Risk Markers Research Articles

Dietary intake of branched-chain amino acids (BCAAs), serum BCAAs, and cardiometabolic risk markers among community-dwelling adults.

To investigate the associations between dietary/serum branched-chain amino acids (BCAAs) and cardiometabolic risk markers. In a cohort of 2791 participants, diet and cardiometabolic risk markers were measured twice at baseline in overall participants and after 1-year in a subset of 423 participants. We assessed serum BCAAs at baseline and arterial stiffness after 1-year. The cross-sectional associations between dietary/serum BCAAs and cardiometabolic risk markers were analyzed using baseline measurements by linear regression, while the 1-year longitudinal association were analyzed using repeated measurements by linear mixed-effects regression. Higher BCAA intake from poultry was associated with lower triglycerides (β=-0.028, P = 0.027) and higher high-density lipoprotein cholesterol (HDL-C, β = 0.013, P = 0.006), while BCAAs in red and processed meat or fish were inversely associated with low-density lipoprotein cholesterol (β = 0.025, P = 0.001) and total cholesterol (β = 0.012, P = 0.033), respectively. BCAAs in whole grains and nuts were associated with higher HDL-C (β = 0.011, P = 0.016), and lower TG (β=-0.021, P = 0.041) and diastolic blood pressure (β=-0.003, P = 0.027). Also, BCAAs from soy or vegetables and fruits were inversely associated with arterial stiffness (β=-0.018, P = 0.047) and systolic blood pressure (β=-0.011, P = 0.003), respectively. However, BCAAs in refined grains were positively associated with triglycerides (β = 0.037, P = 0.014). Total serum BCAAs were unfavorably associated with multiple cardiometabolic risk markers (all P < 0.05). Dietary BCAAs in poultry, whole grains and nuts, soy, and vegetables and fruits may be favorably, while BCAAs in red and processed meat, fish, and refined grains were unfavorably associated with cardiometabolic health. Serum BCAAs showed a detrimental association with cardiometabolic risk markers.

Association of Loneliness with Functional Connectivity MRI, Amyloid-β PET, and Tau PET Neuroimaging Markers of Vulnerability for Alzheimer’s Disease

Background: Loneliness has been declared an “epidemic” associated with negative physical, mental, and cognitive health outcomes such as increased dementia risk. Less is known about the relationship between loneliness and advanced neuroimaging correlates of Alzheimer’s disease (AD). Objective: To assess whether loneliness was associated with advanced neuroimaging markers of AD using neuroimaging data from Framingham Heart Study (FHS) participants without dementia Methods: In this cross-sectional observational analysis, we used functional connectivity MRI (fcMRI), amyloid-β (Aβ) PET, and tau PET imaging data collected between 2016 and 2019 on eligible FHS cohort participants. Loneliness was defined as feeling lonely at least one day in the past week. The primary fcMRI marker was Default Mode Network intra-network connectivity. The primary PET imaging markers were Aβ deposition in precuneal and FLR (frontal, lateral parietal and lateral temporal, retrosplenial) regions, and tau deposition in the amygdala, entorhinal, and rhinal regions. Results: Of 381 participants (mean age 58 [SD 10]) who met inclusion criteria for fcMRI analysis, 5% were classified as lonely (17/381). No association was observed between loneliness status and network changes. Of 424 participants (mean age 58 [SD = 10]) meeting inclusion criteria for PET analyses, 5% (21/424) were lonely; no associations were observed between loneliness and either Aβ or tau deposition in primary regions of interest. Conclusions: In this cross-sectional study, there were no observable associations between loneliness and select fcMRI, Aβ PET, and tau PET neuroimaging markers of AD risk. These findings merit further investigation in prospective studies of community-based cohorts.

The impact of uninterrupted sitting on central and peripheral cardiovascular function in pre-menopausal and post-menopausal women.

Independently, both prolonged uninterrupted sitting and the onset of menopause negatively impact markers of cardiovascular risk. Whether their combination augment these responses additively remains unknown. This study assessed whether prolonged uninterrupted sitting causes greater central and peripheral cardiovascular dysfunction in post-menopausal women compared to pre-menopausal women. To address this, 23 healthy women (13 pre-menopausal [43.77 ± 4.30years] and 10 post-menopausal [57.20 ± 8.55years]) sat uninterrupted for 2-h. Carotid-femoral pulse wave velocity (cf-PWV), pulse wave analysis (PWA), lower limb venous pooling (HHb), and calf circumference were assessed pre-and post-sitting using general linear mixed models, with age as a covariate. Changes in MAP over time (both between and within groups) was assessed using a two-way repeated-measures-ANOVA. There were no significant interactions for any outcome measures. However, for cf-PWV, there was a significant main effect of group (Δ = 0.854 ± 0.354m s-1; p = 0.026, ηp2 = 0.707). For PWA, only heart rate (HR) and pressure forwards (Pf) showed significant main effects 13 of time [Δ = 6 ± 1 bts-min-1, p < 0.001, ηp2 = 0.861] and group [Δ = 3.893 ± 1.450mmHg, p = 0.016, ηp2 = 0.271], respectively. Both HHb (Δ = 2.737 ± 0.952, p = 0.009, ηp2 = 0.742) and calf circumference (Δ = 0.812 ± 0.128cm, p < 0.001, ηp2 = 0.863) significantly increased over time. Whilst post-menopausal women demonstrated greater overall arterial stiffness (increased cf-PWV at baseline), there was no difference in cardiovascular response (central or peripheral) to 2-h of prolonged sitting between the pre- and post-menopausal women.

