Powerful Independent Predictor Research Articles

Combined risk estimates of diabetes and coronary angiography-derived index of microcirculatory resistance in patients with non-ST elevation myocardial infarction

BackgroundDiabetes mellitus (DM) and coronary microvascular dysfunction (CMD) increase the risk of adverse cardiac events in patients with non-ST-segment elevation myocardial infarction (NSTEMI). This study aimed to evaluate the combined risk estimates of DM and CMD, assessed by the angiography-derived index of microcirculatory resistance (angio-IMR), in patients with NSTEMI.MethodsA total of 2212 patients with NSTEMI who underwent successful percutaneous coronary intervention (PCI) were retrospectively enrolled from three centers. The primary outcome was a composite of cardiac death or readmission for heart failure at a 2-year follow-up.ResultsPost-PCI angio-IMR did not significantly differ between the DM group and the non-DM group (20.13 [17.91–22.70] vs. 20.19 [18.14–22.77], P = 0.530). DM patients exhibited a notably higher risk of cardiac death or readmission for heart failure at 2 years compared to non-DM patients (9.5% vs. 5.4%, P < 0.001). NSTEMI patients with both DM and CMD experienced the highest cumulative incidence of cardiac death or readmission for heart failure at 2 years (24.0%, P < 0.001). The combination of DM and CMD in NSTEMI patients were identified as the most powerful independent predictor for cardiac death or readmission for heart failure at 2 years (adjusted HR: 7.894, [95% CI, 4.251–14.659], p < 0.001).ConclusionsIn patients with NSTEMI, the combination of DM and CMD is an independent predictor of cardiac death or readmission for heart failure. Angio-IMR could be used as an additional evaluation tool for the management of NSTEMI patients with DM.Trial registrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT05696379.Graphical

Association between Triglyceride - High Density Lipoprotein Ratio with Angiographic Severity of Coronary Artery Disease in Patients with Non-ST Segment Elevated Myocardial Infarction

Background: Non-ST Segment Elevated Myocardial infarction (NSTEMI) is a potentially life-threatening condition. Dyslipidaemia is a major contributor of coronary artery disease (CAD) and TG/HDL-C ratio can be an important marker for the prediction of the extent of CAD. This study was aimed to find out the relation between TG/HDL-C ratio with severity of coronary artery lesion in NSTEMI patients. Methods: A total of 200 NSTEMI patients were included and classified into two groups on the basis of TG/HDL-C ratio: Group-A (TG/HDL-C ratio ≤4, n=100) and Group-B (TG/HDL-C ratio &gt;4, n=100). Angiographic severity was measured by Gensini score in all the patients during the same hospital stay period. Relation between TG/HDL-C ratio and angiographic severity was evaluated. Results: Mean age of the study populations was 55.13±8.49 (years) with male predominance (75%). Hypertension, diabetes mellitus, dyslipidaemia and obesity were significantly higher in Group-B (p&lt;0.05). Gensini score in Group-B were significantly higher than Group-A (71±23 vs 30±12, p&lt;0.001). A strong positive linear relationship was found between TG/HDL-C ratio and Gensini score (r=+0.803). Multivariate logistic regression found TG/HDL-C ratio &gt;4 as the powerful independent predictor of Gensini score &gt;36 (AOR=7.98, 95% CI=4.0-15.91, p&lt;0.001). Conclusion: There is a significant positive correlation between TG/HDL-C ratio with Gensini score indicating increased severity of coronary disease in patients with NSTEMI. So early risk stratification and intensive management of NSTEMI can be done by using this cheap and easily available marker on admission. Cardiovasc j 2024; 16(2): 63-69

Could the reduced tricuspid annulus plane systolic excursion and right ventricular pulmonary artery be considered the most powerful independent predictors of cardiac mortality?

Could the reduced tricuspid annulus plane systolic excursion and right ventricular pulmonary artery be considered the most powerful independent predictors of cardiac mortality?

Predictive value of early-phase heart rate reduction for subsequent recovery of left ventricular systolic function in heart failure with reduced ejection fraction.

Predictors of heart failure with recovered ejection fraction (HFrecEF) remain to be fully elucidated. This study investigated the impact of heart rate and its change on the recovery of left ventricular ejection fraction (LVEF) in heart failure with reduced ejection fraction (HFrEF). From 398 outpatients who had a history of hospitalisation for heart failure, 138 subjects diagnosed as HFrEF (LVEF < 40%) on heart failure hospitalisation were enrolled and longitudinally surveyed. During follow-up periods more than one year, 64 and 46 patients were identified as HFrecEF (improved LVEF to ≥ 40% and its increase of ≥ 10 points) and persistent HFrEF, respectively. In the overall subjects, the reduction of heart rate through the observation periods was closely correlated with the improvement of LVEF (r = -0.508, p < 0.001). Heart rate on hospital admission for heart failure was markedly higher in patients with HFrecEF (112 ± 26 bpm) than in those with persistent HFrEF (90±18 bpm). Whereas heart rate at the first outpatient visit after discharge was already lower in the HFrecEF group (80 ± 13 vs. 85 ± 13 bpm in the persistent HFrEF group). A multivariate logistic regression analysis revealed that the decrease in heart rate from admission to the first visit after discharge was a significant determinant of HFrecEF (p < 0.001), independently of confounding factors such as ischemic heart disease and baseline LVEF and left ventricular dimension. Our findings suggest that heart rate reduction in the early phase after heart failure onset is a powerful independent predictor of the subsequent recovery of LVEF in HFrEF patients.

