Clinical Risk Markers Research Articles

Stress CMR Perfusion Imaging in the Medicare-Eligible Population: Insights From the SPINS Study.

Patients aged ≥65 years account for a disproportionately large portion of cardiovascular (CV) events and pose a challenge for noninvasive detection of coronary artery disease. This study sought to determine the prognostic value of stress cardiac magnetic resonance (CMR) in a Medicare-eligible group of patients in a multicenter setting in the United States. From a multicenter U.S. registry, the study identified patients aged≥65 years who were referred for stress CMR for evaluation of myocardial inducible ischemia. The primary outcome was defined as CV death or nonfatal myocardial infarction, whereas the secondary outcome was defined as any primary outcome, hospitalization for unstable angina, hospitalization for congestive heart failure, and unplanned late coronary artery bypass grafting. The associations of CMR findings with CV outcomes adjusted to clinical risk markers and health care cost spending were determined. Among 1,780 patients (aged 73 ± 5.7 years; 46% female), study investigators observed 144 primary eventsand 323 secondary events, over a median follow-up of 4.8 years. The presence of inducible ischemia and late gadolinium enhancement (LGE) was associated with incrementally higher event rates. Patients with neither inducible ischemia nor LGE experienced a<1% annualized rate of primary outcome. In a multivariable model adjusted for CV risk factors, inducible ischemia and LGE maintained an independent association with primary (HR: 2.80 [95%CI: 1.93-4.05]; P< 0.001; and HR: 1.85 [95%CI: 1.21-2.82]; P = 0.004, respectively) and secondary (HR: 2.46 [95%CI: 1.90-3.19]; P< 0.001; and HR: 1.72 [95%CI: 1.30-2.27]; P< 0.001, respectively) outcomes. Rates of revascularization, as well as downstream costs for patients without CMR-detected inducible ischemia, remained low throughout the follow-up period. In a multicenter cohort of Medicare-eligible older patients, stress CMR was effective in providing risk stratification. (Stress CMR Perfusion Imaging in the United States [SPINS] study; NCT03192891).

The maternal-fetal neurodevelopmental groundings of preterm birth risk

BackgroundAltered neurodevelopment is a major clinical sequela of Preterm Birth (PTB) being currently unexplored in-utero. AimsTo study the link between fetal brain functional (FbF) connectivity and preterm birth, using resting-state functional magnetic resonance imaging (rs-fMRI). Study designProspective single-centre cohort study. SubjectsA sample of 31 singleton pregnancies at 28–34 weeks assigned to a low PTB risk (LR) (n = 19) or high PTB risk (HR) (n = 12) group based on a) the Maternal Frailty Inventory (MaFra) for PTB risk; b) a case-specific PTB risk gradient. MethodsFetal brain rs-fMRI was performed on 1.5T MRI scanner. First, directed causal relations representing fetal brain functional connectivity measurements were estimated using the Greedy Equivalence Search (GES) algorithm. HR vs. LR group differences were then tested with a novel ad-hoc developed Monte Carlo permutation test. Second, a MaFra-only random forest (RF) was compared against a MaFra-Neuro RF, trained by including also the most important fetal brain functional connections. Third, correlation and regression analyses were performed between MaFra-Neuro class probabilities and i) the GA at birth; ii) PTB risk gradient, iii) perinatal clinical conditions and iv) PTB below 37 weeks. ResultsFirst, fewer fetal brain functional connections were evident in the HR group. Second, the MaFra-Neuro RF improved PTB risk prediction. Third, MaFra-Neuro class probabilities showed a significant association with: i) GA at birth; ii) PTB risk gradient, iii) perinatal clinical conditions and iv) PTB below 37 weeks. ConclusionFetal brain functional connectivity is a novel promising predictor of PTB, linked to maternal risk profiles, ahead of birth, and clinical markers of neurodevelopmental risk, at birth, thus potentially “connecting” different PTB phenotypes.

Abstract 4581: Identifying class 1 HDACs as a vulnerability for aggressive uveal melanoma

Abstract Uveal melanoma (UM) is the most common primary intraocular cancer in adults, with a strong propensity to metastasize, primarily to the liver. Metastatic UM is notoriously unresponsive to existing therapies, rendering it almost uniformly lethal. Virtually all UM tumors have activating mutations in the Gq signaling pathway, predominantly in GNAQ/11, and around half of tumors have additional loss-of-function mutations in the tumor suppressor BAP1. Mutations in the epigenetic modulator BAP1 are the most significant clinical marker of metastatic risk. The limited efficacy of current treatment options necessitates an urgent exploration of novel therapeutic approaches to improve patient prognosis. Thus, we conducted a large epigenetic compound library screen with the currently most well characterized, focused epigenetic library available, which consisted of 960 potent, cell permeable, medically active, epigenetic-directed small molecule modulators (TargetMol, L1200). We screened BAP1-mutant as well as BAP1-wildtype uveal melanoma cell lines and followed up with comprehensive dose-response and synergy tests. Our lead compounds were highly efficient in reducing viability of UM cells. We find that inhibitors with high specificity for class 1 HDAC inhibition are especially cytotoxic to UM cells. Together, our results reveal a possible mechanism of interfering with UM progression and identify lead compounds to be tested in clinical trials. Citation Format: Gulum Yenisehirli, Ashley Zuniga, Sara Rodriguez, Emily V. Adis, Gabriela Quintana, Sebastian Borges, Sofia Lopez, Kassandra Lopez, Steffanie Braun, Claude H. Volmar, J. W. Harbour, Stefan Kurtenbach. Identifying class 1 HDACs as a vulnerability for aggressive uveal melanoma [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 4581.

