Faculty Bibliography

BACKGROUND:The association of PREVENT-HF (Predicting Risk of Cardiovascular Events-Heart Failure) risk estimates with preclinical heart failure (HF) and whether preclinical HF measures add to the predictive utility of PREVENT-HF remain undefined. OBJECTIVES/OBJECTIVE:The aims of this study were to evaluate the association between PREVENT-HF risk estimates and preclinical HF, to examine how preclinical HF measures correspond to absolute HF risk within PREVENT-HF categories, and to determine whether they provide predictive value beyond the PREVENT-HF score. METHODS:The authors performed a prospective analysis of 2,714 ARIC (Atherosclerosis Risk In Communities) Visit 5 participants <80 years of age, without baseline cardiovascular disease. Preclinical HF was defined by elevated cardiac biomarkers (N-terminal of pro-b-type natriuretic peptide ≥125 pg/mL or high-sensitivity cardiac troponin T ≥22 ng/L/≥14 ng/L in men/women) and/or abnormal echocardiographic findings. Within PREVENT-HF 10-year risk categories (<7.5%, ≥7.5% to <10%, ≥10% to <15%, ≥15% to <20%, and ≥20%), we assessed preclinical HF prevalence and compared 10-year HF incidence rates for those with and without preclinical HF. We assessed changes in predictive utility by adding preclinical HF measures to PREVENT-HF. RESULTS:The mean age was 74 years, with 63% women, and 22% Black adults. Higher PREVENT-HF risk was associated with higher preclinical HF prevalence, with the highest prevalence of combined elevated biomarkers plus abnormal echocardiograms (37%) in those with PREVENT-HF ≥20%. Over a median follow-up of 9.9 years, 262 HF events occurred. Within PREVENT-HF categories, preclinical HF measures were strongly associated with absolute HF risk: among those with PREVENT-HF ≥20%, HF incidence rates (per 1,000 person-years) were 9.5 with no preclinical HF and 51.5 with elevated biomarkers plus abnormal echocardiography. Adding cardiac biomarkers to PREVENT-HF improved risk discrimination (C statistic change 0.69 to 0.75; P < 0.001) and reclassification (categorical Net Reclassification Index: 0.17; 95% CI: 0.09-0.26), with modest further improvement from adding echocardiographic measures. CONCLUSIONS:Preclinical HF measures indicate higher absolute HF risk within PREVENT-HF categories and enhance HF risk prediction.

BACKGROUND:Prior prediction equations for heart failure (HF) omitted cardiac biomarkers and used select populations. We assessed the added value of NT-proBNP (NT-terminal pro-brain natriuretic peptide) and hsTnT (high-sensitivity troponin T) as predictors of HF, across a broad population, including participants with chronic kidney disease or atherosclerotic cardiovascular disease. METHODS:Among 41 427 individuals free of HF from 9 prospective cohort studies, we performed an individual-participant data meta-analysis, quantifying the associations of NT-proBNP and hsTnT with incident HF when added to a clinical model. Changes in Harrel's C-statistic with and without NT-proBNP or hsTnT were estimated within each cohort and then pooled using random effects meta-analysis. RESULTS:<0.001). CONCLUSIONS:NT-proBNP improved risk discrimination of incident HF when added to traditional HF risk factors, even in individuals with chronic kidney disease and atherosclerotic cardiovascular disease. The contribution of hsTnT was modest. Measurement of NT-proBNP may help identify individuals at risk of HF.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Vascular dysfunction contributes to Alzheimer disease (AD) and related dementias (ADRDs), but the underlying mechanisms remain unclear. Previous studies link midlife hemostasis and platelet aggregation measures to late-life dementia risk. We aimed to determine whether platelet aggregation in midlife is associated with imaging markers of AD pathology. METHODS:F-flortaucipir) PET uptake in dementia-free, middle-aged adults from the Framingham Heart Study. Co-primary outcomes included amyloid and tau uptake in AD-vulnerable regions. We also examined an MRI-based cortical thickness signature of AD risk as a secondary outcome. We used multivariable regression models adjusted for demographic and clinical factors, considering potential nonlinear associations. RESULTS:< 0.035), consistent with a neurodegenerative pattern. DISCUSSION/CONCLUSIONS:Our findings indicate that platelet aggregation is linked to PET and MRI markers of AD pathology as early as midlife. These findings support further investigation of platelet-mediated mechanisms in AD pathogenesis.

AIMS/OBJECTIVE:To evaluate a previously proposed type 2 diabetes staging schema by examining the decline in oral beta-cell compensation and the increase in diabetes risk. METHODS:We analyzed 1,235 participants (43-85 years) from one ELSA-Brasil center. We defined stages as previously proposed: stage 1, isolated 1-h PG ≥155 mg/dL; stage 2, also having prediabetes/intermediate hyperglycemia (preDM/IH) defined by the American Diabetes Association (ADA); and stage 3, diabetes. We made additional evaluations defining IH based on the World Health Organization (WHO)/International Expert Committee (IEC) criteria. We estimated beta-cell compensation with the insulin secretion-sensitivity index-2 (ISSI-2). RESULTS:ISSI-2 declined (p < 0.001) across stages. After 5.29 (0.44) years (n = 850), the adjusted diabetes incidence increased from stage 0 (normoglycemia) to stage 1 (RR = 2.64;1.12,6.22) and stage 2 (RR = 5.94;2.83,12.44), considering WHO/IEC criteria. With the ADA criteria, RRs were larger but not progressive. Adding 1-h PG testing doubled the detection of unknown diabetes. A strategy combining FPG with 1-h PG performed just as well as using all four tests. CONCLUSIONS:Staging captured progressive deterioration to type 2 diabetes. Adding 1-h PG improved current and future case detection, which represents a major advance in diabetes prevention. However, refinements in staging will require further evaluation of tests and their thresholds.