Evaluations of the combined use of blood- and tissue-based protein biomarkers for pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a low 5-year survival rate. Biomarkers may be of value for the early diagnosis of pancreatic cancer. This study assessed blood- and tumour tissue-based biomarkers associated with pancreatic cancer. We studied 61 patients who underwent pancreatic resection. Of these 61 patients, 46 patients had PDAC, and 15 patients had inflammatory tumours. Blood and tumour tissue levels of VEGF, hypoxia-inducible factor 1α (HIF-1α) and glucose transporter 1 (GLUT1) were measured. Blood concentrations of VEGF (p < 0.000001) and HIF-1α (p = 0.000002) were significantly higher in the PDAC group than in the inflammatory tumour group. Tumour tissue concentrations of VEGF (p < 0.000001), HIF-1α (p = 0.000005) and GLUT1 (0.000002) were also significantly higher in the PDAC group. Univariate analyses revealed that age, BMI, and blood levels of CA19-9, VEGF, and HIF-1α were potential predictors of PDAC. Potential predictors of PDAC in tumour tissue were VEGF, HIF-1α and GLUT1. Multivariate analyses found that VEGF was the most powerful independent predictor of PDAC in blood (OR = 1.016; 95% CI: 1.007-1.025; 0.001) and tumour tissue (OR = 1.02; 95% CI: 1.008-1.032, p = 0.001). The cut-off point for blood VEGF was 134.56 pg/ml, with a sensitivity of 97.8%, specificity of 86.7%, PPV of 95.7%, and NPV of 92.9%. The cut-off point for tissue tumour VEGF in PDAC was 208.59 pg/mg, with a sensitivity, specificity, PPV and NPV of 97.7%, 92.9%, 97.7%, and 92.9%, respectively. There are significant differences in blood-based biomarkers for differentiating between PDAC and inflammatory tumours of the pancreas. VEGF was an independent predictor of PDAC independent of its addition to the routinely used tumour marker CA19-9 antigen.

Abstract 4801: Clinical polygenic model to stratify risk of any, metastatic, and fatal prostate cancer in a randomized controlled trial of precision screening

Abstract Introduction: Lifetime risk of prostate cancer (PCa) is strongly associated with three factors: ancestry, family history, and genetics. We previously developed a polygenic hazard score (PHS) for PCa comprised of 290 common genetic variants (PHS290). When accounting for family history and ancestry (self-reported or genetically determined), PHS290 remained a powerful independent predictor of age at PCa diagnosis, metastatic PCa diagnosis, and PCa death. Additional variants associated with PCa susceptibility or benign elevation of prostate-specific antigen (PSA) have since been published. Here, we evaluate their impact on lifetime risk predictions for metastatic and fatal PCa and develop an updated polygenic score. This score will inform the design of the Prostate Cancer, Genetic Risk, and Equitable Screening Study (ProGRESS, ClinicalTrials.gov ID NCT05926102), a nationwide randomized controlled trial evaluating precision PCa screening in the VA healthcare system. Methods: We utilized a machine learning approach to update the PHS. Over 450 variants associated with PCa, aggressive PCa, benign prostatic hyperplasia, or benign PSA elevation were evaluated for inclusion. First, we identified pairs of variants with highly correlated genotype (defined as R2 &amp;gt; 0.95) and utilized univariable Cox proportional hazards models (using age at diagnosis of PCa) to exclude one variant from each pair. We then evaluated all remaining candidate variants for inclusion in a new PHS using a LASSO-regularized Cox proportional hazards model. We combined the new PHS with clinical predictors (ancestry and family history) to create a comprehensive, quantitative polygenic score in a diverse, population-based cohort of n=590,750 (Million Veteran Program). Both self-reported and genetic ancestry (based on 2,309 ancestry informative markers) were assessed. We estimated hazard ratios (HRs) to compare men with high versus low polygenic score and evaluated absolute predictions of any, metastatic, and fatal PCa. Results: The updated polygenic score included 356 variants, as well as family history and genetic ancestry. When comparing the highest to the lowest quintile of the population for polygenic score, the HRs for any PCa, metastatic PCa, and fatal PCa were 5.6, 5.8, and 5.2 respectively. These HRs are all greater than those achieved with PHS290, which yielded 5.2, 4.9, and 4.4 respectively. Risk stratification improved within each ancestry group, including within the &amp;gt;100,000 participants of African ancestry—a group known to have elevated risk of fatal PCa. Absolute risk prediction was accurate for both metastatic and fatal PCa. Conclusion: The polygenic score accurately predicts risk of metastatic and fatal PCa in multiple ancestry groups. A clinical polygenic model has potential utility for precision PCa screening and will now be evaluated prospectively in the ProGRESS trial. Citation Format: Anna M. Dornisch, Roshan Karunamuni, Kara N. Maxwell, Julie Lynch, Isla P. Garraway, Adam Kibel, Charles A. Brunette, Morgan E. Danowski, Kyung M. Lee, Scott L. DuVall, J M. Gaziano, Brent S. Rose, Richard L. Hauger, Jason L. Vassy, Tyler M. Seibert. Clinical polygenic model to stratify risk of any, metastatic, and fatal prostate cancer in a randomized controlled trial of precision screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4801.