Relation of plasma neuropeptide-Y with myocardial function and infarct severity in acute ST-elevation myocardial infarction

BackgroundAcute myocardial infarction is associated with the release of the co-transmitter neuropeptide-Y (NPY). NPY acts as a potent vasoconstrictor and is associated with microvascular dysfunction after ST-elevation myocardial infarction (STEMI). This study comprehensively evaluated the association of plasma NPY with myocardial function and infarct severity, visualized by cardiac magnetic resonance (CMR) imaging, in STEMI patients revascularized by primary percutaneous coronary intervention (PCI). MethodsIn this observational study, we included 260 STEMI patients enrolled in the prospective MARINA-STEMI (NCT04113356) study. Plasma NPY concentrations were measured by an immunoassay 24h after PCI from peripheral venous blood samples. Left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), infarct size (IS) and microvascular obstruction (MVO) were determined using CMR imaging. ResultsMedian plasma concentrations of NPY were 70 [interquartile range (IQR):35-115] pg/ml. NPY levels above median were significantly associated with lower LVEF (48%vs.52%, p=0.004), decreased GLS (-8.8%vs.-12.6%, p<0.001) and larger IS (17%vs.13%, p=0.041) in the acute phase after infarction as well as after 4 months (LVEF:50%vs.52%, p=0.030, GLS:-10.5vs.-12.9,p<0.001,IS:13%vs.10%,p=0.011). In addition, NPY levels were significantly related to presence of MVO (58%vs.52%, p=0.041). Moreover, in multivariable linear regression analysis, NPY remained significantly associated with all investigated CMR parameters (LVEF:p<0.001,GLS:p<0.001,IS:p=0.003,MVO:p=0.042) independent of other established clinical variables including high-sensitivity cardiac troponin T, pre-interventional TIMI flow 0 and left anterior descending artery as culprit lesion location. ConclusionHigh plasma levels of NPY, measured 24h after STEMI, were independently associated with lower LVEF, decreased GLS, larger IS as well as presence of MVO, indicating plasma NPY as a novel clinical risk marker post STEMI.

Body Composition Evaluation and Clinical Markers of Cardiometabolic Risk in Patients with Phenylketonuria.

Cardiovascular diseases are the main cause of mortality worldwide. Patients with phenylketonuria (PKU) may be at increased cardiovascular risk. This review provides an overview of clinical and metabolic cardiovascular risk factors, explores the connections between body composition (including fat mass and ectopic fat) and cardiovascular risk, and examines various methods for evaluating body composition. It particularly focuses on nutritional ultrasound, given its emerging availability and practical utility in clinical settings. Possible causes of increased cardiometabolic risk in PKU are also explored, including an increased intake of carbohydrates, chronic exposure to amino acids, and characteristics of microbiota. It is important to evaluate cardiovascular risk factors and body composition in patients with PKU. We suggest systematic monitoring of body composition to develop nutritional management and hydration strategies to optimize performance within the limits of nutritional therapy.

The role of Mild Behavioral Impairment in a future era of Alzheimer’s disease modifying treatments

Early clinical risk markers of neurodegenerative diseases, such as Alzheimer’s disease (AD), can be considered fundamental in a new era with novel disease modifying treatments on the horizon. Mild Behavioral Impairment (MBI) is a diagnostic construct defined by the later-life emergence of persistent neuropsychiatric symptoms (e.g. apathy, anxiety, depression, amongst others) displayed by older adults, with the aim to identify individuals at increased risk of future dementia. According to established MBI criteria the syndrome can co-occur with mild cognitive impairment due to a neurodegenerative disease or even precede it, and in fact, MBI is most meaningful when reported in conjunction with cognitive status, as MBI-associated risk is moderated by cognitive status. MBI symptomatology has been reported prevalent among older adults, as well as in patients with early stages of neurodegenerative disease. Symptoms of MBI are further associated with several clinically negative outcomes, such as a reduced quality of life, increased caregiver burden and earlier institutionalization. In support of the MBI construct, several previous reports have demonstrated MBI to be predictive of future cognitive decline, dementia, or AD. The construct is also related to AD biomarkers including beta-amyloid, tau, and cerebral atrophy. Intriguingly, an earlier study indicates that MBI even can precede memory deficits in its association with early tau deposition in cognitively unimpaired elderly with confirmed amyloid-beta pathology, strengthening its position as an early marker of dementing biochemical processes. Despite this growing evidence of being both prevalent and an early prognostic marker, MBI is still only given diminutive consideration in contemporary clinical diagnostic criteria for AD. Perhaps so since the added value of MBI in such criteria has rarely been investigated. Consequently, cognitively unimpaired subjects with positive MBI and AD biomarker status face the risk of not being eligible for a future disease modifying AD treatment since they formally do not fulfill AD diagnostic criteria. Hence, studies exploring the added value of MBI in clinical diagnostic criteria for neurocognitive disorders are prompted.

