Disease Risk Stratification Research Articles

A high polygenic risk score is associated with SSA/SSB antibody positivity and early onset in primary Sjögren's disease.

To calculate a polygenic risk score (PRS) based on single nucleotide variants (SNVs) previously associated with primary Sjögren's disease (SjD) with genome-wide significance, and determine the genetic risk for SjD stratified by antibodies, sex and age at diagnosis. Patients with SjD (n = 1065) were genotyped using Illumina OmniExpressExome chip. Control genotype data were available (n = 7742). Two PRSs were constructed, one including HLA gene variants (n = 21 SNVs), and one without HLA (n = 18 SNVs). High PRS quartile (Q4) individuals were compared with low PRS (Q1-3). A high PRS was associated with SSA antibody positive SjD (OR 9.16, 95% CI 7.75-10.85, p= 3.7x10-146), and strengthened in SjD positive for both SSA/SSB antibodies (OR 13.67, 95% CI 10.88-17.32, p= 4.6x10-108). High PRS classified SSA/SSB antibody positive SjD with very good accuracy (AUC 0.86). PRS without HLA showed a weaker association with SSA/SSB positive SjD (OR 2.09, 95% CI 1.71-2.55, p= 6.4x10-13). Antibody negative SjD displayed a PRS similar to controls. Patients in the high PRS quartile were significantly younger at diagnosis, 48.9 ± 14.9 vs 53.4 ± 13.4 years in the low PRS quartiles (Q1-3), p= 2.2x10-6, and presented higher frequencies of ANA, SSA and SSA/SSB antibodies, p < 1x10-5. A high PRS is associated with SSA/SSB antibody positivity and early disease onset, both largely attributed to the weight of the HLA alleles. Integration of PRS with other biomarkers applied to clinical phenotypes, could be a useful tool for disease risk stratification and treatment decisions.

Incidence, progression, and outcomes of heart failure with improved ejection fraction: The added value of longitudinally assessed ejection fraction

BackgroundThe revised universal definition of heart failure (HF) established a standardized definition for HF with improved ejection fraction (HFimpEF) and emphasized the importance of longitudinally assessing left ventricular EF (LVEF). We aim to investigate the incidence, disease progression, and clinical outcomes of HFimpEF in a longitudinal cohort of hospitalized HF patients. MethodsWe retrospectively included HF patients with baseline LVEF ≤40 % and satisfactory echocardiographic follow-ups. HFimpEF was defined as a ≥ 10-point increase in LVEF to >40 %. Transient HFimpEF was defined as a recurrent LVEF ≤40 % after achieving HFimpEF. Clinical outcomes were all-cause death, cardiovascular death, and HF rehospitalization. ResultsDuring a median follow-up of 47.9 months, 517 of 923 patients met HFimpEF criteria; 65.0 % HFimpEF cases occurred within 12 months. HFimpEF patients had lower risks of all-cause death (hazard ratio [HR] = 0.16, P < 0.001), cardiovascular death (HR = 0.19, P < 0.001), and HF rehospitalization (HR = 0.39, P < 0.001). However, 160 HFimpEF patients experienced LVEF worsening during follow-up; their risks for adverse events were higher (HR = 1.89 for all-cause death, HR = 2.13 for cardiovascular death, HR = 2.13 for HF rehospitalization, P < 0.05 for all) compared to persistent HFimpEF patients, and their capability of LVEF re-improvement was diminished. An inverted U-shaped LVEF profile for HFimpEF—characterized by a slow, modest increase followed by a decline—portended a higher mortality risk. ConclusionsHFimpEF was observed in 56.0 % of HF patients. Longitudinally assessing LVEF helps identify HFimpEF patients and facilitates disease progression monitoring and risk stratification.

How can Four-Dimensional Magnetic Resonance Imaging Improve the Diagnosis of Heart Disease?

This review describes the evolution and enhanced diagnostic capabilities introduced by four-dimensional (4D) flow cardiac magnetic resonance (CMR) in cardiovascular imaging. It charts the historical advancements from echocardiography through to two-dimensional phase-contrast magnetic resonance imaging (2D-PC MRI), culminating in the adoption of 4D flow MRI. This technique affords exhaustive, time-resolved, three-dimensional visualisations of intracardiac and vascular blood flow, refining the accuracy of cardiovascular assessments over traditional methods, especially in complex anatomical settings. The review elaborates on the capacity of 4D flow MRI to offer unparalleled insights into flow dynamics, vessel wall interactions, and cardiac function, thereby enhancing disease detection, risk stratification, and therapeutic evaluations. It accentuates the impact of 4D flow MRI on modern cardiological practices, highlighting its pivotal role in advancing diagnostics and patient management in the context of diverse cardiovascular pathologies.

The potential utility of cord blood DNA methylation in pediatric clinical practice.