Depth of implantation in relation to membranous septum as a predictor of conduction disturbances after transcatheter aortic valve implantation

BackgroundConduction disturbances remain one of the most common complications occurring post TAVI. We aim to determine the predictors of cardiac conduction disturbances after Transcatheter Aortic Valve Implantation (TAVI) and propose a relevant predictive model.We included 70 consecutive patients with severe symptomatic AS who underwent TAVI using the self-expanding valve Evolut R or the balloon expandable Sapien XT valve. All patients were subjected to electrocardiographic evaluation pre- and post-TAVI and at 30 days. Clinical, echocardiographic, CT-derived, and procedural parameters were collected and analyzed. ResultsConduction disturbances affected 28 patients (40%): 16 patients (22.9 %) developed Left Bundle Branch Block (LBBB), 7 patients (10%) experienced transient Complete Heart Block (CHB), and 5 patients (7.1%) experienced permanent CHB requiring Permanent Pacemaker Implantation (PPI). We classified predictors into preprocedural and procedural predictors. Multivariate logistic regression analysis of pre-procedural predictors showed that the presence of basal septal calcification is the most powerful independent predictor (OR: 28.63, 95% CI: 4.59–178.68, p < 0.001). Multivariate logistic regression analysis for pre and post procedural predictors showed that the relationship between depth of implantation at the septum and membranous septum expressed in percentage (sDIMS) with cut-off >70.42% is the most powerful independent procedural predictor (OR: 1.11, 95% CI: 1.03–1.2, p 0.006). ConclusionConduction disturbances remain a common complication of TAVI. Presence of basal septal calcification is a non-modifiable risk factor that increase patient propensity of development such complication after TAVI. A depth of implantation exceeding 70% of the membranous septal length has been found to strongly predict conduction disturbances post TAVI. sDIMS can be used in planning the depth of implantation to reduce incidence of conduction disturbances post TAVI.

Loss of Mir-221/222 Cluster Expression Results in Short-Term Disease Progression and Poor Post-Treatment Outcome in Multiple Myeloma

Despite the notable progress that has been achieved in the realm of MM treatment, the persistence of elevated relapse rates and therapy resistance remain a substantial hindrance to effective management of the patients. Therefore, the development of modern tools to ameliorate patients' prognosis and predict treatment outcome is of first clinical priority. MicroRNAs (miRNAs) have emerged as powerful post-transcriptional regulators of gene expression, while recent advances in high-throughput sequencing techniques have unveiled their prognostic utility in numerous pathologies. Herein, using a miRNA-seq we have investigated miRNA profiles in association with Revised International Staging System (R-ISS), aiming to reveal potential MM-related miRNAs able to improve patients' risk stratification. Bone marrow (BM) aspiration samples were collected from 120 MM patients at diagnosis (screening cohort). Mononuclear cells were isolated using Ficoll-Paque, while CD138 + plasma cells were positively selected using anti-CD138 mAbs magnetic beads. miRNA-seq was performed in CD138 + cells from 8 R-ISS I, 8 R-ISS II and 8 R-ISS III MM patients. Following 3‘-end polyadenylation of total RNA, miR-221/222 levels were quantified in our screening cohort by RT-qPCR. Disease progression (relapse and/or death) and patients’ mortality were assessed as clinical endpoint events, while internal validation was accomplished by bootstrap Cox proportional regression analysis. Aash et al. 2023 (n=86) and Kruykov et al. 2016 (n=149) served as external validation cohorts. miRNA-seq revealed miR-221/222 to be concurrently downregulated in R-ISS III versus R-ISS I/II MM patients (miR-221: FC=0.356; miR-222: FC=0.357; Fig.1B,C). The analysis of our screening cohort documented that CD138 + miR-221/222 loss is significantly associated with higher risk for short-term disease progression ( p=0.010; Fig.1D) and poor survival ( p=0.001; Fig.1E) of MM patients. Furthermore, the analysis of the two independent validation cohorts (Aass et al. cohort A, p=0.019; and Kryukov et al. cohort B, p=0.013) clearly confirmed the worse treatment outcome of the patients with miR-221/222 loss (Fig.1F,G). Moreover, miR-221/222-fitted multivariate models demonstrated the ability of miR-221/222 cluster to ameliorate the clinical routine of the established MM prognostic markers, including “R-ISS stage”, “high-risk cytogenetics” [+1q21, t (4;14) del(17p13), t(14;16), t(11;14), del(13q)] and “response to 1 st line therapy” (IMWG guidelines). In this context, the evaluation of CD138 + miR-221/222 levels significantly improved the risk-stratification of MM patients, resulting in the advanced positive prediction of patients' poor treatment outcome within R-ISS III (PFS: p=0.006, OS: p=0.019; Fig.2A,B) and high-risk cytogenetics groups (PFS: p=0.025, OS: p=0.022; Fig.2C,D). Finally, focusing on patients' response to 1 st line therapy stratification, loss of miR-221/222 could efficiently define optimal (sCR/CR/VGPR) and poor (PR/SD/PD) responders' subgroups (PFS: p&amp;lt;0.001, OS: p&amp;lt;0.001; Fig.2E,F). In conclusion, we identified miR-221/222 loss in CD138 + plasma cells as a powerful independent predictor of patients' risk for disease progression and poor treatment outcome, while miR-221/222-fitted multivariate prognostic models resulted to improved patients' risk-stratification and prediction of MM treatment outcome.

