Publications

BACKGROUND: Risk stratification for sudden cardiac death (SCD) in patients with nonischemic cardiomyopathy (NICM) remains challenging.

OBJECTIVES: This study aimed to investigate the impact of epicardial adipose tissue (EAT) on SCD in NICM patients.

METHODS: Our study cohort included 173 consecutive patients (age 53 ± 14 years, 73% men) scheduled for primary prevention implantable cardioverter-defibrillators (ICDs) implantation who underwent preimplant cardiovascular magnetic resonance. EAT volume surrounding both ventricles was manually quantified from cine left ventricular short-axis images by summation of the EAT volume of each slice using the modified Simpson rule. The primary endpoint was appropriate ICD therapy.

RESULTS: During the mean follow-up of 3.6 years, 24 patients (14%) experienced an endpoint. An inverse and proportional relationship was evident between EAT and subsequent ICD therapies (P = 0.004). Even after adjusting for left ventricular mass and ejection fraction, EAT was significantly lower in patients with ICD therapy than those without. Low EAT was independently associated with an increased risk of ICD therapy in NICM patients (HRad per 10 mL/m2 decrease, 1.65; 95% CI: 1.17-2.42; P = 0.007). EAT ≤50 mL/m2 demonstrated a 3-fold increase in SCD event risk, with an estimated likelihood of 57% at 5 years. When considered with other potential risk factors, EAT provided incremental prognostic value in predicting ICD therapy.

CONCLUSIONS: Low ventricular EAT was associated with increased SCD risk in NICM patients receiving primary prevention ICD implantation, even in the presence of other risk markers. These data suggest a potential clinical role of EAT in selecting NICM patients who would benefit most from ICD implantation.

OBJECTIVES: In observational studies, older adults with low serum vitamin D levels are at higher risk of cardiovascular disease (CVD), but randomized trials have failed to demonstrate reduction in CVD risk from vitamin D supplementation, possibly because the doses of vitamin D supplements tested were too low. Our objective was to determine if higher doses of vitamin D supplementation reduce high-sensitivity cardiac troponin (hs-cTnI) and N-terminal pro-b-type natriuretic peptide (NT-proBNP), markers of subclinical CVD.

METHODS: The Study to Understand Fall Reduction and Vitamin D in You (STURDY) was a double-blind, randomized, response-adaptive trial that tested the effects of 4 doses of vitamin D3 supplementation (200, 1000, 2000, 4000 IU/day) on fall risk among older adults with low serum 25-hydroxyvitamin D concentrations (10-29 ng/mL). Hs-cTnI and NT-proBNP levels were measured at baseline, 3-, 12-, and 24-month follow-up visits. For this ancillary study, we used data from the original trial and compared participants by treatment group: low-dose (200 IU/day) or high-dose (1000+ IU/day). The effects of vitamin D dose on biomarkers were assessed via mixed effects tobit models.

RESULTS: Among 688 participants (mean age of 76.5) hs-cTnI increased in both the low- and high-dose groups by 5.2 % and 7.0 %, respectively; likewise, NT-proBNP increased by 11.3 % and 9.3 %, respectively. Compared to the low-dose, high-dose vitamin D supplementation did not affect hs-cTnI (1.6 %-difference; 95 % CI: -5.3, 8.9) or NT-proBNP (-1.8 %-difference; 95 % CI: -9.3, 6.3).

CONCLUSIONS: Compared to low-dose vitamin D supplementation, doses ≥1,000 IU/ day did not affect markers of subclinical CVD in older adults with low serum vitamin D levels.

BACKGROUND: A healthier diet is associated with lower chronic disease burden, but the impact of neighbourhood food environments on disability and death in older adults is not known.

METHODS: In the Cardiovascular Health Study, a cohort study of adults aged 65+, we calculated study years until death (years of life (YOL)), study years without activities of daily living (ADL) difficulty (years of able life; YoAL) and percent of study years without ADL difficulty (compression of disability). Linear regression quantified associations of food establishments within 5 km of baseline home address (as a z-score) with each outcome, adjusted for sociodemographic characteristics. Sensitivity analyses considered adjustment for risk factors and comorbidities, multiple imputation, alternate neighbourhood definitions (1-km radial buffer, census tract) and restriction on residential stability.