Our understanding of the origins of noncommunicable diseases has evolved over the years with greater consideration given to the lasting influence exposures and experiences during the preconceptional and prenatal periods can have. Research highlights the associations of parental exposures (e.g., diet, obesity, gestational diabetes, lipid profile, toxic exposures and microbiome) with the infant/fetal methylome and suggest associations with infant, child and/or adolescent chronic health outcomes. Thus, epigenetics and specifically cord blood DNA methylation may have utility as biomarkers for disease risk identification and stratification in pediatrics. However, for cord blood DNA methylation analyses to be leveraged as biomarkers of disease risk in pediatric clinical practice, the results must be replicable, validated and clinically meaningful. Challenges and opportunities to this prospect are herein discussed.

Abstract 4136462: Provider understanding of Coronary Artery Calcium Scoring (CAC) testing in Atherosclerotic CArdiovascular Disease risk stratification and Racial Disparities Study (CAC-CARD) to reduce healthcare disparities

Background: Coronary Artery Calcium (CAC) scoring is critical in assessing Atherosclerotic Cardiovascular Disease (ASCVD) risk. Despite its utility, many primary care physicians lack confidence and familiarity with its application. Significant racial disparities in CAC scoring utilization have been observed, potentially affecting patient outcomes. Hypothesis: We hypothesized that a short targeted educational intervention would enhance physicians' confidence, knowledge, and utilization of CAC scoring and awareness of racial disparities. Methods: A pre- and post-intervention study (Image 1) was conducted among 39 physicians at the University of Louisville. The intervention included a 20-minute educational session on CAC scoring and racial disparities. A video summarizing the ACC2018 guidelines for prevention and cholesterol treatment was provided. A summary of key points for clinical practice was given. The ASCVD plus calculator app was provided. Data were collected using a structured questionnaire before and after the intervention. Viewing time and engagement were recorded. Descriptive and inferential statistics analyzed the data. Results: The average correct physician responses increased from a mean of 59.5% pre-intervention to 92.0% post-intervention. Post-intervention, the number of physicians who felt confident or very confident in CAC testing increased from 17.9% to 94.8%. Additionally, 33 out of 39 physicians (84.6%) reported likely to use CAC testing more frequently. Correct responses on racial disparities improved from 59% pre-intervention to 92.0% post-intervention. (Image 2). The average viewing time was 28 minutes. Time spent on the questionnaires was 14 min pre and 12 min post. Conclusion: Our targeted educational intervention significantly enhanced physicians' knowledge and confidence in CAC scoring for ASCVD risk assessment and raised awareness about racial disparities, promoting more equitable practices.

Association between the plasma ceramide and coronary microvascular resistance

BackgroundPlasma ceramide plays a potentially significant role in the pathogenesis of coronary microvascular dysfunction. However, the relationship between plasma ceramide and coronary microvascular resistance in patients remains unclear. This study aimed to evaluate the association between plasma ceramide levels, as well as their distinct ratios, and coronary microvascular resistance.MethodsThis single-center observational study retrospectively enrolled patients who underwent both ceramide measurement and coronary angiography during hospitalization. The microvascular resistance of the coronary arteries was assessed in all patients using the angiography-derived index of microcirculatory resistance (Angio-IMR). The cumulative coronary microvascular resistance was calculated by summing the microvascular resistance of the three main coronary arteries. Multiple linear and logistic regression analyses were employed to evaluate the relationship between plasma ceramide and cumulative coronary microvascular resistance. Restricted cubic spline (RCS) analysis was conducted to investigate the association between plasma ceramide levels and cumulative coronary microvascular resistance. Receiver operating characteristic (ROC) curves were employed to evaluate the predictive value of plasma ceramide for coronary microvascular resistance. Additionally, subgroup analyses and interaction tests were performed.ResultsA total of 225 patients were included in this study, with a median cumulative coronary microvascular resistance of 48.04 (40.32–56.73). After adjusting for potential confounding factors, both plasma 16:0 ceramide and the 16:0/24:0 ceramide ratio were positively associated with cumulative coronary microvascular resistance [standardized β ± standard error: 75.05 ± 8.46 (P < 0.001) and 91.72 ± 20.41 (P < 0.001), respectively]. Similar independent associations were observed in predicting high cumulative microvascular resistance [β = 8.03 ± 1.91 (P < 0.001) and 9.98 ± 3.88 (P = 0.010), respectively]. Additionally, a significant nonlinear relationship was observed between plasma 16:0 ceramide, the 16:0/24:0 ceramide ratio, and cumulative coronary microvascular resistance (P for nonlinear < 0.05). The ROC analysis revealed that the optimal cut-off for plasma 16:0 ceramide is 0.178 µmol/L, with a specificity of 57.1% and a sensitivity of 91.2%. For the 16:0/24:0 ceramide ratio, the optimal cut-off is 0.072, yielding a specificity of 73.2% and a sensitivity of 54.9%. Subgroup analysis indicated that the association between plasma ceramide and coronary microvascular resistance was trending toward non-significance in patients with acute coronary syndrome (ACS).ConclusionsA significant nonlinear relationship exists between plasma ceramide and coronary microvascular resistance, which holds important clinical implications for the risk stratification of coronary microvascular disease. New insights into the potential effects of ceramides enhance our understanding of the complex mechanisms underlying coronary microvascular disease and warrant further investigation in a broader population.Graphical abstract