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.

ОСОБЕННОСТИ ФАКТОРОВ РИСКА РАЗВИТИЯ КАРДИОВАСКУЛЯРНЫХ ОСЛОЖНЕНИЙ ПРИ ОЖИРЕНИИ У ДЕТЕЙ

Introduction. The most common risk factors for the development of cardiovascular diseases are hypertension and obesity, which are formed in childhood, however, the most significant clinical and metabolic markers of cardiovascular risk have not yet been identified in pediatric practice. Aim. To study the characteristics and interrelations of cardiovascular risk factors in obese children and adolescents for planning correction at the stage of functional changes. Material and methods. The study included 141 obese children – 69 boys and 72 girls (in whom the degree of standard deviation of the body mass index was 2.88 [2.75; 3.41] and 2.93 [2.59; 4.05], respectively) and 78 healthy children (40 boys and 38 girls), comparable by sex and age. Results and discussion. In the examined children, there is an insufficient decrease in blood pressure at night from both systolic blood pressure and diastolic blood pressure, in the absence of clinically and statistically significant deviations in single measurements. The triglyceride-glucose index and the N-terminal inactive peptide of natriuretic hormone demonstrated high concentrations in normoglycemia and the absence of dyslipidemia. Against the background of obesity, trimethylaminoxide concentrations were lower than in healthy children. Conclusion. In order to timely correct blood pressure, it is necessary to use daily monitoring in obese children, even against the background of the absence of signs of arterial hypertension with single measurements. Even against the background of lean normoglycemia in obese children and adolescents, it is advisable to diagnose the formation of insulin resistance and hyperinsulinemia using indicators of insulin levels, calculation of the HOMA-IR index, triglyceride-glucose index. Correction of blood pressure variability is possible with changes in certain parameters of body composition (decrease in fat mass and increase in muscle mass) and hormonal and metabolic parameters (decrease in glycemia, very low-density lipoproteins, insulin and increase in high-density lipoproteins). The level of trimethylaminoxide showed lower rates of obesity in children compared to healthy peers, which differs from the literature data on the adult population and limits its use as a biomarker for the development of cardiovascular complications in obesity in children

Use of Clinical and Echocardiographic Evaluation to Assess the Risk of Heart Failure

BackgroundClinical and echocardiographic features predict incident heart failure (HF), but the optimal strategy for combining them is unclear. ObjectivesThis study sought to define an effective means of using echocardiography in HF risk evaluation. MethodsThe same clinical and echocardiographic evaluation was obtained in 2 groups with HF risk factors: a training group (n = 926, followed to 7 years) and a validation group (n = 355, followed to 10 years). Clinical risk was categorized as low, intermediate, and high using 4-year ARIC (Atherosclerosis Risk In Communities) HF risk score cutpoints of 9% and 33%. A risk stratification algorithm based on clinical risk and echocardiographic markers of stage B HF (SBHF) (abnormal global longitudinal strain [GLS], diastolic dysfunction, or left ventricular hypertrophy) was developed using a classification and regression tree analysis and was validated. ResultsHF developed in 12% of the training group, including 9%, 18%, and 73% of low-, intermediate-, and high-risk patients. HF occurred in 8.6% of stage A HF and 19.4% of SBHF (P < 0.001), but stage A HF with clinical risk of ≥9% had similar outcome to SBHF. Abnormal GLS (HR: 2.92 [95% CI: 1.95-4.37]; P < 0.001) was the strongest independent predictor of HF. Normal GLS and diastolic function reclassified 61% of the intermediate-risk group into the low-risk group (HF incidence: 12%). In the validation group, 11% developed HF over 4.5 years; 4%, 17%, and 39% of low-, intermediate-, and high-risk groups. Similar results were obtained after exclusion of patients with known coronary artery disease. The echocardiographic parameters also provided significant incremental value to the ARIC score in predicting new HF admission (C-statistic: 0.78 [95% CI: 0.71-0.84] vs 0.83 [95% CI: 0.77-0.88]; P = 0.027). ConclusionsClinical risk assessment is adequate to classify low and high HF risk. Echocardiographic evaluation reclassifies 61% of intermediate-risk patients.