RESULTS: We included 4298 participants followed for up to 26 years. All food retail establishments were associated with 6 months higher YoAL per SD in the main model (beta, 0.50 years; 95% CI 0.01, 0.98; p=0.046), with similar findings across sensitivity analyses except when restricting on residential stability. Supermarkets and produce markets were associated with compression of disability (beta, 2.31; 95% CI, 0.04, 4.57) and when using 1-km buffers with YOL (beta, 0.23 years; 95% CI 0.03, 0.43) and YoAL (beta, 0.21 years; 95% CI 0.01, 0.41). Non-supermarket food stores were associated with YoAL (beta, 0.67 years; 95% CI, 0.07, 1.27) and compression of disability (beta, 3.03; 95% CI 0.44, 5.62), but significance was not consistent across sensitivity analyses. Fast-food restaurants did not reach statistical significance in any model.

CONCLUSION: All food retail was associated with YOL without impairment. Neighbourhood food retail access and type may both have roles in extending YOL and years of able life among older adults, but the findings were sensitive to decisions made during measurement and modelling.

INTRODUCTION: Fear of cancer recurrence (FCR) is prevalent and distressing among survivors of cancer. Evidence-based mind-body and cognitive-behavioral skills lack integration and testing in scalable formats.

OBJECTIVE: This pilot randomized controlled trial (NCT04876599) tested a synchronous, virtual mind-body group resiliency intervention for FCR (IN FOCUS).

METHOD: Adults with elevated FCR (FCR Inventory severity ≥ 16; 16-21 = elevated, 22-36 = clinically elevated) after completing primary treatment for non-metastatic cancer were randomly assigned (1:1) to eight weekly sessions of IN FOCUS or usual care (UC; synchronous, virtual community group support referral). Feasibility metrics included ≥ 70% retention per arm (primary outcome), ≥ 75% attendance in ≥ 6 sessions, ≥ 75% adherence to relaxation skills practice ≥ 3 days per week and by delivery fidelity (% content covered in video-recorded sessions). Acceptability was assessed quantitatively via ratings of enjoyableness, convenience, helpfulness, odds of future use, and satisfaction (benchmark ≥ 80% of ratings ≥ 4 on 1-5 Likert scale) and qualitatively via individual exit interviews. Linear mixed models explicated slopes in FCR (secondary) and resiliency (exploratory; Current Experiences Scale) from baseline to 2 months (primary endpoint) and 5 months using intention-to-treat.

RESULTS: From July 2021 to March 2022, 64 survivors enrolled (25-73 years old, M = 7 years since diagnosis). IN FOCUS was feasible and acceptable (91% retention; attendance median = 7 sessions, 97% relaxation practice adherence, 95% content fully covered; 82% of acceptability ratings ≥ 4). Interviews (n = 59) revealed benefits in both arms. By 2 months, compared to UC, IN FOCUS reduced FCR to a medium-to-large effect (Mdiff = -2.4; 95% CI = -4.2, -0.7; d = 0.66). By 5 months, FCR effects had attenuated (Mdiff = -0.16, 95% CI -1.97, 1.65; d = -0.04), although levels of resiliency had increased with a medium-to-large effect (Mdiff = 10.0; 95% CI = 4.9, 15.1; d = 0.78).

CONCLUSIONS: For survivors of non-metastatic cancer, a synchronous, virtual mind-body resiliency program for FCR is feasible, acceptable, and seemingly beneficial compared to a community group referral.