Fragmented QRS complex as a predictor of all-cause mortality in patients undergoing cardiac resynchronization therapy

Abstract Introduction Heart failure with reduced left ventricle ejection fraction (HFrEF) is a prevalent entity with poor prognosis in the follow-up. Cardiac resynchronization therapy (CRT) in specific situations, have demonstrated to reduce all-cause mortality in this group of patients. However, these patients represent a highly heterogeneous group, so risk stratification is crucial in the approach of these patients. In the recent years, specific electrocardiographic findings such as fragmentation of the QRS complex (fQRS) have been reported as potential prognostic factors in different cardiac conditions, but the role in patients undergoing CRT is unclear. Purpose The aim of this study is to determine if the presence of pre-implantation fQRS in 12-lead surface electrocardiogram (ECG) predicts all-cause mortality in patients undergoing CRT implantation. Methods Consecutive patients undergoing CRT implantation (with or without defibrillator) were prospectively included from October 2009 to December 2022. Demographic, clinical, electrocardiographic and echocardiographic variables as well as outcomes in the follow-up period were recorded from electronic clinical records and telephone interview. Fragmentation of the QRS complex was defined by the presence of different RSR′ patterns including an additional R-wave (R′), notching of the R-wave and S-wave or the presence of more than 1R′ in two contiguous leads corresponding to a main coronary artery territory. Results Finally, 244 patients were included. Mean age at device implantation was 71.8 years (standard deviation, SD ±9.8 years), 79.5% were male and 40.2% were diabetic. Mean left ventricle ejection fraction (LVEF) at baseline was 24.9% and the aetiology was non-ischaemic in 50.8% of the patients and ischaemic in 49.2%. 40.2% had prior history of acute myocardial infarction. Pre-implantation fQRS was found in 58.6% of the patients and mostly in inferior leads. CRT with defibrillator implantation was performed in 71.4% of the patients. The median follow-up time was 27.4 months. At the end of this period, mean LVEF was 33.2% and 76.6% presented NYHA class I-II. 28.7% of the patients died during the follow-up. A multivariate survival study using Cox regression revealed that the only variables were associated with death from any cause were maintaining NYHA functional class III-IV, the aetiology of the LV systolic dysfunction and pre-implantation fQRS. Specifically, the presence of pre-implantation fQRS in the surface ECG was a powerful predictor for all-cause mortality (HR 2.62; 95% CI 1.40-4.91). Kaplan-Meier curves for all-cause mortality are presented in Figure 1. Conclusions According to our results pre-implantation fQRS in the surface ECG is a powerful independent predictor of all-cause mortality in patients undergoing CRT implantation. Consequently, these patients could benefit from stricter follow-up. However, further studies are required to support our results.Figure 1.Kaplan-Meier curves.

Fragmented QRS complex as a predictor of appropriate shocks in patients undergoing cardiac resynchronization therapy and defibrillator. A chronicle of a shock foretold?

Abstract Introduction Cardiac resynchronization therapy (CRT) has demonstrated to reduce mortality and hospitalization for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) in specific subgroups of patients Moreover, adding an implantable cardioverter defibrillator (ICD) to CRT (CRT-D) has demonstrated to reduce the risk of sudden cardiac death in specific subgroups of patients. However, patients undergoing CRT-D are a very heterogeneous group. In the recent years, several clinical findings, such as fragmentation of the QRS complex (fQRS), have been reported as potential prognostic factors in various cardiac diseases. Nevertheless, the evidence to support the prognostic significance of fQRS in patients undergoing CRT-D remains to be scarce. Purpose The objective of this study is to evaluate if the presence of pre-implantation fQRS predicts appropriate ICD shocks in patients undergoing CRT-D implantation. Methods Consecutive patients undergoing CRT-D implantation were prospectively included from October 2009 to December 2022. Demographic, clinical, electrocardiographic and echocardiographic variables as well as appropriate ICD shock events were collected from electronic clinical records and telephone interview. Fragmentation of the QRS complex was defined by the presence of different RSR′ patterns including an additional R-wave (R′), notching of the R-wave and S-wave or the presence of more than 1R′ in two contiguous leads corresponding to a main coronary artery territory. Results A total of 180 patients were included. Mean age at the device implantation was 69.9 years (standard deviation, SD ±9.6 years), 80.6% were male, 63.8% presented hypertension and 40.0% were diabetic. The aetiology of the LV systolic dysfunction was non-ischaemic in 45.6% of the patients and ischaemic in 54.6%. 43.9% had prior history of acute myocardial infarction, while myocardial scar was described in 45.6% of the patients. Pre-implantation fQRS was found in 61.7% of the patients. Mean LVEF at baseline was 23.6%. The median follow-up time was 34.8 months. At the end of the follow-up, 30.5% patients died. 9.8% of the patients presented appropriate ICD shocks (9.2% in patients with pre-implantation fQRS and 0.6% in patients without pre-implantation fQRS). A multivariate survival analysis using Cox regression showed that presence of pre-implantation fQRS complex was a powerful independent predictor for appropriate ICD shocks (HR 8.36; 95% CI 1.08–64.32). Kaplan-Meier curves for appropriate shocks regarding pre-implantation fQRS status are presented in Figure 1. Conclusions According to our results, pre-implantation fQRS seems to be a strong independent predictor for appropriate ICD shocks after CRT-D implantation. Therefore, these patients could benefit from a more rigorous follow-up as they present higher risk of an arrhythmic event. However, further research is needed to confirm these findings.Figure 1.Kaplan-Meier curves

Left ventricular entropy is a novel predictor of major adverse cardiac events (MACE) in patients with coronary atherosclerosis: a multi-center study.