ECG risk markers among premenopausal and postmenopausal SCD victims

Abstract Background Majority of the SCD victims aged 50 years or younger are male. On average menopause occurs at the age of 51.4 years and it has a substantial role in cardiovascular risk burden among women. The mechanisms and risk markers of SCD are not as well defined for women as they are for men possible due to difference in population burden, and electrocardiographic risk markers do not seem to make a difference in this matter. Purpose The aim of this study was to determine electrocardiographic findings among women at pre- and postmenopausal age in a large SCD population. Methods The Fingesture study has systematically collected clinical and autopsy data from SCD victims in Northern Finland between 1998 and 2017. The cohort consists of 5,869 SCD victims of which 1,238 are women (21.1%). Antemortem electrocardiograms (ECG) were recorded in 1,101 subjects (women 25.3%). Women aged ≥ 52 years were considered as postmenopausal and ≤ 51 years old as premenopausal as the direct information of the menopause lacked due to the retrospective nature of this autopsy-based data. Results Only 7.9% of the female subjects experienced SCD under age of 52 years (P&amp;lt;0.001). No statistically significant differences in ECG abnormalities were found between pre- and postmenopausal women. However, almost one female SCD victim out of four lacked any ECG abnormalities in premortem ECG (26.3% of premenopausal and 24.2% of postmenopausal women, P=1.000). In general, ECG abnormalities were more prevalent in SCD victims at postmenopausal age. Though, fragmented QRS, particularly in the lateral ECG leads, was observed in 47.4% of women at premenopausal age group and in 42.1% of women at postmenopausal age even though statistical significance was not obtained (p=0.810). ECG-LVH, as per Cornell's criteria, was present in 4.8% of individuals in premenopausal age group whereas in postmenopausal age group, it was observed in 19.0% of subjects (P=0.140). ECG variables are presented in Table 1. When the analysis was repeated between the women &amp;lt;55 years of age and ≥55 years of age, only left ventricular hypertrophy (LVH; Cornell) was statistically significant and more common in women ≥55 years old (19.5% vs. 3.6%, P=0.037). Conclusion Premenopausal SCDs are rare. Approximately one female SCD victim out of four did not have any ECG abnormalities prior to SCD. Only ECG-LVH remained statistically significant in analysis between younger and older women, and was clearly more prevalent finding among postmenopausal SCD victims.Table 1

Systematic right ventricular electrophysiologic evaluation in patients with repaired tetralogy of Fallot before pulmonary valve replacement

Abstract Introduction Adults with repaired tetralogy of Fallot (rToF) are prone to develop ventricular tachycardia (VT) in adulthood, due to reentry related to slowly conducting anatomical isthmuses (SCAI). Pulmonary valve replacement (PVR) in patients without history of VT, may lead to obliteration of unrecognized SCAI with subsequent catheter ablation failure; electrophysiologic study is thus recommended before PVR. A systematic evaluation of the topology of SCAI in this population is, however, scant. Methods Consecutive rToF patients undergoing PVR with native right ventricular outflow tract were studied with pre-PVR EPS. Electroanatomical mapping with systematic evaluation of all possible anatomical isthmuses (AI) with pacemapping, activation mapping in sinus/paced rhythm and bipolar voltage mapping was performed (AI1: anterior scar/patch to tricuspid annulus; AI2: anterior scar to pulmonary annulus; AI3: pulmonary annulus to ventricular septal defect – VSD- patch; AI4: VSD to tricuspid annulus). Conduction velocity (CV) across all documented AI was calculated (ratio between the distance among the nearest point with bipolar voltage &amp;gt;1.5 mV and their difference in activation timing). Ventricular programmed stimulation was performed at 2 sites (apex and outflow tract) with drive train ad 600/400 ms, up to three extrastimuli until refractoriness or induction, during baseline and isoproterenol infusion. Radiofrequency catheter ablation (RFCA) was performed in all patients with inducible VT and/or SCAI, aiming at conduction block across the SCAI validated with differential pacing. Results Between May 2023 and November 2023, 10 patients with rToF and 1 double outlet right ventricle were studied (73% males, age 46±10 years; 54% with a previous shunt, 46% with a previous transannular patch, 27% pulmonary valvotomy and infundibular boring; median age at surgery 4 years, interquartile range 3-6). EPS was positive for inducible VT in 4 patients (mean cycle length 297 ms, 3 with left bundle branch morphology and 1 right bundle branch morphology, all inferior axis) and polymorphic VT in 1. AI1 was present in 5 patients, AI2 in 5, AI3 in 7, AI 4 in 2. At least 1 SCAI was present in 7 patients (64%), 2 SCAI in 3 patients (43% of patients with SCAI; in every patient SCAI3+SCAI2 in 2 and SCAI 4 in 1 patient). There were no SCAI1; there were 3 SCAI 2 (mean CV 0.43 m/s), 4 SCAI 3 (mean CV 0.3 m/s), 1 SCAI 4 (CV 0.4 m/s). RFCA was performed in 8 patients; acute success was achieved in all patients, achieving bidirectional conduction block across treated SCAI and non-inducibility of VT. Conclusions SCAI are often present in rToF candidate to PVR and without clinical history of spontaneous VT, involving prevalently SCAI3 and SCAI2. Inducible VT is not sufficient as a marker of arrhythmic risk and SCAI should be better sought for. RFCA of SCAI with bidirectional conduction block is acutely highly efficacious.

