Conclusions Our analysis showed an overall benefit of S-DAPT in NACE without any difference in MACE, with similar findings among patients with and without CKD. Thus, DAPT shortening could be a feasible and safe approach when it is required, even in patients with impaired renal function. Further randomized controlled trials focusing on patients with CKD are required for validating the previous results and exploring further benefits of abbreviated duration of DAPT.Net adverse clinical eventsMajor adverse cardiac events

Extracellular vesicles characterization in patients with hypertrophic cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) is a genetic disorder, diagnosed according to the presence of phenotypical traits of the myocardium. A specific biomarker which can associate with the severity of HCM is lacking. Extracellular Vesicles (EVs), nanoparticles released by cells into biological fluids, hold promise as accessible diagnostic tools, as their abundance and molecular composition can reflect the severity of cardiac diseases (Rizzuto 2024). We aim at characterising plasma-derived EVs isolated from 28 HCM patients and 18 healthy volunteers (CTR). Methods The whole cohort underwent transthoracic echocardiography, whereas magnetic resonance and exome sequencing was performed on HCM patients. EVs were isolated via ultracentrifugation from plasma of both groups. Quantitative and qualitative assessments of EVs were performed by nanoparticle tracking analysis, transmission electron microscopy, Western blot, targeted (Olink) and untargeted (nLC-MS/MS) proteomics and FACS analysis. Plasma-derived EV subpopulations were characterised according to their cellular origin. Data are expressed as median and interquartile range (25th, 75th). Results Most patients were male (68% HCM and 66% CTR) with a median age of 58 (49-69) years (HCM) and 47 (44-52) (CTR). Among HCM patients, missense mutations in the MYH7 gene were the most identified. The median maximum wall thickness (WTMax) in HCM was 16 mm (15-19) vs 8 mm (7-9) in CTR. The isolated EVs expressed tetraspanins (CD9, CD63 and CD81), Alix and β-integrin and showed an intact phospholipid bilayer of 100 nm in size. EV concentration was reduced in HCM vs CTRL, respectively 2.8*109 EV/ml/cell count (2*109-4*109) and 4.6*10⁹ EV/ml/cell count (3*109-6*109). Among 15 plasma-derived EV subpopulations studied, those released from platelets (CD41a) and activated platelets (CD62P and CD40L) were increased in HCM patients vs CTR by 1.7 fold. Negative associations were found between E/e’, parameter of diastolic function, and cardiomyocyte-derived EVs (r= -0.2658), and between left ventricle ejection fraction and platelet-derived EVs (r=-0.2189); a positive correlation was found between WTMax and EVs derived from activated endothelial cells (r=0.2330). The proteomic analysis of EVs shows an enrichment in proteins related to platelets adhesion and inflammation in HCM patients. Conclusions HCM patients present a peculiar phenotypic pattern of EVs that may associate with diagnostic clinical features of HCM.