The distribution and mass index of epicardial adipose tissue were correlated with microvascular obstruction formation in patients with ST-segment elevation myocardial infarction

Abstract Introduction Epicardial adipose tissue (EAT), refers to a metabolically active fat depot between the visceral pericardium and the outer margin of the myocardium. EAT has gradually emerged as a novel target for risk stratification of coronary artery disease due to its distinctive location and multifaceted metabolic properties. Microvascular obstruction (MVO) after primary percutaneous coronary intervention (pPCI) is identified as an independent risk factor for poor prognosis in patients with acute myocardial infarction. However, the clinical implications of EAT in MVO formation in patients with ST-segment elevation myocardial infarction (STEMI) remain unclear. Recently, cardiac magnetic resonance (CMR) has emerged as the gold standard technique to detect the extent of MVO and evaluate EAT parameters. Purpose This study aimed to evaluate the correlation between EAT accumulation and MVO occurrence detected by CMR in STEMI patients. Methods A total of 129 STEMI patients who underwent pPCI successfully were enrolled. Clinical characteristics including demographic characteristics, cardiovascular risk factors, laboratory data and angiographic parameters were recorded from each patient by 1 trained physician. All patients underwent CMR within 1 week following pPCI to evaluate infarct size, MVO volume and EAT distribution. All CMR data were transferred to Q-MASS MR 8.1 imaging system (Medis, Leiden, The Netherlands) and interpreted twice by 2 expert radiologists who were blinded to the angiographic and clinical data of patients. Results Compared to STEMI patients without MVO, STEMI patients with MVO presented with higher peak troponin T levels, increase of neutrophil lymphocyte ratio (NLR) and C-reactive protein (CRP), larger infarct size and compromised left ventricular ejection fraction. Total EAT volume, EAT mass index, left atrioventricular EAT volume, left atrioventricular EAT mass index and thickness of EAT in the left atrioventricular groove were unanimously associated with the occurrence of MVO. The left atrioventricular EAT mass index in STEMI patients with MVO were significantly larger than that in STEMI patients without MVO (24.72±5.049 g/m2 vs 18.63±3.670 g/m2, P&amp;lt;0.001). Multivariate logistic regression analysis demonstrated that NLR, peak troponin T levels and left atrioventricular EAT mass index were independent predictors of MVO. LV EAT mass index showed a robust and independent relationship with MVO formation and a cutoff value &amp;gt;21.5192 g/m2 predicted the presence of MVO with a sensitivity and specificity of 79.5% and 80.4%, respectively. Conclusions Left atrioventricular EAT mass index is an independent predictor of MVO. Measurement of EAT using CMR could be used for risk stratification and might be a promising target in developing new therapies to reduce myocardial reperfusion injury in patients with STEMI.

Methylome of circulating cell free DNA as a novel biomarker tool: from acute coronary syndrome to broader risk stratification of cardiovascular disease

Abstract Background Cell death during tissue injury leads to release of chromosomal DNA which is promptly degraded. However, short DNA fragments wrapped around nucleosomes survive longer in the bloodstream and can be isolated as circulating cell-free DNA (ccfDNA). Oncology field pioneered the use of cfDNA as clinical biomarker by identifying sequence modifications induced in cancer cells. Importantly, ccfDNA also retains the same epigenetic information as the tissue of origin. Despite major advances for disease diagnosis and therapy, coronary artery diseases (CAD) and associated conditions such acute myocardial infarction (AMI) or heart failure (HF) are responsible for leading number of deaths worldwide. Preventive and surveillance strategies with non-invasive testing are needed. Purpose Evaluation of ccfDNA methylation profiles as prognostic non-invasive biomarker for risk stratification of acute coronary syndromes and their potential application in preventive and surveillance strategies in other cardiovascular disorders. Methods CcfDNA isolated from citrate-plasma collected from our discovery cohort, comprising healthy controls, STEMI, NSTEMI and unstable angina (UA) patients, was analyzed applying Whole Genome Bisulfite Sequencing (WGBS) using a low-input BS-seq (PBAT) protocol. Computational analysis generated differentially methylated regions (DMRs) by tiling CpG areas and setting a threshold of minimal 25% methylation difference compared to the healthy group. To assess the validity of our findings, a selection of disease-specific DMRs were tested using targeted methylation sequencing protocol in a new set of patients. This procedure consisted in enzymatic conversion of ccfDNA methylated sites followed by probe-specific enrichment libraries and sequencing at a Novaseq 6000 platform. Results The study identified a total of 1941 DMRs and from those 486 were STEMI, 223 NSTEMI and 684 UA specific. From the identified DMRs, 74.13% from STEMI, 72.68% from NSTEMI and 61.62% from UA annotated with heart-related diseases using DisGeNET gene-disease associations. Interestingly, most of identified DMRs located within intronic regions (~60%) and also annotated as enhancers and lncRNAs. The independent validation with targeted methylation sequencing identified 566, 306 and 248 DMRs, respectively, and reduced the number of disease-specific DMRs to 171 in STEMI, 115 in NSTEMI and 82 in UA. Conclusion and Future Approaches Methylation profiles of ccfDNA showed potential as a biomarker to stratify the severity of acute coronary syndromes, a novel non-invasive detection methodology that could be extrapolated to risk stratification in other cardiovascular disease such as heart failure or coronary artery disease.