To investigate the incremental prognostic value of left ventricular (LV) entropy in a large multi-center population with coronary atherosclerotic heart disease (CAD). Current risk stratification of patients with CAD is imprecise and not accurate enough. A total of 314 CAD patients who underwent cardiovascular magnetic resonance (CMR) late gadolinium enhancement (LGE) at two medical centers in China between October 2015 and July 2022 were included in this study. Additionally, the 193 patients under 3.0-T field also underwent CMR T1 mapping. LV entropy and extracellular volume (ECV) were calculated from the LGE image of LV myocardium, and major adverse cardiac events (MACEs) were analyzed. Among 314 patients, 110 experienced MACE during a median follow-up of 13months. The risk of MACE was significantly increased in the high entropy group (log-rank p < 0.001). Entropy maintained an independent association with MACE in a multivariable model including left ventricular ejection fraction (LVEF) and LGE (HR = 1.78; p = 0.001). In addition, the primary endpoint events prognostic value was significantly improved by adding LV entropy to the baseline multivariable model (C-statistic improvement: 0.785-0.818, Delong test: p = 0.001). Similarly, among 193 3.0-T field patients, adding LV entropy to the multivariable baseline model significantly improved the prognostic value of the model for MACE (C-statistic improvement: 0.820-0.898, Delong test: p = 0.004). CMR-assessed LV entropy is a powerful independent predictor of MACE in patients with CAD, incremental to common clinical and CMR risk factors, including LVEF, LGE, Native T1, and ECV. Left ventricular entropy is a powerful independent predictor of major adverse cardiac events in patients with coronary atherosclerotic heart disease, incremental to common clinical and cardiac magnetic resonance risk factors. • Left ventricular entropy, a novel cardiac magnetic resonance parameter of myocardial heterogeneity, demonstrated a robust prognostic association with major adverse cardiac events beyond guideline-based, clinical risk markers. • Entropy can have an important role in the primary prevention of major adverse cardiac events in patients with coronary atherosclerotic heart disease. • Compared with late gadolinium enhancement, extracellular volume, and native T1, entropy could be used to more comprehensively characterize the heterogeneity of left ventricular myocardium.

A urine extracellular vesicle lncRNA classifier for high-grade prostate cancer and increased risk of progression: A multi-center study

To construct a urine extracellular vesicle long non-coding RNA (lncRNA) classifier that can detect high-grade prostate cancer (PCa) of grade group 2 or greater and estimate the risk of progression during active surveillance, we identify high-grade PCa-specific lncRNAs by combined analyses of cohorts from TAHSY, TCGA, and the GEO database. We develop and validate a 3-lncRNA diagnostic model (Clnc, being made of AC015987.1, CTD-2589M5.4, RP11-363E6.3) that can detect high-grade PCa. Clnc shows higher accuracy than prostate cancer antigen 3 (PCA3), multiparametric magnetic resonance imaging (mpMRI), and two risk calculators (Prostate Cancer Prevention Trial [PCPT]-RC 2.0 and European Randomized Study of Screening for Prostate Cancer [ERSPC]-RC) in the training cohort (n= 350), two independent cohorts (n=232; n= 251), and TCGA cohort (n=499). In the prospective active surveillance cohort (n= 182), Clnc at diagnosis remains a powerful independent predictor for overall active surveillance progression. Thus, Clnc is a potential biomarker for high-grade PCa and can also serve as a biomarker for improved selection of candidates for active surveillance.

Overexpressed transferrin receptor implied poor prognosis and relapse in gastrointestinal stromal tumors.

Ferroptosis, as a novel-induced programmed cell death, plays critical roles in the pathogenesis of cancers. However, the promising biomarkers of ferroptosis in gastrointestinal stromal tumor (GIST) remain to be elucidated. Herein, the expression of ferroptosis-related genes was analyzed in GIST. Among the 64 ferroptosis-related genes, transferrin receptor (TFRC) expression presented a remarkable upregulation in high-risk patients through Gene Expression Omnibus (GEO) dataset analysis, as well as its significant change after imatinib was treated. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of TFRC-relevant genes revealed that TFRC expression was closely associated with cell growth pathways and metabolism-related pathways. Furthermore, patients at high risk of recurrence were more likely to exhibit high TFRC expression by immunohistochemistry. Additionally, high TFRC expression indicated an undesirable state of patient relapse, which could serve as a powerful significant independent predictor of recurrence-free survival (RFS). In summary, we systematically summarize the expression characteristics and clinical relevance of TFRC and show that TFRC can be used as a prognostic factor, which can be considered a potential therapeutic target in GIST.