The relationship between key energy metabolites and brain health is not well understood. We investigated the association between circulating ketone bodies, pyruvate, and citrate with cognitive decline, structural brain characteristics, and risk of dementia. We measured ketone bodies (acetoacetate, β-hydroxybutyrate, and acetone), pyruvate, and citrate species using NMR in plasma samples from 1,850 older adults in the Cardiovascular Health Study collected in 1989-90 or 1992-93. Cognitive decline was assessed using the modified Mini-Mental State Examination and the Digit Symbol Substitution Test. Dementia was adjudicated by a committee of experts through comprehensive evaluations including cognitive tests, medical records, and interviews with the next of kin. Dementia-related mortality was confirmed by a committee using death certificates and other clinical data from hospitalization. Multivariable linear mixed models were used to assess 9-year cognitive decline, while multivariable Cox regression models evaluated 6-year dementia incidence and 22-year dementia-related mortality. White matter lesions and ventricular size were measured using MRI in 1992-94 and were analyzed using multivariable linear regression models. Higher plasma levels of ketones, particularly β-hydroxybutyrate, were associated with faster cognitive decline (β, -0.10; 95% CI, -0.15 to -0.05; Padj&;lt.001) and dementia-related mortality (HR per SD, 1.29; 95% CI, 1.07 to 1.56; Padj=0.023). Higher pyruvate concentrations were associated with slower cognitive decline, smaller ventricular size, lower dementia risk (HR per SD, 0.87; 95% CI, 0.77 to 0.97; P=0.013; Padj=0.073), and lower dementia mortality. Higher citrate levels were associated with less cognitive decline and lower dementia risk. In adults aged 65 years and older, circulating ketone bodies are associated with faster cognitive decline and higher dementia mortality, while pyruvate and citrate are associated with lower dementia risk.

INTRODUCTION: The prevalence of peripheral neuropathy (PN) in the lower limb increases with age and with the presence of diabetes. Studies show an association of PN with advanced cognitive impairment. Here we examine the association of PN with measures of early cognitive deficits in a cohort of older adults without apparent cognitive impairment, with or without diabetes.

METHODS: A total of 2,798 participants from the Cardiovascular Health Study were examined, mean age 80 years. All underwent tests of overall cognition (3MSE), executive function (DSST), and visual memory (BVRT). Impairment of vibration sensation in the toes, ankles, and tibial tuberosities was ascertained. Participants were graded according to the extent of impairment. Adjusted linear regression analyses of the extent of impaired vibration sensation with cognitive tests were performed. Results were further categorized by the presence or absence of diabetes.

RESULTS: 70% of participants had intact vibration sensation in the toes; 8% had no vibration sensation in the tibial tuberosities or below. Compared to participants with intact vibration sensation in the toes, those with no vibration sensation in the tibial tuberosities had lower 3MSE scores. Tests of executive function were lower in a stepwise manner with greater impaired vibration sensation. Visual memory was less strongly associated with impaired vibration sensation. Findings did not differ significantly by diabetes status.

CONCLUSION: In older adults, impaired vibration sensation in the lower limb is associated with impaired executive function and visual memory. These findings did not differ by diabetes status.

OBJECTIVE: Acute hyperglycemia following intracerebral hemorrhage (ICH) is associated with poor functional outcomes and may result from a neuroendocrine stress response. Given the proximity of neuroendocrine structures to the cerebral ventricles, we tested the hypothesis that intraventricular hemorrhage (IVH) is associated with hyperglycemia.

MATERIALS AND METHODS: A post-hoc analysis of the ICH Deferoxamine (i-DEF) trial was conducted to determine predictors of IVH. Variables with significant differences (p < 0.1) in univariable tests between patients with and without IVH were entered into a logistic regression model along with age, sex, diabetes, hyperglycemia (admission glucose ≥140 mg/dL), and baseline intraparenchymal hemorrhage (IPH) volume. This model was then applied to an independent cohort of consecutive non-traumatic ICH patients admitted to a single referral center (2007 to 2018).

RESULTS: Among 294 patients in the i-DEF cohort with mean age 60 ± 12 years (IVH in 41 %), hyperglycemia (aOR 1.90, 95 % CI [1.06-3.38]), smoking history (aOR 1.90, 95 % CI [1.11-3.27]), and non-lobar ICH location (aOR 3.38, 95 % CI [1.49-7.69]) were independently associated with IVH. In the independent cohort consisting of 856 patients with mean age 71 ± 12 years (IVH in 37 %), hyperglycemia (aOR 2.23, 95 % CI [1.55-3.20]), non-lobar ICH location (aOR 2.50, 95 % CI [1.75-3.59]), and IPH volume (aOR 1.02, 95 % CI [1.01-1.02]) were associated with IVH.