Long-term outcomes associated with subcutaneous implantable cardioverter-defibrillators in patients with hypertrophic cardiomyopathy

Abstract Background In patients with Hypertrophic Cardiomyopathy (HCM) S-ICD is usually the preferred option as pacing is generally not indicated. However, limited data are available on its current practice adoption and long term follow-up. Purpose The present study was designed to examine in a multicenter, open-label, long-term study, the patient’s selection process for S-ICD implantation, the short and long term complications, the appropriate shock (AS) rates, shock efficacy and outcome. Methods Consecutive HCM patients with an S-ICD implanted between 2013 and 2021 in 3 international centers were enrolled in this prospective observational study. Baseline, procedural and follow-up data together with clinical evaluation, ECG, echocardiography, and telemetry checks of the S-ICD were regularly collected. Results Seventy patients (64% males) were enrolled, implanted at 41±15 years, 62 (89%) in primary prevention with a mean ESC SCD risk score of 4,5±1.9%: 25 (40%) at low risk, 17 (27%) at intermediate and 20 (33%) at high risk. Patients were followed-up for 5.1±2.3 years (327 person-years). Notably, 25 (36%) were followed for more than 6 years up to 10 years. Two patients (3%) received an appropriate shock on ventricular fibrillation and 17 (24%) were diagnosed with a de-novo atrial fibrillation, sub-clinical in 6 (9%). One TIA and 2 strokes were reported. Inappropriate shocks occurred in 4 patients (6%), all before Smart-Pass algorithm implementation. Eight patients experienced device related adverse events (11%). Conclusions S-ICDs in HCM patients followed for over 5 years showed to be effective in the conversion of VF in 2 ESC SCD high risk patients (3%) and useful in the detection of sub-clinical AF in 6 (9%). S-ICDs are implanted in patients with an overall low-intermediate ESC SCD risk, probably reflecting both the inclusion of additional risk markers (i.e extensive LGE, reduced EF and apical aneurism) and the physician perception of low device-related complications S-ICD is generally safe, but greater scrutiny may be required to avoid overtreatment in HCM patients with milder risk profiles.Real world use and candidacy of S-ICDAppropriate and inappropriate shocks

Role of inflammation in atrial fibrillation: specific biomarkers of tissue damage, atrial remodelling and dysregulation of angiogenesis

Abstract Introduction and Objectives The relationship between inflammation and atrial fibrillation (AF) has been poorly studied with common inflammatory markers and limited to analysing one or two markers. Given the large number of pathways in the inflammatory process and the complexity of their relationship with AF, we set out to study a broad panel of more specific biomarkers that attempt to cover as many inflammatory interactions and mechanisms as possible. Our objetive was to evaluate which biomarkers were elevated in AF patients compared to the general population. Methods We studied 74 patients who were to undergo an ablation procedure (53 with AF and 21 controls -microscopic substrates-), drawing a blood sample before the procedure. Exclusion criteria were: cancer, inflammatory diseases, heart failure or major echocardiographic alterations including mild ventricular hypertrophy. Baseline characteristics, basic analytical parameters and levels of 20 specific inflammatory biomarkers were collected and compared in patients with and without AF. Results Figure 1 shows the baseline characteristics of the sample. The usual analytical parameters in clinical practice showed no relevant differences between the two groups. Of the 20 specific inflammatory parameters, significant differences were found in 4: biomarkers of cardiomyocyte damage (NT-proBNP: (AF)130.8 +- 208.0 pg/mL vs (control) 80.3 +- 66.5 pg/mL; p=0.041), of atrial remodelling (Endostatin: 95.0 +- 28.8 ng/mL vs 80.1 +- 17.2 ng/mL; p&amp;lt;0.01), angiogenesis dysregulation (MCAM: 241.8 +- 51.9 ng/mL vs 197.1 +- 96.4 ng/mL; 0.033) and hepato-inflammatory cardiovascular risk markers (SAP; 7426.6 ± 2641.0 ng/mL vs 9406.9 ± 3904.1 ng/mL; p&amp;lt;0.011). In addition to these individual differences, multiple correspondance analysis (figure 2) allowed grouping most of the patients without arrhythmia using information from the biomarker set. Conclusions In patients with AF, several specific parameters of inflammation are elevated compared to controls, supporting the presence of an activation of inflammation in these patients. Due to the large number of factors involved in the inflammatory process and the variability with which they can be activated, future research evaluating the clinical implication of these findings is essential.Baseline CharacteristicsMultiple correspondance analysis

ECG screening and Sudden Cardiac Death prevention in endurance athletes

Abstract Introduction Sudden cardiac death (SCD) is the leading cause of mortality in athletes during sport activity. Identifying non-invasive and repeatable risk markers during annual athletes screening remains a crucial goal for the scientific community for the prevention of cardiovascular disease. The ECG, exercise test and spirometry are part of the annual screening program in the sport population over 40 years of age. The Heart Rate Variability (HRV) has been shown to be an independent predictor of mortality in populations with CV disease, but its relationship with SCD has been little explored in those at low risk, including athletes. This study aims to use a 5 minute ECG screening in a specific population of athletes practicing endurance sports and evaluate its clinical repercussions. Aims The primary aim of the study is to assess whether morphological and spectral ECG analysis in endurance athletes by the 5-minute 'mini Holter ECG' can add information to the annual screening for the prevention of CV diseases and SCD. Materials The study population were selected from Endurance Marathon athletes. A control group was also collected for comparison. The 5 minutes ECG was recorded at rest with the Kardia Mobile 6L™ device that use three electrodes, which allows 6 leads recording. HRV indices were obtained using the Kubios software. A morphological analysis was performed and the HRV parameters were analyzed in the time and frequency domains. Results A total of 554 subjects (220 athletes-334 controls, 325 male-229 women) were analyzed. A higher incidence of sinus arrhythmias, LAFB, 1stdegree AVB, J point/ST-segment abnormalities in athletes compared to controls was observed. Athletes had a significantly shorter QTc than the control group (394.87±30.55 ms vs. 407.01±29.09 ms), suggestive of greater protection from malignant ventricular arrhythmias. The HRV PNS (-0.73±1.25 vs -0.21±1.45) and SNS (1.71±1.91 vs 0.58 ± 1.43) indices were also higher and lower in the athlete group than in the control group, suggestive for higher vagal tone. Given the absence of a normality range of standard HRV parameters in the athlete population, values in the normal range of the 5th to 95th percentile were extrapolated in the whole population for the main HRV parameters. The project, therefore, is to evaluate patients with HRV values higher or lower than 5-95 percentile to identify those deserving further clinical investigations and closer follow-up for suspected increased risk of CV disease and SCD. Conclusions The 5-minute cardiac Holter, combining a more accurate analysis in terms of morphology and arrhythmias than the 12-lead ECG, allows a greater number of static and dynamic alterations to be detected; moreover, the analysis of HRV could provide even more information, such that it could be considered as a complementary tool during the examination and FUP of athletes. Further long-term prospective studies are needed to correlate alterations in HRV and clinical events.