Genetic variant annotation scores in congenital long QT syndrome.

Congenital Long QT Syndrome (LQTS) is a hereditary arrhythmic disorder. We aimed to assess the performance of current genetic variant annotation scores among LQTS patients and their predictive impact. We evaluated 2025 patients with unique mutations for LQT1-LQT3. A patient-specific score was calculated for each of four established genetic variant annotation algorithms: CADD, SIFT, REVEL, and PolyPhen-2. The scores were tested for the identification of LQTS and their predictive performance for cardiac events (CE) and life-threatening events (LTE) and then compared with the predictive performance of LQTS categorization based on mutation location/function. Score performance was tested using Harrell's C-index. A total of 917 subjects were classified as LQT1, 838 as LQT2, and 270 as LQT3. The identification of a pathogenic variant occurred in 99% with CADD, 92% with SIFT, 100% with REVEL, and 86% with PolyPhen-2. However, none of the genetic scores correlated with the risk of CE (Harrell's C-index: CADD = 0.50, SIFT = 0.51, REVEL = 0.50, and PolyPhen-2 = 0.52) or LTE (Harrell's C-index: CADD = 0.50, SIFT = 0.53, REVEL = 0.54, and PolyPhen-2 = 0.52). In contrast, high-risk mutation categorization based on location/function was a powerful independent predictor of CE (HR = 1.88; p < .001) and LTE (HR = 1.89, p < .001). In congenital LQTS patients, well-established algorithms (CADD, SIFT, REVEL, and PolyPhen-2) were able to identify the majority of the causal variants as pathogenic. However, the scores did not predict clinical outcomes. These results indicate that mutation location/functional assays are essential for accurate interpretation of the risk associated with LQTS mutations.

Automated analysis of echocardiograms at diagnosis is able to predict prognosis in ATTR cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: None. Background Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is progressive and ultimately fatal cause of heart failure. ATTR-CM often displays characteristic echocardiographic features, and manual measurements of both stroke volume and longitudinal strain are independent predictors of mortality. We sought to investigate whether automated analysis of echocardiographic parameters at the time of diagnosis were able to predict prognosis in this population. Methods We analysed all consecutive patients between 2006–2021 who underwent an echocardiogram at the time of diagnosis, and analysed their echocardiograms using artificial intelligence software that has been developed and validated by Us2.ai. Results We identified 1972 patients with ATTR-CM (age: 75.6±8.7 years, male: 86.9%), comprising of 1329 wild-type ATTR-CM and 643 hereditary ATTR-CM (V142I = 376, T80A = 171, other = 96). Patients with V142I had an increased relative wall thickness (P&amp;lt;0.001) lower stroke volume indexed (P&amp;lt;0.001), and worse longitudinal strain (P&amp;lt;0.001) than patients with wild-type and T80A ATTR-CM. In a multi-variable analysis of echocardiographic parameters selected a priori (interventricular septal diameter, relative wall thickness, left and right atrial area indexed, biplane stroke volume indexed, full thickness longitudinal strain, and E/e’ lateral), left atrial area indexed (HR=1.08, 95%CI[1.02–1.14], P=0.005), biplane stroke volume indexed (HR=0.96, 95%CI[0.94–0.98], P&amp;lt;0.001) and full thickness longitudinal strain (HR=1.04, 95%CI[1.01–1.08], P=0.009) all remained independent predictors of mortality. Conclusions Automated of analysis echocardiograms using artificial intelligence demonstrated that patients with V142I had more advanced cardiac disease at diagnosis. Automated measurements produced by artificial intelligence software are able to predict prognosis and identify the same parameters as those identified using manual analysis as powerful independent predictors of mortality.

Tracking treatment response in cardiac AL amyloidosis with native-T1 mapping

Abstract Funding Acknowledgements Type of funding sources: None. Background Cardiac magnetic resonance (CMR) derived extracellular volume (ECV) mapping has demonstrated utility in determining the cardiac response to chemotherapy in systemic AL amyloidosis, but concomitant renal dysfunction is a common contraindication for the required gadolinium contrast. Objectives To assess the ability of native-T1 mapping to measure the cardiac response to treatment, and assess the association between changes in native-T1 and prognosis. Methods We studied 221 patients who underwent cardiac magnetic resonance (CMR) scans at diagnosis and a repeat scan following chemotherapy. Results At 6-months a reduced native-T1 of ≥50ms occurred in 8(4%) patients, all of whom had a good haematological response; by contrast an increased native-T1 of ≥50ms occurred in 42(23%) patients, most of whom had a poor haematological response (n=27,68%). At 12-months, a reduced native-T1 occurred in 24(15%) patients, all of whom had a good haematological response, and was associated with a reduction in median N-terminal pro-brain natriuretic peptide (NT-proBNP) (2638ng/L vs 432ng/L,P&amp;lt;0.001) and E/e’ (14.9±6.8 vs 12.0±5.2, P=0.007), improved longitudinal strain (−14.8±4.0 vs −16.7±4.0, P=0.004) and reduction in both T2 (52.3±2.9 vs 49.4±2.0, P&amp;lt;0.001) and ECV (0.47±0.07 vs 0.42±0.08, P&amp;lt;0.001); increased native-T1 occurred in 24(15%) patients, most of whom had a poor haematological response (n=17,71%) and was associated with an increased median NT-proBNP (1622ng/L vs 3150ng/L, P=0.007), reduced ejection fraction (65.8±11.4% vs 61.5±12.4%, P=0.009) and both increased T2 (52.5±2.7 vs 55.3±4.2, P&amp;lt;0.001) and ECV (0.48±0.09 vs 0.56±0.09, P&amp;lt;0.001). Change in native-T1 at 6-months predicted mortality even after adjusting for haematological response and NT-proBNP response (HR=2.41,95%CI[1.36–4.27],P=0.003). Conclusion Changes in myocardial native-T1 in response to treatment, are reflected in changes in the traditional markers of the cardiac response provide a powerful independent predictor of mortality. Change in native-T1 represents an important addition to the standard armamentarium of amyloid assessment, and provides an alternative measure of the cardiac treatment response, that not only limits exposure of patients to contrast but could also have implications on clinical workflow by reducing scan time.