PURPOSE/OBJECTIVE:Many studies estimate that more than 50% of non-hospitalized patients with long-COVID develop moderate to severe autonomic dysfunction. However, the specific impact of autonomic dysfunction as it relates to quality of life in long-COVID is not fully understood. The aim of the current study is to assess autonomic symptoms and quality-of-life in patients with Post-Acute Sequelae of COVID-19 (PASC) recruited from a neurology department outpatient setting. METHODOLOGY/METHODS:In a two-year follow-up study of a baseline cohort of 93 non-hospitalized SARS-CoV-2 laboratory-positive patients evaluated for PASC between November 2020-August 2021, 44 participants completed follow-up telephone questionnaires examining quality-of-life as well as neurologic and autonomic symptoms. RESULTS:Among 93 participants, 44 (47 %) completed the two-year follow-up evaluation and 27 (61 %) were female with a median age of 55 years (IQR = 24-88). Most participants (95 %, 42/44) were vaccinated against COVID-19 and 43 % (19/44) had a pre-existing neurological disorder. Median time from index COVID-19 infection to follow-up was 26 months (IQR = 23-17), with a median of 15 months (IQR = 15-16) between visits. Fatigue, word finding difficulty, and changes in memory were the most commonly reported PASC symptoms. Sixty-six percent (29/44) of individuals met criteria for autonomic dysfunction as defined by the Composite Autonomic Symptom Score-31 (COMPASS-31) scale. Secretomotor and gastrointestinal subdomains demonstrated significant associations with Neuro-QoL metrics for Anxiety, Depression, and Fatigue. For every 1 additional PASC symptom reported at a follow-up study visit, there was an average increase of 1.5 points on the COMPASS-31 composite score. In addition, visual disturbances and sleep impairment were both associated with increased autonomic dysfunction. CONCLUSION/CONCLUSIONS:The strong association between autonomic dysfunction and reduced QoL in PASC and the relation to insomnia, visual dysfunction, and functional impairment are valuable findings, reinforcing the clinical impact of these symptoms longitudinally after index COVID-19 infection.

This cross-sectional pilot study aimed to examine associations between urinary metabolites of organophosphate (OP) pesticides and semen quality in 42 healthy young men. Participants answered questionnaires, provided semen and urine samples, and had anthropometric measures taken. Urine and seminal plasma were assayed for dialkylphosphate (DAP) metabolites of OP pesticides using high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. Semen quality parameters were analyzed according to the World Health Organization protocol, and seminal oxidative stress was assayed using MiOXSYS, a galvanic cell-based technology that yields an integrated measure of oxidants and antioxidants. Associations of OP pesticide metabolites with continuous and dichotomous sperm concentration, percent motility, and percent normal morphology, and with seminal oxidative-reduction potential (ORP) were analyzed statistically. OP pesticide exposure was associated with lower overall semen quality. Specifically, ∑DAP metabolites, driven by diethyl metabolites, was inversely associated with percent sperm motility, but this relationship was not mediated by seminal ORP. Seminal ORP was inversely associated with sperm concentration, but OP pesticide exposure was not associated with seminal ORP.

Phenolic compounds may be harmful to the developing fetus, but many have not been studied in-depth for adverse childhood allergic and respiratory health effects. We hypothesized that higher levels of phenolic compounds in prenatal spot urine would be associated with greater odds of childhood atopic dermatitis, allergic rhinitis, and asthma, and that child sex may modify these associations. 3198 mother-child paired cases were enrolled from 16 cohorts in the U.S. ECHO consortium. Fifteen phenols (e.g. benzophenones, parabens, bisphenols, triclosans) were measured from mother's urine during pregnancy using a multi-class chemical panel. Childhood outcomes included parent-reported atopic dermatitis (1466 mother-child pairs) between ages 0-3 years, and allergic rhinitis (901 mother-child pairs) and asthma (1662 mother-child pairs) between ages 5-9 years. Prenatal parabens were associated with increased odds of atopic dermatitis (odds ratio (OR) 1.13, 95 % confidence intervals (CI) 1.02, 1.26). Benzophenones were associated with lower odds of asthma (OR 0.77, CI 0.66, 0.90). Compared to boys, girls demonstrated higher odds of parabens (1.21, CI 1.04, 1.42), benzophenones (1.18, CI 1.00, 1.38) and bisphenol S (1.21, CI 1.03, 1.43) being associated with atopic dermatitis, and of the benzophenones (1.46, CI 1.11, 1.93) being associated with allergic rhinitis. An association of benzophenones (0.66, CI 0.53, 0.83) with lower odds of asthma was stronger among boys. These findings suggest that prenatal paraben and other phenol exposures may adversely affect early-life allergic and respiratory outcomes, with sex-specific vulnerability. Novel, multi-modality approaches to reduce maternal phenol exposure during pregnancy are urgently needed to protect children's health.