Association of medical conditions and firearm suicide among legal handgun purchasers in California: a case–control study

BackgroundSuicide is a pressing public health problem, and firearm owners are at especially elevated risk. Certain health conditions are markers of suicide risk, but more research is needed on clinical risk markers for suicide among firearm owners specifically. Our goal was to examine associations of emergency department and inpatient hospital visits for behavioral and physical health conditions with firearm suicide among handgun purchasers.MethodsThis was a case–control study of 5415 legal handgun purchasers in California who died between January 1, 2008, and December 31, 2013. Cases were firearm suicide decedents; controls were motor vehicle crash decedents. Exposures were emergency department and hospital visits for six categories of health diagnoses in the 3 years prior to death. To account for selection bias due to deceased controls, we used probabilistic quantitative bias analysis to generate bias-adjusted estimates.ResultsThere were 3862 firearm suicide decedents and 1553 motor vehicle crash decedents. In multivariable models, suicidal ideation/attempt (OR 4.92; 95% CI 3.27–7.40), mental illness (OR 1.97; 95% CI 1.60–2.43), drug use disorder (OR 1.40; 95% CI 1.05–1.88), pain (OR 1.34; 95% CI 1.07–1.69), and alcohol use disorder (OR 1.29; 95% CI 1.01–1.65) were associated with higher odds of firearm suicide. When adjusting for all conditions simultaneously, only the associations for suicidal ideation/attempt and mental illness remained significant. Quantitative bias analysis indicated that observed associations were generally biased downward. For example, the bias-adjusted OR for suicidal ideation/attempt was 8.39 (95% simulation interval 5.46–13.04), almost twice that of the observed OR.ConclusionsDiagnoses for behavioral health conditions were markers for firearm suicide risk among handgun purchasers, even for conservative estimates that did not adjust for selection bias. Encounters with the healthcare system may provide opportunities to identify firearm owners at high risk of suicide.

Assessing falls in the elderly population using G-STRIDE foot-mounted inertial sensor

Falls are one of the main concerns in the elderly population due to their high prevalence and associated consequences. Guidelines for the management of the elder with falls are comprised of multidimensional assessments, especially gait and balance. Daily clinical practice needs for timely, effortless, and precise tools to assess gait. This work presents the clinical validation of the G-STRIDE system, a 6-axis inertial measurement unit (IMU) with onboard processing algorithms, that allows the calculation of walking-related metrics correlated with clinical markers of fall risk. A cross-sectional case-control study was conducted with 163 participants (falls and non-falls groups). All volunteers were assessed with clinical scales and conducted a 15-min walking test at a self-selected pace while wearing the G-STRIDE. G-STRIDE is a low-cost solution to facilitate the transfer to society and clinical evaluations. It is open hardware and flexible and, thus, has the advantage of providing runtime data processing. Walking descriptors were derived from the device, and a correlation analysis was conducted between walking and clinical variables. G-STRIDE allowed measuring walking parameters in non-restricted walking conditions (e.g. hallway). Walking parameters statistically discriminate between falls and non-falls groups. We found good/excellent estimation accuracy (ICC = 0.885; p<0.000) for walking speed, showing good/excellent correlation between gait speed and several clinical variables. G-STRIDE can calculate walking-related metrics that allow for discrimination between falls and non-falls groups, which correlates with clinical indicators of fall risk. A preliminary fall-risk assessment based on the walking parameters was found to improve the Timed Up and Go test in the identification of fallers.

Ventricular conduction is a marker for arrhythmic risk in overlap sodium channel disease

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): National Institute of Health Research St George's, University of London Background SCN5A-E1784K (c.5350G&amp;gt;A) is the most common variant associated with the LQT3 long QT syndrome (LQTS) and Brugada syndrome (BrS). It exhibits incomplete penetrance and can manifest variably as a mixed clinical phenotype of LQTS, BrS and/or conduction disorders (1-4). This presents a challenge for risk stratification and optimal management. We aimed to describe the clinical characteristics and risk markers in a large, well characterised international cohort of SCN5A-E1784K subjects and identify demographic and/or ECG parameters associated with event free survival. Methods Comprehensive clinical data, including initial presentation and follow-up data, were collected from SCN5A-E1784K subjects. Outcome ‘events’ included sudden death, aborted cardiac arrest, and documented VF or VT or arrhythmic syncope. ‘Lethal events’ included sudden death, aborted cardiac arrest or documented VF or VT. Associations between clinical characteristics and event free survival were investigated using Cox proportional hazard regression models. Results SCN5A-E1784K subjects (n=231) were recruited from 16 centres. Median follow up was 24.9 years (15.2 - 43.3) and 45 individuals (19%) experienced an event. Lethal events were observed in 14 subjects (6%). Figure 1 shows event (A) and lethal event (B) free survival in SCN5A-E1784K subjects. Higher QRS duration (corrected for age) was associated with shorter event-free interval. QRS duration was the only characteristic associated with increased risk with a hazard ratio (HR) of 1.04 or 1.05 per ms for events and lethal events, respectively. The observed survival for events and lethal events for QRS tertiles are shown in Figure 2. Discussion Ventricular myocardial conduction, as evidenced by QRS duration, appears to play a role in the risk of arrhythmic events in patients with SCN5A-E1784K. Corrected QT interval and BrS phenotype were, however, not associated with risk. This provides an important opportunity for the personalisation of risk stratification of these patients, whose management can otherwise be very challenging. Figures