#4566 PREDICTIVE ADMISSION RISK FACTORS, CLINICAL FEATURES AND KIDNEY OUTCOMES IN COVID-19 HOSPITALISED PATIENTS WITH ACUTE KIDNEY INJURY

Abstract Background and Aims Kidneys in COVID-19 patients demonstrate high vulnerability and acute kidney injury (AKI) is recognized as a cause of poor outcome and high mortality, in those requiring hospitalisation. The aim of our study was to assess the predictors and rate of AKI involvement among COVID-19 hospitalised patients at the day of admission, and to see the impact of AKI on patient's prognosis and life expectancy. Method We analysed admission data of COVID-19 patients, hospitalized in a tertiary nephrology hospital, during the first pandemic wave. Outcome data were recorded, including the need for renal replacement therapy (RRT) and inpatient mortality at 30 days. Results Out of 115 admitted patients included into the final analysis, 62(53.9%) presented with AKI, 21(33.9%) met KDIGO criteria for stage 1, 7(11.3%) for stage 2 and 34(54.8%) for stage 3 of AKI. RRT was required in 26 patients (22.6% of total, 41.9% of all AKI). From the discharged patients, AKI has been resolved in 76% and no need of RRT following hospital discharge was noted. Pre-existing CKD was associated with a 13-fold risk of AKI (OR 13.04; 95% CI:3.85–44.06, p &amp;lt; 0.0001) adjusted for demographics and comorbidities, low albumin (OR 0.895; 95% CI: 0.797–0.970, p = 0.017), thrombocytopenia (OR 0.994; 95% CI:0.988–0.999, p = 0.022) and increase of CK over 350UI (OR 3.60; 95% CI:1.184–10.95, p = 0.024) were all independently associated with a higher risk for AKI. Mortality rates were significantly higher among patients who developed AKI compared to those without (59.6% vs 30.2%, p &amp;lt; 0.003). The low oxygen blood saturation at admission and albumin were presented as powerful independent predictors of mortality (OR 0.937; 95%CI: 0.917 – 0.958, p = 0.000; OR 0.987; 95%CI: 0.885–0.991, p &amp;lt; 0.024, respectively). The Kaplan-Meier curve illustrated longer survival in patients without AKI compared to patients with AKI (22.01± 1.703 vs 16.69 ± 1.54, log rank p = 0.009). Conclusion Renal impairment in COVID-19 patients occurs in significant percentage, and it is a factor of poor prognosis. The severity of the disease itself is emphasized as main contributing mechanism in the occurrence of AKI, and the lower blood saturation at admission is the strongest mortality predictor, outreaching the significance of the AKI itself.

C2 DIFFERENT CLINICAL PREDICTORS OF EARLY AND LATE PRIMARY VENTRICULAR FIBRILLATION: RESULTS OF THE PREDESTINATION STUDY

Abstract Introduction Few studies evaluated risk factors for primary ventricular fibrillation (VF) before reperfusion during a first acute myocardial infarction (AMI). Important parameters such as kalemia, blood pressure (BP) and heart rate (HR) at presentation were rarely considered. Furthermore, potential differences according to the time elapsed between symptoms onset and VF onset have never been investigated. Objectives to evaluate predictors of primary VF in the PREDESTINATION (PRImary vEntricular fibrillation and suDden dEath during a firST myocardIal iNfArcTION) study cohort also differentiating between early (&amp;lt;60 min from symptoms onset) and late (&amp;gt;60 min) VF. Early VF is more likely to cause sudden death (SD) before medical services arrival. Patients and Methods PREDESTINATION is a prospective, multicenter, case–control (1:2 age– and sex–matched) study enrolling patients aged 18–80 years with a first AMI, either complicated (cases) or not (controls) by primary VF before reperfusion. Results 1478 patients were analysed: mean age was 59 years, 83% were male, 36% cases. The multivariate analysis (logistic regression) on the whole population (c–statistic= 0.74) identified 8 independent predictors of primary VF: atrial fibrillation as presenting rhythm (OR 4.61), kalemia ≤3.5 mEq/L (OR 2.8), HR at presentation ≥90 bpm (OR 2.25), first–degree family history of SD (OR 2.08), anterior infarct site (OR 1.54), physical inactivity (OR 1.59), systolic BP at presentation (OR 0.98 for each mmHg), and first–degree family history of coronary artery disease/myocardial infarction (OR 0.71). The time elapsed between symptoms onset and VF was known for 405 cases (184 early and 221 late VF). There were 6 predictors of early VF, with loss of significance of physical inactivity and of family history of coronary artery disease/infarction, and an increase in the OR of family history of SD to 2.85 (95% CI: 1.6–5.08), and in the c–statistic of the model to 0.80. Among the 6 predictors of late VF, on the other hand, anterior site of AMI and family history of SD were not confirmed (c–statistic of the model 0.7). Conclusions The present study identified 8 independent predictors of primary VF. First–degree family history of SD is a powerful independent predictor of early VF, but not of late VF, suggesting that genetic predisposition plays a determining role only in early–onset VF cases and therefore the advisability of a specific genetic investigation in these patients.

