sPDGFRß and neuroinflammation are associated with AD biomarkers and differ by race: The ASCEND Study.

INTRODUCTION: There remains an urgent need to identify preclinical pathophysiological mechanisms of Alzheimer's disease (AD) development in high-risk, racially diverse populations. We explored the relationship between cerebrospinal fluid (CSF) markers of vascular injury and neuroinflammation with AD biomarkers in middle-aged Black/African American (B/AA) and non-Hispanic White (NHW) participants. METHODS: Adults (45-65 years) with a parental history of AD were enrolled (n = 82). CSF and blood biomarkers were collected at baseline and year 2. RESULTS: CSF total tau (t-tau), phosphorylated tau (p-tau), and amyloid beta (Aß)40 were elevated at year 2 compared to baseline. CSF soluble platelet-derived growth factor receptor ß (sPDGFRß) levels, a marker of pericyte injury, correlated positively with t-tau, p-tau, Aß40 markers of vascular injury, and cytokines at baseline and year 2. CSF sPDGFRß and tau were significantly lower in B/AA than NHW. DISCUSSION: Vascular dysfunction and neuroinflammation may precede cognitive decline and disease pathology in the very early preclinical stages of AD, and there are race-related differences in these relationships. HIGHLIGHTS: Cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers changed over 2 years in high-risk middle-aged adults. Markers of vascular dysfunction were associated with the CSF biomarkers amyloid beta and tau. AD biomarkers were lower in Black compared to non-Hispanic White individuals. Markers of vascular dysfunction were lower among Black individuals.

The Effects of Exercise on Telomere Length in Persons With Heart Failure.

BACKGROUND: Telomere length is reduced in persons with heart failure (HF). Inflammation is a putative mechanism contributing to telomere shortening. Although physical activity is known to increase telomere length, its effects in HF are unknown. OBJECTIVE: The aim of this study was to examine the effects of exercise on telomere length and its relationship with interleukin (IL)-1ß in persons with HF. METHODS: This secondary analysis of a 3-month home-based aerobic exercise intervention measured total telomere length and IL-1ß levels in persons with HF (69% with reduced ejection fraction). RESULTS: Total telomere length increased and plasma IL-1ß levels decreased in the exercise group from baseline to 3 months. Total telomere length was negatively associated with IL-1ß at baseline (r = -0.441 P = .001). CONCLUSIONS: The association between telomere length and IL-1ß suggests a relationship between inflammation and cellular aging. Moderate-intensity exercise may help maintain cellular functions. Further research is needed to examine the effects on outcomes in persons with HF.

Adaptation of Metabolomics and Microbiomic Research Protocols During the COVID-19 Pandemic.

BACKGROUND: When the COVID-19 pandemic hit in 2020, researchers in the P30 Center for the Study of Symptom Science, Metabolomics, and Multiple Chronic Conditions at Emory University's Nell Hodgson Woodruff School of Nursing faced major challenges in recruitment and data collection because of limited access to the clinic and community facilities and the risk of COVID-19 exposure associated with in-person study contact. OBJECTIVES: The purpose of this article is to (a) describe how a cadre of pilot/supplement principal investigators adapted their studies to allow for safe and trustworthy data collection during the COVID-19 pandemic (March 2020 through date of publication) and (b) discuss steps that facilitated the technical aspects of remote data collection, especially involving biological specimens. RESULTS: Four pilot studies and two administrative supplements within the center-all at different stages of execution-adopted various alternative remote recruitment, enrollment, and data and specimen collection approaches to continue their research endeavors in a way that maximized the safety of both the research participants and the research teams. DISCUSSION: The article concludes with a discussion on the importance of a participant-centered approach when using remote methods, actions, or steps initiated to facilitate the technical aspects of remote data collection and reflections on the continued use of remote research strategies beyond the COVID-19 pandemic.

Potential Protective Mechanisms of S-equol, a Metabolite of Soy Isoflavone by the Gut Microbiome, on Cognitive Decline and Dementia.

S-equol, a metabolite of soy isoflavone daidzein transformed by the gut microbiome, is the most biologically potent among all soy isoflavones and their metabolites. Soy isoflavones are phytoestrogens and exert their actions through estrogen receptor-ß. Epidemiological studies in East Asia, where soy isoflavones are regularly consumed, show that dietary isoflavone intake is inversely associated with cognitive decline and dementia; however, randomized controlled trials of soy isoflavones in Western countries did not generally show their cognitive benefit. The discrepant results may be attributed to S-equol production capability; after consuming soy isoflavones, 40-70% of East Asians produce S-equol, whereas 20-30% of Westerners do. Recent observational and clinical studies in Japan show that S-equol but not soy isoflavones is inversely associated with multiple vascular pathologies, contributing to cognitive impairment and dementia, including arterial stiffness and white matter lesion volume. S-equol has better permeability to the blood-brain barrier than soy isoflavones, although their affinity to estrogen receptor-ß is similar. S-equol is also the most potent antioxidant among all known soy isoflavones. Although S-equol is available as a dietary supplement, no long-term trials in humans have examined the effect of S-equol supplementation on arterial stiffness, cerebrovascular disease, cognitive decline, or dementia.

Exercise and Cognitive Training as a Strategy to Improve Neurocognitive Outcomes in Heart Failure: A Pilot Study.