Exploring Causal Relationships between Circulating Inflammatory Proteins and Thromboangiitis Obliterans: A Mendelian Randomization Study.

Thromboangiitis obliterans (TAO) is a vascular condition characterized by poor prognosis and an unclear etiology. This study employs Mendelian randomization (MR) to investigate the causal impact of circulating inflammatory proteins on TAO. In this MR analysis, summary statistics from a genome-wide association study meta-analysis of 91 inflammation-related proteins were integrated with independently sourced TAO data from the FinnGen consortium's R10 release. Methods such as inverse variance weighting, MR-Egger regression, weighted median approaches, MR-PRESSO, and multivariable MR (MVMR) analysis were utilized. The analysis indicated an association between higher levels of C-C motif chemokine 4 and a reduced risk of TAO, with an odds ratio (OR) of 0.44 (95% confidence interval [CI]: 0.29-0.67; p = 1.4 × 10-4; adjusted p = 0.013). Similarly, glial cell line-derived neurotrophic factor exhibited a suggestively protective effect against TAO (OR: 0.43, 95% CI: 0.22-0.81; p = 0.010; adjusted p = 0.218). Conversely, higher levels of C-C motif chemokine 23 were suggestively linked to an increased risk of TAO (OR: 1.88, 95% CI: 1.21-2.93; p = 0.005; adjusted p = 0.218). The sensitivity analysis and MVMR revealed no evidence of heterogeneity or pleiotropy. This study identifies C-C motif chemokine 4 and glial cell line-derived neurotrophic factor as potential protective biomarkers for TAO, whereas C-C motif chemokine 23 emerges as a suggestive risk marker. These findings elucidate potential causal relationships and highlight the significance of these proteins in the pathogenesis and prospective therapeutic strategies for TAO.

#2154 Rituximab in the treatment of PLA2R-associated membranous nephropathy: insights from a hospital centre experience

Abstract Background and Aims Rituximab (RTX) is recommended as the first-line therapy for PLA2R-associated Membranous Nephropathy in patients with a moderate to high risk of progressive loss of kidney function, according to the KDIGO 2021 guidelines. This recommendation is based on the superior long-term efficacy and improved safety profile of RTX. This study aims to assess the use of RTX for the treatment of for PLA2R-associated Membranous Nephropathy at a hospital centre. Method A retrospective study was conducted on patients diagnosed with PLA2R-associated Membranous Nephropathy who underwent their first RTX administration between 2017 and 2022 at a tertiary hospital centre. Exclusion criteria involved patients with less than 6 months of follow-up post-RTX. The study evaluated the occurrence of immune remission, clinical remission, as well as instances of immune and proteinuria relapse, and recorded any adverse events. Results A total of 11 patients were included, with 54.5% being male. The mean age was 60.4 ± 14.7 years, and the median disease duration 69.0 [8.0-87.0] months. The mean follow-up time post-RTX was 36.7 ± 23.3 months. Regarding the risk of progressive loss of kidney function, 8 patients were classified as high risk, 1 as moderate risk, and 2 as low risk. RTX served as the initial immunosuppressive therapy for only 3 patients. Additional immunosuppressive therapies post-RTX, including further RTX doses, were administrated in 63.6% (n = 7) of patients. No response was observed in 18.2% (n = 2). Immune remission was achieved in 81.8% (n = 9), mean time of 3.8 ± 1.4 months. Within this group 55.5% (n = 5) patients achieved complete remission, 22.2% (n = 2) experienced partial remission, and 22.2% (n = 2) maintained nephrotic proteinuria, with immune remission consistently preceding clinical remission. Relapses occurred in 45.5% (n = 5), at a mean time of 20.8 ± 13.5 months. Patients with lower serum albumin at time of RTX administration were more likely to experience non-response or relapse (T (9) = 2.51, p = 0.03), with a Youden Index cut-off of 3.2 g/dL, demonstrating a sensitivity of 100% and a specificity of 85.7%. Patients with anti-PLA2R exceeding 150 RU/mL exhibited no response or relapsed. Four patients (36.4%) remained free of relapses throughout the entire follow-up period, mean time of 22.8 ± 10.0 months, with 1 keeping RTX maintenance therapy. During the 6 months post-RTX, 36.4% (n = 4) of patients experienced adverse events. Conclusion Rituximab demonstrated both efficacy and safety in treating PLA2R-associated Membranous Nephropathy. However, lower serum albumin levels and anti-PLA2R &amp;gt; 150 RU/mL at time of RTX administration were associated with worse response. Given the substantial need for additional immunosuppression, and considering lower albumin values and higher anti-PLA2R titres as risk markers, it is recommended to closely monitor these patients. Anti-PLA2R titres showed a meaningful association with disease activity, preceding changes in proteinuria levels. Therefore, tracking disease progression through the measurement of anti-PLA2R titres not only guides clinical decisions but also enables a judicious approach to subsequent RTX administrations.