EN-452414-5 VENTRICULAR CONDUCTION IS A MARKER FOR ARRHYTHMIC RISK IN OVERLAP SODIUM CHANNEL DISEASE

SCN5A-E1784K (c.5350G>A) is the most common variant associated with LQT3 long QT syndrome (LQTS) and Brugada syndrome (BrS). It exhibits incomplete penetrance and can manifest variably as a mixed clinical phenotype of LQTS, BrS and/or conduction disorders. This presents a challenge for risk stratification and optimal management. The objective was to describe the clinical characteristics and risk markers in a large, well characterised international cohort of SCN5A-E1784K subjects and identify parameters that associate with event-free survival. Comprehensive clinical data, including initial presentation and follow-up data, were collected from SCN5A-E1784K subjects. Outcome ‘events’ included sudden death, aborted cardiac arrest, and documented VF, VT or arrhythmic syncope. ‘Lethal events’ included sudden death, aborted cardiac arrest or documented VF or VT. The effect of age at the time of ECG acquisition on ECG parameters was modelled and the residual, i.e. difference between observed value and the predicted age-corrected value, was calculated for each individual and referred to as residual PR, residual QRS, residual QTc and residual RR. Common variants previously associated with QRS duration were genotyped and a polygenic risk score (PRSQRS) derived. Associations between clinical characteristics, PRSQRS and event free survival were investigated using Cox proportional hazard regression models. SCN5A-E1784K subjects (n=231) were recruited from 20 centres. Four (1.7%) had a mixed phenotype of BrS, LQT3 and cardiac conduction disease. A mixed phenotype of BrS and LQT3 without any evidence of conduction disease was seen in 18.1% and a mixed phenotype of BrS and conduction disease, and Long QT and conduction disease, were seen in 3.1% and 12.9% respectively. There was no phenotype in 9.9% (includes n=6 with missing data). Median follow-up was 24.9 years (15.2 - 43.3) and 45 (19%) experienced an event. Lethal events were observed in n=14 (6%). Longer QRS duration (corrected for age) and PRSQRS were both associated with shorter event-free intervals (Table 1 and Figure 1). QTc and BrS phenotype were not associated with risk. Ventricular myocardial conduction, as evidenced by QRS duration and its genomic associations, appears to play a role in the risk of arrhythmic events in patients with SCN5A-E1784K. This provides an important opportunity for the personalisation of risk stratification of these patients, whose management can otherwise be challenging.Tabled 1Hazard ratios estimated in SCN5A-E1784K using Cox regression with adjustment for ethnicityVariableEventsLethal eventsHR [95% CI]p-valueHR [95% CI]p-valueMale1.33 [0.71-2.48]0.3692.22 [0.77-6.44]0.142Residual PR (ms)1.01 [1.00-1.02]0.2261.02 [1.00-1.03]0.012Residual QRS (ms)1.04 [1.02-1.06]<0.001*1.05 [1.02-1.09]0.002*Abnormal QRS-axis1.48 [0.69-3.19]0.3160.89 [0.19-4.10]0.879Residual QTc (ms)1.00 [0.99-1.01]0.9691.00 [0.97-1.02]0.664Long QTc0.87 [0.38-2.00]0.7461.05 [0.28-3.90]0.943Residual RR (s)1.10 [0.18-6.80]0.9159.51 [0.37-242]0.173Spontaneous type 1 Brugada ECG1.60 [0.50-5.11]0.4262.25 [0.50-10]0.290HR: hazard ratio; 95% CI: 95% confidence interval; ∗p-value reaching Bonferroni corrected significance threshold Open table in a new tab

Cardiovascular and Diabetes Risk in Preschoolers

Objective: To perform an exploratory analysis of possible alterations in clinical markers of cardiovascular risk and type 2 diabetes in preschoolers living in urban and suburban areas of the municipality of Hermosillo, Sonora, Northwest Mexico. Methods: An observational and cross-sectional study was carried out on children from urban and suburban areas. Their weight, height, waist circumference, body fat percentage, and blood pressure were measured, and their lipid profile, glucose, and insulin concentrations were evaluated. Results: Eighty-two children with an average age of five were included in the study; 48 from the conurbation and 34 from the urban area. We found that malnutrition, overweight, and high body fat percentage (27 ± 0.52) coexist. In the suburban area, there was a higher percentage of children with pre-hypertension and alterations in lipids: elevated triglycerides (35%) and low HDL-c (25%) (p &lt; 0.01). In the urban area, there was a higher percentage of children with altered glucose (12%), elevated insulin concentrations, and insulin resistance. Conclusion: The findings of this study show that cardiovascular risk factors and type 2 diabetes are prevalent in children aged three to six living in urban and conurbation areas of Hermosillo, Sonora.

Metformin Monotherapy Alters the Human Plasma Lipidome Independent of Clinical Markers of Glycemic Control and Cardiovascular Disease Risk in a Type 2 Diabetes Clinical Cohort.