Prognostic implication of computational angiography-derived fractional flow reserve in patients with non-obstructive coronary artery disease

Abstract Background Non-obstructive coronary artery disease (NOCAD) is proved to have high association with rate of major adverse cardiovascular events (MACE) in recent studies, yet risk stratification of symptomatic Non-Obstructive Coronary Artery Disease (NOCAD) patients remains uncertain. Objectives Our study assessed clinical value of single-vessel, multi-vessel, and three-vessel computational angiography-derived fractional flow reserve (caFFR) measurement in NOCAD patients. Methods We enrolled patients with ≤ 50% stenosis with a caFFR value ≥ 0.8 in all three coronary arteries on coronary angiography. The sum of caFFR values in the three vessels was computed for each patient. Patient stratification was based on median value of the following criteria: single vessel analysis, multi-vessel analysis, 3-vessel (3V) analysis. The primary endpoint of this study was major adverse cardiac events (MACE) at 5 years, defined as a composite of cardiac death, myocardial infarction, and ischemia-driven revascularization. Results A total of 490 patients were included (mean age 64.39 ± 11.16, 55.5% male). The 5-year MACE rates in single-vessel analysis were statistically insignificant between low and high caFFR groups (Left anterior descending artery (P=0.163); Left circumflex artery (P=0.797); Right coronary artery (P=0.127)). In multi-vessel analysis, patients in multiple-vessel low-caFFR group (with 2-3 vessels lower than median value of all coronary arteries) show an increased risk of 5-year MACE than patients in single-vessel low-caFFR group (0-1 vessel) (hazard ratio [HR] 2.648, 95% confidence interval [CI] 1.141 - 6.145, P = 0.023). In 3-vessel analysis, patients in the low 3V-caFFR group demonstrated a greater 5-year MACE risk than the high 3V-caFFR group ([HR] 2.43, 95% 95%[CI] 1.087 - 5.433, P = 0.031). Conclusion In patients with NOCAD, the higher count of vessels exhibiting with low caFFR values and the low 3V-caFFR values have been found to be associated with increased rate of MACE over a 5-year period. We demonstrated that both multiple-vessel and 3V-caFFR measurements serve as valuable prognostic indicators for risk assessment in NOCAD patients.

Proteomic and genomic evaluation of plasma protein biomarkers for atrial fibrillation

Abstract Background Atrial fibrillation (AF) is a common arrhythmia and an important cause of ischemic stroke. Several plasma proteins have been suggested as biomarkers for the risk of AF and subsequent stroke in previous studies, but validation in independent cohorts is needed. Large-scale integration of proteomics with genetic and clinical data holds potential for refinement of disease prediction and risk stratification. Purpose This study aimed to evaluate previously suggested plasma protein biomarkers of AF and ischemic stroke using plasma protein measurements in a large cohort. Methods Ten tentative protein biomarkers previously associated with AF or ischemic stroke in AF patients, were evaluated in a nested case-control study comprising 49,757 individuals from the UK biobank (UKB). Plasma proteins were measured by normalized protein expression on the Olink platform. Outcomes were incident AF and ischemic stroke. The proteins were evaluated in Cox regression models adjusted for sex, age, and clinical risk factors. To assess whether the proteins were independent predictors, they were evaluated in sensitivity analyses with additional adjustment for NT-proBNP levels. Polygenic risk scores were calculated for plasma protein concentrations using the PRS-CS-auto algorithm and tested for association with AF or ischemic stroke in an independent subset of the UKB cohort without plasma protein measurements (n=379,392). Results All ten plasma proteins were associated with incident AF in the primary model, and eight were associated with incident ischemic stroke (P-values &amp;lt; 0.0025 for all). Adjusted for NT-proBNP levels, the proteins interleukin-6, GDF15, angiopoietin 2, and Troponin-I remained independently associated with AF, and the proteins GDF15, Cystatin-C, interleukin-6, ADAMTS13, and FGF23 remained independently associated with ischemic stroke. Polygenic risk scores for NT-proBNP and angiopoietin 2 were associated with increased rates of AF. No polygenic scores were significantly associated with ischemic stroke. Conclusion Large-scale proteomic evaluation validated ten plasma proteins associated AF and found eight to be associated with ischemic stroke. Seven proteins were associated with AF or ischemic stroke independently of NT-proBNP levels. Additional genomic evaluation provided evidence of associations between incident AF and genetically predicted plasma levels of angiopoietin 2 and NT-proBNP. As proteomic analyses of the plasma proteome become cheaper and more readily available, these findings could contribute to future risk stratification and selection of individuals for AF screening programs.Proteins associated with AFProteins associated with ischemic stroke