#755 Endotrophin as an early marker of kidney outcomes in persons with type 2 diabetes: findings from the PROVALID study

Abstract Background and Aims Diabetic kidney disease (DKD) is driven by a set of pathophysiological processes, including fibrosis. Endotrophin (ETP), a pro-fibrotic fragment generated during collagen type VI formation, has previously been shown to be a biomarker of DKD progression. The aim of this study was to investigate, for the first time, circulating ETP as a risk marker for kidney outcomes in persons with type 2 diabetes (T2D) being taken care of at the primary level of healthcare. Method Levels of ETP were measured using the nordicPRO-C6TM ELISA in plasma at baseline from 3226 persons with T2D enrolled in the Prospective Cohort Study in Patients with Type 2 Diabetes Mellitus for Validation of Biomarkers (PROVALID). Outcomes included a composite kidney endpoint defined as a sustained 40% decline in estimated glomerular filtration rate (eGFR) &amp;lt; an eGFR of 60 ml/min/173 m2, sustained 30% increase in albuminuria including a transition in albuminuria stage, or kidney failure with replacement therapy or kidney death. A decline in eGFR and an increase in albuminuria were considered sustained if they persisted over at least two consecutive measurements. Crude and adjusted Cox proportional hazards regression models were applied to investigate the potential of ETP as a risk marker of the kidney endpoint. Levels of ETP were log-transformed before analysis. The Kaplan–Meier estimator was used to compare the risks of experiencing the kidney endpoint according to ETP levels split by the median in persons with baseline eGFR &amp;gt; 90 ml/min/1.73 m2 (n = 976). Results The cohort consisted of 57% males; median age was 64 (58-70) years, and mean eGFR was 79 ± 24 ml/min/1.73 m2. Median follow-up was 3.9 years. Higher levels of ETP were associated with a higher risk of developing the kidney endpoint, with a hazard ratio (HR) of 1.63 (p = 0.0012; n = 293/3226). After adjustment for the refined variables: age, diabetes duration, HbA1c, atherosclerotic cardiovascular disease, blood pressure, duration of hypertension, BMI, LDL-cholesterol, HDL-cholesterol, and eGFR, the HR was 1.55 (p = 0.012). In persons with an eGFR &amp;gt; 90 ml/min/1.73 m2, higher ETP was also associated with an increased risk of developing the kidney endpoint (p = 0.03; n = 69/976). Conclusion Plasma ETP was an independent risk marker for kidney outcomes in persons with T2D with early kidney disease. Higher levels of plasma ETP were associated with a significantly increased risk of developing the kidney endpoint in persons with eGFR &amp;gt; 90 ml/min/1.73 m2. These findings demonstrate that biomarkers of fibrosis, such as ETP, may serve as early markers for kidney disease progression or kidney failure in persons with T2D and apparently normal kidney function.

#2945 Albuminuria – a neglected cause of referral to Nephrology

Abstract Background and Aims Albuminuria has been a recognized marker of cardiovascular risk for several years. Since 2012, the KDIGO guidelines have included this marker in the definition of chronic kidney disease (CKD), regardless of the Glomerular Filtration Rate (GFR). Despite this, a decade after, albuminuria is rarely researched as a marker of kidney disease, especially in Primary Health Care. We aim to assess the percentage of patients referred from the Health Centre to the Nephrology consultation of a district hospital, with an indication of the albuminuria value and also which percentage considered it the main cause of referral. Method Retrospective observational study of all patients referred from the Health Centre to the Nephrology consultation, from January 2022 to May 2023. A statistical analysis was carried out using Microsoft Excel 2016 (Microsoft ™). Results A total of 248 patients were referred and accepted for the nephrology consultation, 52.4% female, average age 74.8 years, with almost 80% (n = 198) of patients aged 65 or over and 41.5% (n = 103) aged over 80. The reasons for referral were: 53.6% due to an increase in creatinine levels; 21% due to imaging alterations; 19% due to a reduction in GFR and only 6.4% (16 patients) due to a urinary alteration, which included the presence of albuminuria. Only 26.2% (n = 65) of the patients referred had mentioned the value of albuminuria, and of these, around 73% (n = 49) already had an albuminuria value greater than or equal to 30 mg/dL; however, in only 14 of these patients (5.6% of all the patients referred) was albuminuria the main reason for the referral. Of the 49 patients with albuminuria: 44 patients (89.8%) had cardiovascular disease (around 98% with hypertension and around 28% with HF) and 34 patients (69.4%) had diabetes; 32 patients (65.3%) were medicated with ACE inhibitors/ARBs and only 13 patients (26.5%) were medicated with iSGLT2. The percentages of use of ACEIs/ARAs and iSGLT2 remain the same when analyzing the 14 patients who were referred for albuminuria. Conclusion Albuminuria remains an overlooked marker of CKD despite being an early marker and for which there are several interventions that seem to prevent the worsening and progression of CKD. It is imperative to train doctors, especially family doctors, in the early diagnosis of CKD, particularly in the presence of albuminuria and to implement measures to control it.

#900 Endotrophin is associated with long-term risk of kidney function decline in normoalbuminuric persons with type 2 diabetes in the Joslin Kidney Study