BACKGROUND:High 1-h-post-load plasma glucose (1 h-PG) is an early diabetes risk marker. We hypothesized that isolated high 1 h-PG represents an intermediate state between normal glucose regulation (NGR) and impaired glucose regulation (IGR) and is amendable to greater lifestyle intervention (LI) benefit. METHODS:In the Tübingen Lifestyle Intervention Program, 317 people with either NGR, IGR or isolated high 1 h-PG without IGR underwent LI for 9 months to achieve ≥5 % weight loss. RESULTS:Before LI initiation, insulin sensitivity and β-cell function declined progressively from NGR (n = 106) to high 1 h-PG (n = 96) and to IGR (n = 115). Visceral adipose tissue (VAT) volume and liver fat content increased from NGT to high 1 h-PG and to IGR. LI improved insulin sensitivity and ß-cell function in the high 1 h-PG group to levels observed in NGR together with a marked reduction in hepatic fat content. Compared to the IGR group, T2D risk was reduced by 80 % (37-96 %, p = 0.005) in the high 1 h-PG group during a 12-year follow-up period. The odds of remission to complete normoglycemia were doubled in the high 1 h-PG group compared to the IGR group (2.18 [1.13-4.28], p = 0.021). CONCLUSION/CONCLUSIONS:High 1 h-PG indicates an intermediate metabolic state with pathophysiological changes more severe than in NGR but milder than in IGR. In people with high 1 h-PG, LI significantly improved insulin sensitivity and β-cell function and reduced ectopic lipid deposition and the risk of developing T2D compared to IGR. These findings highlight the value of 1 h-PG as a clinically useful biomarker, providing a critical window for early intervention to reverse core metabolic defects driving prediabetes and T2D.

IMPORTANCE/UNASSIGNED:Estimated glomerular filtration rates (eGFRs) can differ according to whether creatinine or cystatin C is used for the eGFR calculation, but the prevalence and importance of these differences remain unclear. OBJECTIVES/UNASSIGNED:To evaluate the prevalence of a discordance between cystatin C-based eGFR (eGFRcys) and creatinine-based eGFR (eGFRcr), identify characteristics associated with greater discordance, and evaluate associations of discordance with adverse outcomes. DATA SOURCES/UNASSIGNED:Participants in the Chronic Kidney Disease Prognosis Consortium (CKD-PC). STUDY SELECTION/UNASSIGNED:Participants with concurrent cystatin C and creatinine measurements and clinical outcome measurement. DATA EXTRACTION AND SYNTHESIS/UNASSIGNED:Between April 2024 and August 2025, data were synthesized using individual-level meta-analysis. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary independent measurement was a large negative eGFR difference (eGFRdiff), defined as an eGFRcys that was at least 30% lower than eGFRcr. Secondary (dependent) outcomes included all-cause and cardiovascular mortality, atherosclerotic cardiovascular disease, heart failure, and kidney failure with replacement therapy. RESULTS/UNASSIGNED:A total of 821 327 individuals from 23 outpatient cohorts (mean [SD] age, 59 [12] years; 48% female; 13.5% with diabetes; 40% with hypertension) and 39 639 individuals from 2 inpatient cohorts (mean [SD] age, 67 [16] years; 31% female; 30% with diabetes; 72% with hypertension) were included. Among outpatient participants, 11% had a large negative eGFRdiff (range, 3%-50%). Among inpatients, 35% had a large negative eGFRdiff. Among outpatient participants, at a mean (SD) follow-up of 11 (4) years, a large negative eGFRdiff, compared with an eGFRdiff between -30% and 30%, was associated with higher rates of all-cause mortality (28.4 vs 16.8 per 1000 person-years [PY]; hazard ratio [HR], 1.69 [95% CI, 1.57-1.82]), cardiovascular mortality (6.1 vs 3.8 per 1000 PY; HR, 1.61 [95% CI, 1.48-1.76]), atherosclerotic cardiovascular disease (13.3 vs 9.8 per 1000 PY; HR, 1.35 [95% CI, 1.27-1.44]), heart failure (13.2 vs 8.6 per 1000 PY; HR, 1.54 [95% CI, 1.40-1.68]), and kidney failure with replacement therapy (2.7 vs 2.1 per 1000 PY; HR, 1.29 [95% CI, 1.13-1.47]). CONCLUSIONS AND RELEVANCE/UNASSIGNED:In the CKD-PC, 11% of outpatient participants and 35% of hospitalized patients had an eGFRcys that was at least 30% lower than their eGFRcr. In the outpatient setting, presence of eGFRcys at least 30% lower than eGFRcr was associated with significantly higher rates of all-cause mortality, cardiovascular events, and kidney failure.