External validation of the Systematic COronary Risk Evaluation 2 (SCORE2) model in cancer patients

Abstract Background Guidelines recommend cardiovascular disease (CVD) risk stratification before cancer treatment to better identify patients for intensified follow-up or cardioprotective treatment. Only a limited number of CVD risk stratification tools exists for cancer patients which at present is not widely used nor extensively validated. The ESC Guidelines on Cardio-oncology 2022 suggest using traditional CVD models like the SCORE2 (Systematic Coronary Risk Estimation 2). However, external validation in cancer populations is lacking. Purpose Our aim was to study the prevalence of CVD risk factors and incidence of cardiovascular events in a cancer cohort and externally validate the Systematic COronary Risk Evaluation 2 (SCORE2) model in this context. Methods We included 1058 patients from a large-scale populational study without diabetes or established CVD aged 40 to 69 years and diagnosed with cancer between 2006 and 2012. Participants were assessed for cardiovascular risk factors at baseline and followed until Sept 2023. The Norwegian Cancer Registry provided patient specific information about cancer characteristics and therapy. The primary outcome was the combination of myocardial infarction (MI), stroke or CVD mortality, which was retrieved from the local hospitals’ registries and the national causes of death registry. Performance was assessed using smooth calibration curves of predicted and observed risk and Harrel’s C-statistic for discrimination, both corrected for competing risks. SCORE2 was recalibrated by adapting the model with a single multiplicative constant based on the expected-to-observed ratio (E/O-ratio). Results The most common cancer types were gastrointestinal cancer (19%), male genital including prostate cancer (19%) and breast cancer (18%). Mean (SD) age was 58.6 (7.6) years, 54% were female. Prevalence of cardiovascular risk factors are shown in Table 1. In total, 121 (11%) individuals had a CVD event (MIs 53 (44%), strokes 46 (38%) and CVD deaths 22 (18%)) during a median (interquartile range) follow-up of 11.1 (3.4 to 13.1) years, and 360 (34%) died due to non-CVD causes. Calibration plots showed adequate agreement between estimated and observed 10-year prognosis after recalibration (C-statistics 0.685, 95% CI 0.643 to 0.728), Figure 1. E/O-ratio for men was 0.65 and for women 0.63, indicating underestimation of the observed CVD incidence. After recalibration, the median estimated 10-year risk was 8.1% (IQR 5 to 11), 36% had &amp;gt;10% 10-year risk and 9% had &amp;gt;15% 10-year risk. Conclusion SCORE2 underestimated CVD risk in a general cancer population but showed adequate agreement after recalibration and C-statistics aligned with the original external validation cohorts. SCORE2 is useful also in cardio-oncology setting (after recalibration) to identify individuals at higher risk of developing CVD.

Biomarkers in early and late period after radiofrequency and pulsed field catheter ablation of atrial fibrillation

Abstract Introduction Biomarkers are routinely used parameters for disease diagnosis, treatment control and risk stratification. In connection with atrial fibrillation (AF), the importance of GDF-15 (growth differentiation factor 15), NT-proBNP (N-terminal fragment brain natriuretic factor) and hs-TnT (high sensitivity cardiac troponin T) is discussed. Catheter ablation is an established treatment method in selected population with AF. However, biomarker response to radiofrequency catheter ablation (RFCA) and pulsed field ablation (PFA) of AF has not been precisely described. Purpose Purpose of the study was to describe early and late dynamics of GDF-15, hs-TnT and NT-proBNP in different ablation technologies. Methods We prospectively enrolled 48 patients (median (IQR) age 62 (55; 70) years, 30 males) undergoing RFCA, which we compared with 30 patients (median (IQR) age 64 (56; 71) years, 18 males) undergoing PFA. All patients underwent 6 sequential blood takes: before ablation (baseline), right after ablation (0h), 24 and 48 hours after procedure (24h and 48h), 90 and 180 days after procedure. Levels of GDF-15, hs-TnT and NT-proBNP were analyzed. Results Out of all patients, 19 (40 %) and 20 (67 %) patients had paroxysmal AF in RFCA and PFA group, respectively. Additional ablation lesions over pulmonary vein isolation were done in 26 (54 %) patients in RFCA group and 11 (43 %) patients in PFA group. Median procedural time was significantly longer in RFCA than in PFA group (155 (130; 190) vs. 80 (70; 90) min; p &amp;lt; 0.01). Early dynamics of GDF-15 and cardiac hs-TnT are visualised in Figure 1 and 2. GDF-15 level peak was registered 48 hours after ablation with median (IQR) 1183 (824; 1988) ng/l. Compared to baseline, GDF-15 values sustained elevated up to 90 days after ablation in both groups and decreased to baseline levels after 180 days. No significant differences were found in GDF-15 levels between patients treated with RFCA and PFA. Maximal values of hs-TnT were significantly higher in PFA group than in RFCA group (1001±589 vs. 458±202 ng/l; p &amp;lt; 0.001). We have recognised decrease of NT-proBNP between baseline and 90 days after procedure in both groups: 338 (112; 613) vs. 209 (101; 545) ng/l; p &amp;lt; 0.05. Conclusion Eventhough GDF-15 is considered as a nonspecific biomarker reflecting general condition of patient, the levels are significantly affected by catheter ablation of AF for several months irrespective to ablation technology. PFA is associated with advanced elevation of hs-TnT.Dynamics of GDF-15 (median; IQR)Dynamics of hs-TnT (median; IQR)