Abstract Background and Aims Endotrophin is a pro-fibrotic and pro-inflammatory molecule derived from the post-translational processing of type VI collagen. Evidence for an association of increased circulating levels of endotrophin with increased risk of kidney and cardiovascular-related outcome and all-cause mortality in persons with type 2 diabetes have recently emerged. Here we want to investigate endotrophin as an early marker of kidney-related outcome risk in persons with type 2 diabetes with normal levels of albuminuria. Method Endotrophin was measured using the nordicPRO-C6TM assay (Nordic Bioscience, Herlev, Denmark) in serum of 1088 individuals with type 2 diabetes from the Joslin Diabetes Study. 635 individuals had normal to mildly increased albuminuria (&amp;lt;30 mg/g), 379 had moderately increased albuminuria (30-300 mg/g) and 74 had severely increased albuminuria (&amp;gt;300 mg/g). All patients had eGFR &amp;gt;60 and where hence classified as CKD stage 1 and 2. Risk of kidney disease progression was defined as a 40% decline in eGFR within 10 years. Results In the cohort (n = 1088), a total of 128 patients progressed to 40% eGFR decline. High levels of circulating endotrophin were associated with an increased risk of kidney disease progression in unadjusted logistic regression analysis (OR for T3 vs T1+T2 (PRO-C6): 2.1 [95% CI: 1.4-3.0], p = 0.0001) and after adjustment for eGFR, HbA1c, age and sex (OR for T3 vs T1+T2 (PRO-C6): 1.8 [95% CI: 1.1-2.6], p = 0.005). When looking at patients classified in albuminuria stages, endotrophin was significantly associated with kidney disease progression in the individuals with normal to mildly increased albuminuria (39 events) (OR for T3 vs T1+T2 (PRO-C6): 2.6 [95% CI: 1.3-4.9], p = 0.005 in unadjusted analysis and 2.3 [95% CI: 1.1-4.5], p = 0.02 after adjustment for eGFR, HbA1c, age and sex, but it was not significantly associated to kidney progression in the groups with moderately (49 events) and severely (40 events) increased albuminuria. Conclusion This study sheds further light on the potential of endotrophin as an early marker of long-term adverse kidney outcome in persons with type 2 diabetes. The association of circulating endotrophin with increased risk of kidney disease progression had already been reported both in CKD and DKD patients (for shorter-term outcome), and this study further expands on the applicability of endotrophin as a biomarker in persons with type 2 diabetes without an overt kidney disease, who will nevertheless progress to develop CKD in a 10-year time horizon.

#2061 Perirenal fat thickness as a potential marker for cardiovascular risk in chronic kidney disease: the influence of vitamin D analogs

Abstract Background and Aims Patients with CKD show high cardiovascular complication rates. There are classical cardiovascular risk factors, such as obesity, dyslipidemia, and diabetes; however, other cardiovascular disease risk factors are associated with mineral metabolism disorders (phosphorus, hyperparathyroidism, etc.) typically appear in CKD. Due to their pleiotropic effects, vitamin D analogs, such as cholecalciferol, calcitriol, or paricalcitol, have proven effective in controlling bone mineral disease secondary to CKD and cardiovascular pathologies. On the other hand, visceral adiposity has been shown as a risk factor in the general population and in patients with CKD. Specifically, the fat deposited in regions such as the epicardium generates a complex autocrine and paracrine hormonal mechanism that has been associated with cardiovascular complications. Although it has not been widely evaluated, the adipose tissue surrounding the kidneys (perirenal fat [PRF]) could provide additional information of interest in the CKD population. The aim of the study is to assess the relationship between cardiovascular disease, PRF, and the effect of therapeutic interventions for bone and mineral metabolism in patients with CKD. Method This prospective observational and cross-sectional study was designed to evaluate the usage of vitamin D analogs in patients with CKD, focusing on cardiovascular history and PRF accumulation. All the patients were evaluated at the outpatient clinic in Consuelo Hospital in Valencia Spain (January-November 2022). Eighty-three patients with different grades of CKD (G1A1 to G5A3 not on dialysis) were included and follow-up for 24 months. All the patient's data from electronic medical and analytical records were entered into a protocol sheet. The patients that meet the inclusion criteria (eGFR ≤90 or&amp;gt;15 ml/min/1.73 m2; age ≥18 years at the time of signing informed consent, and a life expectancy higher than 1 year) were eligible to participate in the study. As exclusion criteria, patients with an active inflammatory process such as infection, active cancer, or other inflammatory states were excluded beyond those mentioned in inclusion. Patients with an AKI, ADPKD, or CKD requiring RRT were also excluded. Patients were discriminated according to their history of cardiovascular disease (coronary artery disease, stroke, and peripheral vascular disease) and the use of Vitamin D analogs (Cholecalciferol, Calcitriol, and Paricalcitol). The thickness of the PRF was measured in centimeters (cm) through a B-mode ultrasound with a 3.5-MHz convex transductor (Alpinion®; Alpinion Medical Systems, Korea). Patients underwent a bilateral renal ultrasound, and the kidneys were measured anteroposteriorly, transversally, and longitudinally. PRF was measured in the distal third between the cortex and the hepatic border and/or spleen. Results The mean age of the patients was 58.3 ± 16 years. Patients with a cardiovascular disease history showed significantly higher levels of urea (62.0 vs 45.2 mg/dl, p &amp;lt; 0.05), uric acid (5.5 vs 4.3 mg/dl; p &amp;lt; 0.03), intact parathyroid hormone (iPTH) (186.2 vs 65.2 pcg/dl; p0.05) and decreased eGFR (53.55 vs 89.00 ml/min/1.73 mts2). The mean PRF thickness (0.99 vs 0.80 cm; SD ± 0.30; p0.05) was also observed to be elevated with respect to the group who had no previous cardiovascular events (Fig. 1). Moreover, this group showers higher levels (1.2 vs 7.1; p &amp;lt; 0.005) of CRP. Those patients on oral treatment with Paricalcitol (1 mcg/day) had lesser PRF accumulation than those treated with Cholecalciferol (1000 IU/day) or Calcitriol (0.5 mcg/day) (p &amp;lt; 0.05) (Fig. 2). It was not adjusted for confounding factors such as weight, height, or BMI. Conclusion These results show a close relationship between the presence of cardiovascular disease history and a higher accumulation of PRF. The mechanisms by which paricalcitol could influence the decrease in PRF are so far unknown, however, some studies have shown an association between PTH elevation and obesity. Finally, achieving a decrease in the latter could reduce visceral adipose tissue, thus reducing the cardiovascular risk in CKD-affected patients.