CONCLUSIONS: Hyperglycemia is associated with IVH and may be a peripheral marker for the inflammatory response to hemorrhage within the ventricles. Further translational studies are needed to elucidate the pathophysiological basis for this phenomenon.

BACKGROUND: Although the pathogenesis of delirium is poorly understood, increasing evidence supports a role for inflammation. Previously, individual inflammatory biomarkers have been associated with delirium. Aggregating biomarkers into an index may provide more information than individual biomarkers in predicting certain health outcomes (e.g., mortality); however, inflammatory indices have not yet been examined in delirium.

METHODS: Four inflammatory markers, C-reactive protein, Interleukin-6, Soluble Tumor Necrosis Factor Alpha Receptor-1, and Chitinase-3 Like Protein-1 (CHI3L1), were measured preoperatively (PREOP) and on postoperative day 2 (POD2) in 548 adults aged 70+ undergoing major noncardiac surgery (mean age 76.7 [standard deviation 5.2], 58% female, 24% delirium). From these markers, four inflammatory indices were considered: 1) quartile summary score, 2) weighted summary score (WSS), 3) principal component score, 4) a well-established inflammatory (LASSO-derived) index associated with mortality. Delirium was assessed using the Confusion Assessment Method (CAM), supplemented by chart review. Generalized linear models (GLM) with a log-link term were used to determine the association between each inflammatory index and delirium incidence.

RESULTS: Among the inflammatory indices, WSS demonstrated the strongest association with delirium: participants in WSS quartile (Q)4 had a higher risk of delirium vs. participants in Q1, after clinical variable adjustment (relative risk [RR], 95% confidence interval [CI] for PREOP: 3.07, 1.80-5.22; and POD2: 2.65, 1.63-4.30). WSS was more strongly associated with delirium than the strongest associated individual inflammatory marker (PREOP CHI3L1 [RR 2.45, 95% CI 1.53-3.92]; POD2 interleukin-6 [RR 2.39, 95% CI 1.50-3.82]).

CONCLUSIONS: A multi-protein inflammatory index using WSS provides a slight advantage over individual inflammatory markers in their association with delirium.

BACKGROUND: Reliable, noninvasive tools to diagnose at-risk metabolic dysfunction-associated steatohepatitis (MASH) are urgently needed to improve management. We developed a risk stratification score incorporating proteomics-derived serum markers with clinical variables to identify high-risk patients with MASH (NAFLD activity score >4 and fibrosis score >2).

METHODS: In this 3-phase proteomic study of biopsy-proven metabolic dysfunction-associated steatotic fatty liver disease, we first developed a multi-protein predictor for discriminating NAFLD activity score >4 based on SOMAscan proteomics quantifying 1305 serum proteins from 57 US patients. Four key predictor proteins were verified by ELISA in the expanded US cohort (N = 168) and enhanced by adding clinical variables to create the 9-feature MASH Dx score, which predicted MASH and also high-risk MASH (F2+). The MASH Dx score was validated in 2 independent, external cohorts from Germany (N = 139) and Brazil (N = 177).

RESULTS: The discovery phase identified a 6-protein classifier that achieved an AUC of 0.93 for identifying MASH. Significant elevation of 4 proteins (THBS2, GDF15, SELE, and IGFBP7) was verified by ELISA in the expanded discovery and independently in the 2 external cohorts. MASH Dx score incorporated these proteins with established MASH risk factors (age, body mass index, ALT, diabetes, and hypertension) to achieve good discrimination between MASH and metabolic dysfunction-associated steatotic fatty liver disease without MASH (AUC: 0.87-discovery; 0.83-pooled external validation cohorts), with similar performance when evaluating high-risk MASH F2-4 (vs. MASH F0-1 and metabolic dysfunction-associated steatotic fatty liver disease without MASH).

CONCLUSIONS: The MASH Dx score offers the first reliable noninvasive approach combining novel, biologically plausible ELISA-based fibrosis markers and clinical parameters to detect high-risk MASH in patient cohorts from the United States, Brazil, and Europe.