An equation for estimating low-density lipoprotein-triglyceride content and its use for cardiovascular disease risk stratification.

The triglyceride (TG) content of low-density lipoprotein (LDL-TG) has been shown to be more predictive of atherosclerotic cardiovascular disease (ASCVD) events than the cholesterol content of LDL (LDL-C). The goal of our study was to develop an equation for estimating LDL-TG (eLDL-TG) based on the standard lipid panel and to compare it to estimated LDL-C as an ASCVD risk biomarker. Using least-square regression analysis, the following eLDL-TG equation was developed: . LDL-TG was measured by the β-quantification (BQ) reference method (N = 40,202). LDL-C was calculated by the Sampson-NIH equation. The association of LDL-C and eLDL-TG with ASCVD risk markers was performed in the National Heart and Nutrition Examination Survey (NHANES) (N = 37,053) and with ASCVD events in a primary prevention cohort from the UK Biobank (UKB) (N = 429,367) and the Atherosclerosis Risk in Communities (ARIC) study (N = 14,632). eLDL-TG showed better ASCVD risk stratification of UKB participants than LDL-C (Wilcoxon Chi-Square: 2,099.6 vs. 418.7, respectively). Receiving-operating characteristics analysis revealed that eLDL-TG had a stronger association with ASCVD events than LDL-C (AUC: 0.596 vs. 0.542, respectively) and other conventional lipid markers. Similar findings were found in ARIC. Discordance analysis in UKB showed that the group with low LDL-C/high eLDL-TG had a similar risk as the high LDL-C/high eLDL-TG group. Furthermore, these same two groups with the highest eLDL-TG levels and the highest ASCVD event rate also had higher mean levels of systolic blood pressure, Body Mass Index, hemoglobin A1C, and C-reactive protein than the two lower eLDL-TG groups. Using eLDL-TG > 44.6 mg/dl (80th percentile) as a cut-point leads to a hazard ratio of 1.32 (95% CI, 1.29-1.36) for ASCVD events, which remained significant after adjustment for LDL-C and apoB. Furthemore, using eLDL-TG as a risk-enhancer test leads to reclassification of 50% more high-risk individuals than current lipid-enhancer test rules. Like LDL-C, LDL-TG can also be calculated from the results of the standard lipid panel. Compared to estimated LDL-C, eLDL-TG was a better risk marker for primary prevention and hence could improve initial ASCVD risk stratification.

Beyond the Heart: The Predictive Role of Coronary Artery Calcium Scoring in Non-Cardiovascular Disease Risk Stratification.

Coronary artery calcium scoring (CACS), a non-invasive measure of coronary atherosclerosis, has significantly enhanced cardiovascular (CV) risk assessment and stratification in asymptomatic individuals. More recently, a higher score for CAC has been associated with an increased risk of non-CV diseases and all-cause mortality. This review consolidated evidence supporting the role of CAC in assessing non-CV diseases, emphasizing its potential in early diagnosis and prognosis. We observed a strong association between CACS and non-CV diseases, viz., chronic obstructive pulmonary disease, pulmonary embolism, pneumonia, diabetes, chronic kidney disease, osteoporosis, metabolic dysfunction-associated steatotic liver disease, nephrolithiasis, stroke, dementia, malignancies, and several autoimmune diseases. Also, CAC may aid in evaluating the risk of CV conditions developing secondary to the non-CV diseases mentioned earlier. Further evidence from prospective studies, intervention trials, and population-based behavioral studies is needed to establish CAC cutoff values and explore preventative care applications, facilitating their broader integration into healthcare practices.

SPLENDID incorporates continuous genetic ancestry in biobank-scale data to improve polygenic risk prediction across diverse populations.