#2902 How does IGF-1 levels relate to different stages of chronic kidney disease

Abstract Background and Aims Insulin like growth factor-1 (IGF-I) influences glomerular filtration rate (GFR).Chronic kidney disease (CKD) influences the IGF/GH axis also. Serum IGF-I level is proposed to be a risk factor for renal and cardiovascular complications which is accentuated in CKD. This study is undertaken to observe the level of serum IGF-1 in different stages of chronic kidney disease and its association with cardio-metabolic risk factors Method This cross-sectional pilot study included consecutive 102 CKD patients of advanced renal failure (CKD3-5). Also 52 healthy subjects (free from any known disease) served as healthy referent for IGF-1 level. Stable CKD subjects ( &amp;lt; 15% deviation of eGFR in 3 months) from OPD of study center were included as cases. Information on socio-demographic and clinical characteristics with medical histories was collected from all in a predesigned data collection sheet Urine spot samples and fasting blood samples were collected and stored at −80°C for future analyses. The four-variable Modification of Diet in Renal Disease (MDRD) study equation was used for calculation of the eGFR using enzymatic creatinine. IGF-I was determined by ELISA method. Results Mean age was of CKD subjects was 50.45 ± 10.45 years with male-49% female-51%. Most common primary disease responsible for CKD was GN (53%) followed by DM (21%), HTN (13.0%) and rest others. The IGf-1 level was 297 ± 107 (range 79-588) in CKD patients and in healthy it was 246 ± 82 (114-529) ng/ml, (p &amp;lt; 0.004). The IGF-1 value at 25th percentile of healthy was only present in 12.7% of CKD and above 75th it was present in 42% of CKDs (p &amp;lt; 0.11). Study subjects in CKD 3 was 36%, in 4- 44% and in 5- 24%. The serum IGF-1 levels at CKD 3, 4 and 5 was 246 ± 82, 278 ± 95 and 328 ± 101 ng/ml, (p &amp;lt; 0.014); Hb% 11.1 ± 1.4, 11.3 ± 1.5 and 10.6 ± 1.5 g% (p &amp;lt; 0.001); calcium 9.5 ± 1.4, 9.6 ± 1.4 and 8.9 ± 1.0 mg% (P &amp;lt; 0.014); phosphate 3.6 ± 1.1, 3.6 ± 0.4 and 4.2 ± 1.0 mg%(p &amp;lt; 0.02); iPTH 24 ± 27, 22 ± 16 and 61 ± 82 pg/ml (p &amp;lt; 0.01) and albumin 4.5 ± 1.1, 4.56 ± 1.4 and 8.9 ± 1.0 mg%, (p &amp;lt; 0.04) respectively in 3 stages. The correlation study showed only a negative association of IGF-1 with eGFR (p &amp;lt; 0.01).The logistic regression analysis showed (taking in consideration of cardio-metabolic risk factors) only a significant association of eGFR with IGF-1. Conclusion The Serum IGF-1 level had an increasing value along with alterations in other biochemical parameters at advancing stage of CKD. This increase in IGF-1 value seems to be a reflection of progressing CKD rather than a causal relation to other cardio-metabolic risk markers.

Artificial Intelligence in Cardiovascular Disease Prevention: Is it Ready for Prime Time?

This review evaluates how Artificial Intelligence (AI) enhances atherosclerotic cardiovascular disease (ASCVD) risk assessment, allows for opportunistic screening, and improves adherence to guidelines through the analysis of unstructured clinical data and patient-generated data. Additionally, it discusses strategies for integrating AI into clinical practice in preventive cardiology. AI models have shown superior performance in personalized ASCVD risk evaluations compared to traditional risk scores. These models now support automated detection of ASCVD risk markers, including coronary artery calcium (CAC), across various imaging modalities such as dedicated ECG-gated CT scans, chest X-rays, mammograms, coronary angiography, and non-gated chest CT scans. Moreover, large language model (LLM) pipelines are effective in identifying and addressing gaps and disparities in ASCVD preventive care, and can also enhance patient education. AI applications are proving invaluable in preventing and managing ASCVD and are primed for clinical use, provided they are implemented within well-regulated, iterative clinical pathways.

#452 Cardiac troponins are independent predictors of cardiovascular mortality in haemodialysis patients

Abstract Background and Aims Patients with end-stage kidney disease (ESKD) and haemodialysis treatment (HD) have a high risk of cardiovascular (CV) events. The underlying pathophysiology is complex and multifactorial. This study aimed to explore the role of high-sensitivity cardiac Troponin I (hs-cTnI) as a predictor of major adverse cardiac events (MACE), CV- and all-cause mortality. Method A retrospective analysis using data from the AURORA study (CT00240331). Association with baseline hs-cTnI and MACE, CV- and all-cause mortality were assessed using Cox-regression analyses. The analyses were adjusted for multiple background factors and available biomarkers. hs-cTnI was log2 transformed and modelled using a four knot restricted cubic spline. The hazard ratio [HR] estimates are presented for the upper quartile (32.6 pg/mL) vs the lower quartile (10.1 pg/mL) of the distribution of hs-cTnI. Variables were ordered by variable importance in the models using χ2 value minus degrees of freedom. Results During the follow-up, there were 1094 total deaths of which 598 were CV deaths, and 734 MACE in patients with hsTnI measurements available at baseline. Baseline hs-cTnI was associated with an increased risk for MACE (HR 1.92; 95% Confidence interval [CI] 1.57-2.35), CV mortality (HR 2.12; 95% CI 1.69-2.66), all-cause mortality (HR 1.84; 95% CI 1.55-2.17) and non-CV mortality (HR 1.59; 95% CI 1.23-2.05) after adjustments for age, ethnicity, sex, smoking status, diabetes status, history of coronary heart disease, atrial fibrillation, blood pressure, heart rate, height, weight, years on HD, hemoglobin, cholesterol, LDL-C, HDL-C, triglycerides, hs-CRP, creatinine, albumin, phosphate, erythropoietin treatment, ACE -inhibitor use, anticoagulation treatment, treatment with rosuvastatin, sevelamer use, iron supplements, ferritin, transferrin, galectin-3, pro-BNP, CICP and SCF. When ranking variables by variable importance, hs-cTnI was the strongest predictor for MACE (Fig. 1), CV- and all-cause mortality. For non-CV mortality age was the most important variable. Conclusion Baseline hs-cTnI, is a strong and independent risk marker for MACE and all-cause mortality in patients with haemodialysis treatment.