Type 2 diabetes (T2D) is a rising pandemic worldwide. Diet and lifestyle changes are typically the first intervention for T2D. When this intervention fails, the biguanide, metformin, is the most common pharmaceutical therapy. Yet, it's full mechanisms of action remain unknown. In this work, we applied an ultrahigh resolution, mass spectrometry-based platform for untargeted plasma metabolomics to human plasma samples from a case-control observational study of non-diabetic and well-controlled T2D subjects, the latter treated conservatively with metformin or diet and lifestyle changes only. No statistically significant differences existed in baseline demographic parameters, glucose control, or clinical markers of cardiovascular disease risk between the two T2D groups, which we hypothesized would allow the identification of circulating metabolites independently associated with treatment modality. Over 3000 blank-reduced metabolic features were detected, with the majority of annotated features being lipids or lipid-like molecules. Altered abundance of multiple fatty acids and phospholipids were found in T2D subjects treated with diet and lifestyle changes as compared to non-diabetic subjects: changes that were often reversed by metformin. Our findings provide direct evidence that metformin monotherapy alters the human plasma lipidome independent of T2D disease control and support a potential cardioprotective effect of metformin worthy of future study. Significance Statement This work provides important new information on the systemic effects of metformin in type 2 diabetic subjects. We observed significant changes in the plasma lipidome with metformin therapy, with metabolite classes previously associated with cardiovascular disease risk significantly reduced as compared to diet and lifestyle changes. While cardiovascular disease risk was not a primary outcome of our study, our results provide a jumping-off point for future work into the cardioprotective effects of metformin, even in well-controlled type 2 diabetes.

Diagnostic and prognostic value of the electrocardiogram in stable outpatients with type 2 diabetes

Aims . The European Society of Cardiology guidelines on diabetes and cardiovascular disease (CVD) recommend an electrocardiogram (ECG) in patients with diabetes and hypertension or with suspected CVD. We investigated whether ECG abnormalities can be used as a diagnostic and prognostic marker of heart failure (HF) in patients with type-2 diabetes (T2D) in secondary care diabetes-clinics. Methods . We included 722 patients with T2D in sinus rhythm. HF with preserved ejection fraction (HFpEF) was defined according to the European Society of Cardiology guidelines. Heart failure with mid-range ejection fraction (HFmrEF) was patients with dyspnoea and an LVEF 41–49%. Heart failure with reduced ejection fraction (HFrEF) or asymptomatic left ventricular systolic dysfunction (ALVSD) was defined as a LVEF ≤40%. Results . Overall, 24% patients had ECG abnormalities. A total of 15% had HF whereof 48% had ECG abnormalities. A normal ECG had a 99.3% negative predictive value (NPV) of ruling out HFrEF/ALVSD. In a sub-group with 0-1 simple clinical risk markers, the ECG ruled out both HFrEF/ALVSD, HFmrEF, and HFpEF with an NPV of 96.6%. The hazard-ratio (HR) of incident CVD or death in patients with HF and a normal ECG compared with patients without HF was 1.85 [95%CI 1.01–3.39], p = .05, while an abnormal ECG increased the HR to 3.84 [2.33–6.33], p < .001. Conclusion . HFrEF/ALVSD and HFmrEF were rare and HFpEF was frequent in this T2D population. A normal ECG ruled out HFrEF/ALVSD and in a sub-population with 0–1 simple clinical risk markers also both HFrEF/ALVSD, HFmrEF, and HFpEF. Key messages What is already known about this subject? In early studies of unselected patients from primary care with suspected chronic heart failure, the presence of a normal ECG was found be useful to rule out heart failure with reduced ejection fraction. What does this study add? This study confirms that a standard electrocardiogram when normal in 722 stable outpatients with type 2 diabetes can be used to rule out HFrEF/ALVSD. Further, it adds knowledge about the risk of incident cardiovascular disease or death as a pathologic electrocardiogram increases the hazard ratio. How might this implicate clinical practice? With this study clinicians in secondary diabetes care clinics can use an electrocardiogram to select patients to undergo echocardiography when suspecting heart failure with reduced ejection fraction, as a normal electrocardiogram will rule out this diagnosis with a negative predictive value of >99%.

Tumor Microenvironment Determinants of Immunotherapy Response Identified By Integrated Host & Viral Analysis of Post-Transplant Lymphoproliferative Disorders