Polygenic risk scores are widely used in disease risk stratification, but their accuracy varies across diverse populations. Recent methods large-scale leverage multi-ancestry data to improve accuracy in under-represented populations but require labelling individuals by ancestry for prediction. This poses challenges for practical use, as clinical practices are typically not based on ancestry. We propose SPLENDID, a novel penalized regression framework for diverse biobank-scale data. Our method utilizes ancestry principal component interactions to model genetic ancestry as a continuum within a single prediction model for all ancestries, eliminating the need for discrete labels. In extensive simulations and analyses of 9 traits from the All of Us Research Program (N=224,364) and UK Biobank (N=340,140), SPLENDID significantly outperformed existing methods in prediction accuracy and model sparsity. By directly incorporating continuous genetic ancestry in model training, SPLENDID stands as a valuable tool for robust risk prediction across diverse populations and fairer clinical implementation.

D-dimer-An International Assessment of the Quality of Laboratory Testing: Implications for D-dimer Use in the Real World.

D-dimer assessment has several established roles in venous thromboembolism (VTE) and disseminated intravascular coagulation diagnosis, and recently the risk stratification of coronavirus disease 2019 (COVID-19). D-dimer assays are neither standardized nor harmonized, use varying methodologies, and use different reporting units, all resulting in a lack of interchangeability and generalizability of assays. Using large multiyear datasets from an international laboratory quality assurance program, we assessed (1) common D-dimer assays in use worldwide, (2) differences in analytical performance between different methods, and (3) interlaboratory variability between positive samples. External proficiency testing results from laboratories participating in the External Quality Control for Assays and Tests (ECAT) Foundation were analyzed from 2017 to 2023. Annually, between 578 and 690 laboratories participated in the D-dimer sample surveys with response rates ranging from 88 to 97%. The three most common assays in use in 2023 were the Siemens Innovance D-dimer (42%), the IL HemosIL D-dimer HS 500 (20%), and the Diagnostica Stago (Stago) Liatest D-dimer Plus (10%)-all these are automated, quantitative, latex immunoassays expressed in fibrinogen equivalent units (FEU). The highest interlaboratory variability was observed around the typical VTE exclusion threshold of 0.5 mg/L FEU. Lower interlaboratory variability was observed at values above 0.8 mg/L FEU. Our study provides recent, international performance data on currently used D-dimer assays and describes the significant variability between assays and across D-dimer concentrations. We demonstrate that assays are not interchangeable and that using them interchangeably has the potential to result in clinically important errors. There is an urgent need to educate users about these issues and to work towards harmonizing D-dimer units and reporting.

Beyond the Agatston calcium score: role of calcium density and other calcified plaque markers for cardiovascular disease prediction.

To review the current evidence and highlight future strategies regarding consideration of coronary artery calcium (CAC) density in cardiovascular disease (CVD) risk stratification. Expressed as the product of plaque area and a peak calcium density weighting factor, the Agatston method is the gold-standard for measuring CAC on noncontrast cardiac computed tomography. Over the last decade, observational data have suggested that calcium density is inversely associated with CVD events and confers additional prognostic information independent of traditional risk factors and Agatston CAC scores. Specific density measures have been assessed including peak calcium density, mean CAC density, and CAC area-density discordance. Beyond calcium density, the number of affected arteries and regional distribution of CAC which may be correlated with CAC density have also improved the predictive utility of the Agatston score. Calcium density is inversely associated with CVD risk after considering plaque area and/or volume. Calcium markers including density, vessel involvement, and regional distribution confer additional prognostic information for the prediction of incident CVD among those with prevalent subclinical atherosclerosis. A future area of study includes calcium radiomics ('calcium-omics') and whether the artificial intelligence-derived automated measurement of calcium markers beyond the Agatston score may be of value in CVD risk stratification among individuals with early to advanced subclinical atherosclerosis.

Unraveling aortic hemodynamics using fluid structure interaction: biomechanical insights into bicuspid aortic valve dynamics with multiple aortic lesions.

Aortic lesions, exemplified by bicuspid aortic valves (BAVs), can complicate congenital heart defects, particularly in Turner syndrome patients. The combination of BAV, dilated ascending aorta, and an elongated aortic arch presents complex hemodynamics, requiring detailed analysis for tailored treatment strategies. While current clinical decision-making relies on imaging modalities offering limited biomechanical insights, integrating high-performance computing and fluid-structure interaction algorithms with patient data enables comprehensive evaluation of diseased anatomy and planned intervention. In this study, a patient-specific workflow was utilized to biomechanically assess a Turner syndrome patient's BAV, dilated ascending aorta, and elongated arch. Results showed significant improvements in valve function (effective orifice area, EOA increased approximately twofold) and reduction in valve stress (~ 1.8-fold) following virtual commissurotomy, leading to enhanced flow dynamics and decreased viscous dissipation (~ twofold) particularly in the ascending aorta. However, increased viscous dissipation in the distal transverse aortic arch offset its local reduction in the AAo post-intervention, emphasizing the elongated arch's role in aortic hemodynamics. Our findings highlight the importance of comprehensive biomechanical evaluation and integrating patient-specific modeling with conventional imaging techniques for improved disease assessment, risk stratification, and treatment planning, ultimately enhancing patient outcomes.