Genetic Comorbidity of Depression and Somatic Diseases: Rationale Study Design in a Population Cohort Using Polygenic Risk Scores

Background: depression is widespread in the population, and one of the leading causes of disability, reduced life expectancy and mortality. Such a significant effect is based on the high frequency of comorbidity of depression with severe chronic somatic diseases. Genetic studies can provide tools to identify groups with a high level of genetic risk of comorbidity of these diseases in a population for their early specific prevention. The aim of review article was to justify the methodology and design of research directed for joint genetic risk markers for depression and chronic somatic diseases linked with each other in terms of genetic comorbidity. Publication, patients and methods: population cohort of depressive patients examined using international clinical and psychometric instruments. The study will allow: 1) to evaluate the risks of developing chronic somatic diseases in a population of patients with depression; 2) to assess the predictive power of polygenic risk scores of somatic diseases for symptoms of depression and somatic diseases in a population sample; 3) to validate polygenic risk scores for genetic comorbidity of depression and somatic diseases in a qualitatively described sample of patients using modern clinical and psychometric tools. Conclusion: the methodology and results of the study can be used for an evidence-based preventive approach in the field of mental and physical health.

#1568 Cardiometabolic benefits of low dose zibotentan and dapagliflozin 10 mg in the ZENITH-CKD study

Abstract Background and Aims Positive effects of endothelin receptor antagonists on blood pressure and urinary albumin excretion have been well described, although their use in a wider population of patients with chronic kidney disease with increased cardiovascular risk has been limited by potential fluid retention. Here we present the effects of low dose zibotentan in combination with dapagliflozin on a range of cardiometabolic risk factors. Method In a post-hoc analysis of the ZENITH-CKD trial, a randomized, double-blind, active-controlled trial conducted in 170 clinical sites in 19 countries, adults with a urinary albumin-creatinine ratio (UACR) of 150 to 5000 mg/g and eGFR ≥20 mL/min/1.73 m2 not on SGLT2i were randomized to zibotentan/dapagliflozin, 0.25 mg/10 mg, zibotentan/dapagliflozin, 1.5 mg/10 mg, or placebo/dapagliflozin 10 mg. Effects on fluid retention events, defined as body weight increase from baseline &amp;gt;3% (of which at least 2.5% from total body water) or BNP increase &amp;gt;100% to &amp;gt;200 pg/mL without atrial fibrillation or 100% increase to &amp;gt;400 pg/mL with atrial fibrillation were assessed (NCT04724837). Results Data from the full analysis set is presented including 91 participants treated with 0.25 mg zibotentan and 10 mg dapagliflozin, and 177 participants treated with 10 mg dapagliflozin and placebo. UACR reduction for 0.25 mg zibotentan and 10 mg dapagliflozin was −47.7%, for 10 mg dapagliflozin alone it was −28.3%, making an adjusted mean difference for the combination versus dapagliflozin alone of −27.0%. Cardiometabolic markers are shown in the table. Conclusion In the ZENITH-CKD study zibotentan used at low dose combined with dapagliflozin had incremental effects versus dapagliflozin alone on a range of cardiometabolic risk markers including blood pressure, LDL cholesterol, HbA1c and uric acid, without a significant increase in fluid retention.

Identification of plasma protein markers of allergic disease risk: a mendelian randomization approach to proteomic analysis

BackgroundWhile numerous allergy-related biomarkers and targeted treatment strategies have been developed and employed, there are still signifcant limitations and challenges in the early diagnosis and targeted treatment for allegic diseases. Our study aims to identify circulating proteins causally associated with allergic disease-related traits through Mendelian randomization (MR)-based analytical framework.MethodsLarge-scale cis-MR was employed to estimate the effects of thousands of plasma proteins on five main allergic diseases. Additional analyses including MR Steiger analyzing and Bayesian colocalisation, were performed to test the robustness of the associations; These findings were further validated utilizing meta-analytical methods in the replication analysis. Both proteome- and transcriptome-wide association studies approach was applied, and then, a protein-protein interaction was conducted to examine the interplay between the identified proteins and the targets of existing medications.ResultsEleven plasma proteins were identified with links to atopic asthma (AA), atopic dermatitis (AD), and allergic rhinitis (AR). Subsequently, these proteins were classified into four distinct target groups, with a focus on tier 1 and 2 targets due to their higher potential to become drug targets. MR analysis and extra validation revealed STAT6 and TNFRSF6B to be Tier 1 and IL1RL2 and IL6R to be Tier 2 proteins with the potential for AA treatment. Two Tier 1 proteins, CRAT and TNFRSF6B, and five Tier 2 proteins, ERBB3, IL6R, MMP12, ICAM1, and IL1RL2, were linked to AD, and three Tier 2 proteins, MANF, STAT6, and TNFSF8, to AR.ConclusionEleven Tier 1 and 2 protein targets that are promising drug target candidates were identified for AA, AD, and AR, which influence the development of allergic diseases and expose new diagnostic and therapeutic targets.