Background: Post-transplant lymphoproliferative disorder (PTLD) is a major cause of morbidity in transplantation; however, some PTLD subtypes are curable using anti-CD20 immunotherapy alone or with reduction of immunosuppression (R-ISR). We hypothesized that a comprehensive integrated analysis of the tumor immune microenvironment (TME), virome, genome, transcriptome, and cell-free DNA (cfDNA) could offer biologically and clinically relevant insights into the immunobiology of PTLD. Methods: We identified 75 patients with PTLD after solid organ (n=69) or hematopoietic stem cell (n=6) transplantation. 32 cases occurred <2 years post-transplant (TTD<2, 43%) and 69% were EBV+ by clinical Epstein-Barr-encoded small RNA (EBER) ISH (Table 1). Tumor and cfDNA hybrid capture was performed as previously described, utilizing panels for 322 B-cell lymphoma genes (Kurtz JCO 2018), 180 viral species (Garofalo Blood 2019), and TCR-loci for repertoire profiling (Shukla Blood 2020). Tumor RNAseq was quantified with Salmon & analyzed by DESeq2, fgsea, CIBERSORTx, and Ecotyper. Results: Tumor microenvironment Compared to EBV-negative DLBCL-PTLD, EBV+ cases showed significantly higher expression of IFN-associated (MX1, IFI44, IFIT3) and antiviral response genes including CD30/TNFRSF8 and APOBEC3A. TME immune cell subset deconvolution revealed no difference in B-cell populations, but EBV+ cases were enriched in CD4+ memory activated T-cells, M1 macrophages, activated DCs, and eosinophils. Considering lymphoma TME ecotypes (Steen Cancer Cell 2021), the immunoreactive LE4 ecotype identified EBV+ non-GCB cases with median TTD 93 days, while the immune-poor LE8 aligned with EBV- GCB with median TTD 3686 days. TCR repertoires revealed DLBCL-PTLD tumors to have lower T-cell diversity as compared to DLBCL-NOS (p=0.007, Chao1 index), driven by dominant T-cell clones in EBV+ cases. Virome enrichment by targeted capture confirmed elevated EBV DNA in EBER+ cases, allowing stratification of clinical EBV status by sequencing. While total viral burden and anellovirus level (a marker of immunosuppression) were higher at TTD<2, CMV and HHV6 were similar for later diagnoses. Mutations & mechanisms Compared to DLBCL-NOS, DLBCL-PTLD had significantly fewer variants in the NFkB pathway genes MYD88 and PIM1 and several immune regulatory genes (TNFRSF14, B2M, and CD58). In contrast, TP53, CARD11, and TNFAIP3 were similar. Notably, 12 tumors had no detected oncogenic single-nucleotide variants: these cases were all TTD<2 & EBV+. Overall, more coding variants were seen in EBV- PTLD and TTD>2 (p<0.001 for both comparisons) (Fig 1). We compared mutational signatures within targeted genes to evaluate mechanisms driving these differences. Compared to EBV+ DLBCL-PTLD, EBV- cases were enriched in SBS84, an AID/SHM signature seen in DLBCL-NOS (p<0.001), and had higher AICDA mRNA expression (padj=0.003). Conversely, EBV+ DLBCL-PTLD was enriched in DNA mismatch repair signatures SBS6/21 (p=0.01); and SBS17 (p<0.001), a cryptic mechanism also reported in EBV+ Burkitt lymphomas (Grande Blood 2019). mRNA from EBV+ cases showed corresponding downregulation in the DNA MMR pathway (padj=0.004). Likewise, MSI quantification with mSINGS (Hause Nat Med 2016) showed more altered loci in EBV+ tumors (p=0.013), together suggesting EBV-induced inhibition of MMR as a mutational mechanism. Clinical response We compared DLBCL-PTLD patients with complete response to R-ISR to those requiring chemotherapy. Patients with response had shorter TTD but no difference in coding mutation burden. However, the TME of patients requiring chemotherapy contained more M0/non-activated macrophages and regulatory T-cells; similarly, all patients with the immune-depleted TME ecotype LE8 received chemotherapy. While no difference was seen in NFkB pathway genes, patients requiring chemotherapy showed higher expression of MYC & E2F targets. Conclusions: Through multimodal characterization of the TME and virome in the largest sequencing cohort to date, we identify distinct immunogenomic features reflecting divergent PTLD biology. These include evidence of MMR defects in EBV+ PTLD and TME depletion & MYC pathway enrichment in patients failed by R-ISR, suggesting potential markers of clinical risk. Additional analyses including non-DLBCL cases, viral, and cfDNA data are in progress to further clarify these pathogenetic mechanisms. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Risk stratification in Arrhythmogenic Right Ventricular Cardiomyopathy: the impact of genotype on the 2019 ARVC risk calculator

Abstract Introduction Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is associated with sudden cardiac death (SCD). The 2019 ARVC risk model has been proposed as a method to quantify arrhythmic risk, but the impact of genotype its performance has not been addressed. Purpose To study arrhythmic outcomes in patients with ARVC and the performance of the 2019 ARVC risk model in predefined genetic subgroups. Methods This is an international, retrospective observational cohort study on consecutively evaluated patients with ARVC recruited from 17 centres in 7 countries. Inclusion criteria were: (i) a definite diagnosis of ARVC according to the 2010 Task Force Criteria; (ii) no history of sustained ventricular arrhythmia (VA) prior to first assessment at the participating centre; (iii) a follow up period of ≥1 month; (iv) age of diagnosis ≥14 years. Sustained ventricular arrhythmia (sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator intervention, aborted SCD, or SCD) comprised the primary outcome (VA). Discriminative ability was assessed by Uno's concordance index (c-statistic) and calibration with the calibration plot slope. Fine-Gray regression was used to model the impact of clinical predictors on the arrhythmic outcome, in the context of competing risks (heart transplantation and non-arrhythmic death). The cumulative probability and 95% confidence intervals (95% CI) for the occurrence of an outcome were estimated using the Aalen-Johansen estimate in order to take into account competing risks. Results The study cohort comprised 554 ARVC patients. During a median follow-up of 6.0 [3.1,12.5] years, 100 patients (18%) experienced VA (Figure). Risk estimates for VA using the 2019 ARVC risk model showed good discriminative ability (c-statistic 0.75 (95% CI 0.70–0.81)) but with overestimation of risk (slope 0.46 (95% CI 0.33–0.63)). The ARVC risk model was compared in 4 gene groups: PKP2 (n=118, 21%); DSP (n=79, 14%); other desmosomal (n=59, 11%); and gene elusive (n=160, 29%). Discrimination and calibration were highest for PKP2 [c-statistic 0.83 (95% CI 0.75–0.91); calibration slope 0.67 (95% CI 0.40–1.04)] and lowest for the gene elusive group [c-statistic 0.65 (95% CI 0.57–0.74); calibration slope 0.26 (95% CI 0.06–0.49)]. Univariable analyses revealed variable performance of individual clinical risk markers in the different gene groups (see heatmap of hazard ratios and statistical significance in Figure). For example, RV dimensions and systolic function are significant risk markers in PKP2 but not in DSP patients and the opposite is true of LV systolic function (Figure). Conclusion The 2019 ARVC risk model performs reasonably well in gene positive ARVC, (particularly for PKP2) but is more limited in gene elusive patients. Genotype specific risk factors should be considered in ARVC patients. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): British Heart Foundation