A-228 Evaluation of an Equation for Low-Density Lipoproteins-Triglycerides in Predicting ASCVD Risk in the UK Biobank Population

Abstract Background Low-density lipoprotein-cholesterol (LDL-C) is the main univariate risk marker recommended for initial atherosclerotic cardiovascular disease (ASCVD) risk stratification. LDL, however, transports other constituents that can serve as pro-atherogenic risk markers. Like LDL-C, the triglyceride content of LDL (LDL-TG) can also be estimated from the lipid panel. Using data from UK Biobank (UKB), we compared LDL-C to LDL-TG for predicting future ASCVD events. Methods A UKB dataset (N=270,436) of primary prevention individuals not on lipid lowering therapy was used for analysis. LDL-C was calculated by the following equations: Friedewald, Extended Martin-Hopkins, Sampson-NIH, and Enhanced Sampson-NIH. LDL-TG was calculated by our newly devised equation (eLDL-TG = TG/38.46 + nonHDL-C/5.75 + (TG/nonHDL-C)/0.103 + (1/HDL-C)/0.0041 - 2.95)), which was derived from a dyslipidemic cohort (N=40,202) analyzed by the beta-quantification reference method. Results Although there was only a modest comparison between eLDL-TG and measured LDL-TG (R2=0.601, slope=0.611), eLDL-TG appeared to be a better risk marker than LDL-C in UKB. When the population was divided into quintiles and analyzed by survival curve analysis, eLDL-TG was better than LDL-C in segregating patients into low- and high-risk groups (Figure). Similar findings on the relative value of LDL-TG over other risk markers were also found when analyzed by ROC analysis (AUC: eLDL-TG&amp;gt;HDL-C&amp;gt;remnant-cholesterol&amp;gt;NonHDL-C&amp;gt;TG&amp;gt;apoB&amp;gt;Sampson-NIH-LDL-C). By Cox-proportional hazard analysis eLDL-TG showed alongside apoB and NonHDL-C the strongest association with future ASCVD events. Discordance analysis showed that when stratified as LDL-TG/LDL-C as High/Low there was an 26% increased risk for ASCVD, and when as High/High showed an 40% increased risk for ASCVD. Conclusions Like LDL-C, LDL-TG levels can also be estimated from the standard lipid panel. If our findings hold in other populations, the superiority of LDL-TG over LDL-C as a risk marker suggest that the reporting of calculated LDL-TG along with LDL-C could be a new strategy for improving ASCVD risk stratification.

A-224 Non HDL Cholesterol: could be e new cardiovascular disease risk stratification factor?

Abstract Background A worldwide study demonstrated that among all modifiable risk factors of Cardiovascular Disease (CVD) to the abnormal cholesterol levels is attributable the highest risk of events. LDL-C is considered the most important lipoprotein risk factor. Some recent epidemiologic studies have suggested that non-HDL cholesterol (N-HDL-C) may be superior to LDL-C for identifying CVD risk. N-HDL-C is easily calculated from a lipid profile and represents all apolipoprotein B containing lipoproteins. Recent guidelines recommend LDL-C as a primary indicator and non-HDL-C as secondary. Moreover, cholesterol ratios are useful to stratification; the TC/HDL-C is associated with morbidity and mortality in the general population; in addition, several studies have stated that high triglycerides (TG) levels and low HDL-C are associated with increased risk and could function as atherogenic index. Methods 11399 samples were analyzed on Atellica Solution for the determination of Total Cholesterol (TC), D-LDL-C, HDL-C and TG. In the absence of clinical parameters, based on the desirable levels recommended by the guidelines, CVD risk was evaluated by assigning a cut-off of 100 and 130 mg/dL for D-LDL-C and N-HDL-C respectively Results Patients cohort mean (±SD) for CT, D-LDL, HDL, TG and N-HDL-C are 180 mg/dL (±43.2), 113 mg/dL (± 38.5), 51.7 mg/dL (±15.6), 116 mg/dL (±73.8), 128 mg/dL (±39.5) respectively. Of the examined patients, the 57.7% were outpatients, 21.8% of infectious diseases and 12.6% of the cardiovascular department. Data about D-LDL-C and N-HDL-C comparison, evaluated on discordant patients, are shown in table 1. Conclusions The data obtained from evaluation would seem to confirm hypothesis according to which non-HDL cholesterol would have a greater power in the identification of CVD risk because of cholesterol ratios are suggestive of increased risk for patients with an LDL-C&amp;lt;100 and N-LDL-C&amp;gt;130 mg/dL. Further studies assessing CVD risk, not only through laboratory data, are necessary to confirm this supposition.