Right ventricular-arterial uncoupling as an independent prognostic factor in acute heart failure with preserved ejection fraction accompanied with coronary artery disease.

Right ventricular (RV)-arterial uncoupling is a powerful independent predictor of prognosis in heart failure with preserved ejection fraction (HFpEF). Coronary artery disease (CAD) can contribute to the pathophysiological characteristics of HFpEF. This study aimed to evaluate the prognostic value of RV-arterial uncoupling in acute HFpEF patients with CAD. This prospective study included 250 consecutive acute HFpEF patients with CAD. Patients were divided into RV-arterial uncoupling and coupling groups by the optimal cutoff value, based on a receiver operating characteristic curve of tricuspid annular plane systolic excursion to pulmonary artery systolic pressure (TAPSE/PASP). The primary endpoint was a composite of all-cause death, recurrent ischemic events, and HF hospitalizations. TAPSE/PASP ≤0.43 provided good accuracy in identifying patients with RV-arterial uncoupling (area under the curve, 0.731; sensitivity, 61.4%; and specificity, 76.6%). Of the 250 patients, 150 and 100 patients could be grouped into the RV-arterial coupling (TAPSE/PASP >0.43) and uncoupling (TAPSE/PASP ≤0.43) groups, respectively. Revascularization strategies were slightly different between groups; the RV-arterial uncoupling group had a lower rate of complete revascularization (37.0% [37/100] vs . 52.7% [79/150], P <0.001) and a higher rate of no revascularization (18.0% [18/100] vs . 4.7% [7/150], P <0.001) compared to the RV-arterial coupling group. The cohort with TAPSE/PASP ≤0.43 had a significantly worse prognosis than the cohort with TAPSE/PASP >0.43. Multivariate Cox analysis showed TAPSE/PASP ≤0.43 as an independent associated factor for the primary endpoint, all-cause death, and recurrent HF hospitalization (hazard ratios [HR]: 2.21, 95% confidence interval [CI]: 1.44-3.39, P <0.001; HR: 3.32, 95% CI: 1.30-8.47, P = 0.012; and HR: 1.93, 95% CI: 1.10-3.37, P = 0.021, respectively), but not for recurrent ischemic events (HR: 1.48, 95% CI: 0.75-2.90, P = 0.257). RV-arterial uncoupling, based on TAPSE/PASP, is independently associated with adverse outcomes in acute HFpEF patients with CAD.

MiRNA-seq identification and clinical validation of CD138+ and circulating miR-25 in treatment response of multiple myeloma

BackgroundDespite significant advancements in multiple myeloma (MM) therapy, the highly heterogenous treatment response hinders reliable prognosis and tailored therapeutics. Herein, we have studied the clinical utility of miRNAs in ameliorating patients’ management.MethodsmiRNA-seq was performed in bone marrow CD138+ plasma cells (PCs) of 24 MM and smoldering MM (sMM) patients to analyze miRNAs profile. CD138+ and circulating miR-25 levels were quantified using in house RT-qPCR assays in our screening MM/sMM cohort (CD138+ plasma cells n = 167; subcohort of MM peripheral plasma samples n = 69). Two external datasets (Kryukov et al. cohort n = 149; MMRF CoMMpass study n = 760) served as institutional-independent validation cohorts. Patients’ mortality and disease progression were assessed as clinical endpoints. Internal validation was performed by bootstrap analysis. Clinical benefit was estimated by decision curve analysis.ResultsmiRNA-seq highlighted miR-25 of CD138+ plasma cells to be upregulated in MM vs. sMM, R-ISS II/III vs. R-ISS I, and in progressed compared to progression-free patients. The analysis of our screening cohort highlighted that CD138+ miR-25 levels were correlated with short-term progression (HR = 2.729; p = 0.009) and poor survival (HR = 4.581; p = 0.004) of the patients; which was confirmed by Kryukov et al. cohort (HR = 1.878; p = 0.005) and MMRF CoMMpass study (HR = 1.414; p = 0.039) validation cohorts. Moreover, multivariate miR-25-fitted models contributed to superior risk-stratification and clinical benefit in MM prognostication. Finally, elevated miR-25 circulating levels were correlated with poor survival of MM patients (HR = 5.435; p = 0.021), serving as a potent non-invasive molecular prognostic tool.ConclusionsOur study identified miR-25 overexpression as a powerful independent predictor of poor treatment outcome and post-treatment progression, aiding towards modern non-invasive disease prognosis and personalized treatment decisions.