Association between inflammation and left ventricular thrombus formation following ST-elevation myocardial infarction

Abstract Background Current evidence suggests a link between the inflammatory state and left ventricular thrombus (LVT) formation following ST-elevation myocardial infarction (STEMI). However, a comprehensive study investigating the association between inflammatory biomarkers and LVT diagnosed by cardiac magnetic resonance (CMR) is lacking. Purpose The present study aimed to investigate the association of biochemical markers of inflammation with LVT as assessed by CMR imaging among patients with STEMI. Methods We studied 309 patients with acute STEMI treated with primary percutaneous coronary intervention (pPCI) from the prospective MARINA-STEMI cohort study. Concentrations of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), white blood cell count (WBCc), fibrinogen and D-dimer were measured two days after STEMI. Infarct characteristics and presence of LVT were assessed with the use of contrast-enhanced CMR at a median of 4 (interquartile range [IQR] 3–5) days after pPCI. Results In total, 309 STEMI patients (18% female) with a median age of 57 (IQR 52–65) years were included. An LVT was observed in 8% (n=24) of the overall cohort and in 15% of patients with an anterior STEMI. Hs-CRP (OR: 2.16, 95% CI: 1.54–3.02, p&amp;lt;0.001), IL-6 (OR: 2.38, 95% CI: 1.48–3.81, p&amp;lt;0.001) and fibrinogen levels (OR: 2.05, 95% CI: 1.40–3.00, p&amp;lt;0.001) were significantly associated with presence of LVT. Among all assessed inflammatory biomarkers, only hs-CRP was independently associated with LVT after adjustment for markers of inflammation and CMR parameters (OR: 1.77, 95% CI: 1.21–2.59, p=0.004). Conclusion In patients with STEMI treated with pPCI, inflammatory markers (hs-CRP, IL-6 and fibrinogen) are associated with the presence of LVT. However, only hs-CRP was independently associated with the occurrence of LVT, highlighting the key role of CRP as clinical risk marker for LVT formation in STEMI patients treated with pPCI. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Austrian Science Fund (FWF)Austrian Society of Cardiology

Sinonasal Symptoms in COPD: Burden and Associations with Clinical Markers of Disease.

PurposeSinonasal symptoms are prevalent in COPD, and knowledge of the relationship between these symptoms and clinical markers of COPD is limited. This study explores the associations between the burden of sinonasal symptoms and clinical markers and thresholds recommended for guiding treatment decisions in the GOLD guidelines.Patients and MethodsSinonasal symptoms were quantified with the rhinological subscale of the Sino-Nasal-Outcome-Test (SNOT-22) in 93 COPD patients characterized by the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) 2012 diagnostic criteria for rhinosinusitis without nasal polyps (RSsNP). Associations between a high burden, defined as a SNOT22_rhinological score of ≥11, and the following markers were assessed by adjusted multivariable linear regressions; severity of dyspnea [modified Medical Research Council (mMRC)] and cough [Visual Analogue Scale (VAS)], physical activity [6-minute walking distance (6MWD)], mortality risk (BODE index), and HRQoL [disease-specific COPD Assessment Test (CAT) and St. Georges Respiratory Questionnaire (SGRQ), and physical component summary, Short Form-36 version 2.0 (PCS SF-36v2)]. Odds ratios for the association of a high burden and threshold levels for regular treatment were estimated by adjusted binomial logistic regression models.ResultsA high burden was associated with greater severity of dyspnea and cough, lower 6MWD, higher BODE index and poorer HRQoL. The odds ratio of having CAT and SGRQ scores that are above the thresholds recommended for treatment was 5–7-fold greater in the high burden group.ConclusionA high burden of sinonasal symptoms is positively associated with the clinical markers of symptom severity and mortality risk and is inversely associated with physical activity and HRQoL in COPD. These findings add further support that the UAD concept also applies to COPD. Enquiry about sinonasal symptoms in COPD patients should be incorporated into the clinical routine.