OBJECTIVE: Mild cognitive impairment, especially memory loss, is prevalent in patients with heart failure (HF) and contributes to poor clinical outcomes and higher mortality. METHODS: This study evaluated a combined aerobic exercise and cognitive training (EX/CT) program on memory, executive function, attention, processing speed and reaction time compared to exercise only or a usual care attention control (UCAC) stretching and flexibility program. Participants completed a standardized neurocognitive battery at baseline, 3 months, and 6 months along with demographic, clinical, and functional capacity (6-minute walk test). A linear mixed model analysis was used with comorbidity as a covariate. RESULTS: Sixty-nine participants were enrolled, the mean age was 61 ± 10 years, 54% were women, 55% were African American, and the mean left ventricular ejection fraction percentage was 35 ± 15. A significant group by time interaction for verbal memory was found at 3 months (F [2, 53] = 4.3, p = 0.018) but was not sustained at 6 months in the EX/CT group. Processing speed/attention differed across treatment groups between baseline and 6 months, but improvement occurred among UCAC participants. There were also significant group differences in the 6MWT distance occurring at 3 months (F [2, 52] = 3.5, p = 0.036); however, significant improvement was observed within the EX/CT group only. There were no significant differences in 6MWT in the other groups at 3 or 6 months. CONCLUSION: An EX/CT intervention was associated with improved memory in persons with HF and warrants further investigation in a larger trial. The relationship between functional capacity and cognitive function also needs further study.

The Third Time's a Charm: Psychometric Testing and Update of the Atlanta Heart Failure Knowledge Test.

BACKGROUND AND OBJECTIVE: Since first being published in 2009, the Atlanta Heart Failure Knowledge Test (AHFKT) has proven a reliable and valid instrument and has been used in multiple studies. Given advances in heart failure (HF) self-care, we proposed to reevaluate the psychometric properties of the AHFKTv2 across these recent studies and update the instrument. METHODS: Demographic, clinical, and baseline AHFKTv2 data from 4 intervention studies in persons with HF were combined for this analysis (N = 284). The 30 questions of the AHFKT are focused on 5 HF self-care knowledge domains: pathophysiology, nutrition, behavior, medications, and symptoms. Characteristics of the sample were analyzed using descriptive statistics; validity testing with t tests and Mann-Whitney 2-group tests and Pearson r and Spearman ρ correlations; and reliability calculations and factor analysis were performed based on tetrachoric correlations. RESULTS: Participants were 22 to 84 years of age, 66% were African American, 63% were male, and 94% had New York Heart Association class II to III HF. Mean AHFKT score was 80.6% (±11%). Hypotheses that higher levels of knowledge would be associated with higher education level (t = -2.7, P < .01) and less sodium consumption (ρ = -0.22, P = .03) were validated. Factor analysis revealed 1 general knowledge factor with good reliability, Cronbach's α was .87. Item response analysis identified individual questions requiring review and revision. CONCLUSION: Comprehensive psychometric evaluation of the AHFKTv2 confirmed its internal consistency reliability and validity and provided direction for production of the AHFKTv3 available for use in research and clinical practice.

Methylation of Apoptosis-Associated Speck-Like Protein With a Caspase Recruitment Domain and Outcomes in Heart Failure.

BACKGROUND: Heart failure (HF) is associated with inflammation characterized by the formation of the inflammasome, which triggers maturation of inflammatory cytokines. Apoptosis-associated speck-like protein with a caspase recruitment domain (ASC), a vital component of the inflammasome, is controlled through epigenetic modification, which may be a candidate pathway for worsening HF. This study examined the inflammasome pathway in HF and the relationships between ASC CpG methylation and outcomes in HF. METHODS AND RESULTS: Stored samples from 155 HF outpatients (ejection fraction 29.9 ± 14.9%) were analyzed for percentage methylation of 7 CpG sites in the intron region preceding exon 1 of the ASC gene. ASC methylation was inversely related to ASC mRNA (r = -0.33; P < .001) and protein (r = -0.464; P < .001). ASC methylation had a positive linear relationship with ejection fraction (r = 0.85; P < .001), quality of life (r = 0.83; P < .001), and 6-minute walk test (r = 0.59; P = .023) and a negative linear relationship with depression (r = -0.81; P < .001) and anxiety (r = -0.75; P < .001). Higher ASC methylation was associated with a lower risk for clinical events (hazard ratio [HR] 0.16; P = .025), whereas higher protein (HR = 1.78; P = .045) and mRNA expression (HR = 1.18; P = .05) were associated with a greater risk. CONCLUSIONS: Increased methylation of CpG sites in the intron region of ASC is associated with improved outcomes in HF. The associated decrease in ASC expression implicates this inflammatory mediator as a possible driver of HF outcomes and may represent a therapeutic target.

The Importance of NLRP3 Inflammasome in Heart Failure.

Patients with heart failure continue to suffer adverse health consequences despite advances in therapies over the past 2 decades. Identification of novel therapeutic targets that may attenuate disease progression is therefore needed. The inflammasome may play a central role in modulating chronic inflammation and in turn affecting heart failure progression. The inflammasome is a complex of intracellular interaction proteins that trigger maturation of proinflammatory cytokines interleukin-1ß and interleukin-18 to initiate the inflammatory response. This response is amplified through production of tumor necrosis factor α and activation of inducible nitric oxide synthase. The purpose of this review is to discuss recent evidence implicating this inflammatory pathway in the pathophysiology of heart failure.

Randomized clinical trial of an integrated self-care intervention for persons with heart failure and diabetes: quality of life and physical functioning outcomes.

OBJECTIVES: Persons with concomitant heart failure (HF) and diabetes mellitus (DM) have complicated, often competing, self-care expectations and treatment regimens that may reduce quality of life (QOL). This randomized controlled trial tested an integrated self-care intervention on outcomes of HF and DM QOL, physical function, and physical activity (PA). METHODS AND RESULTS: Participants with HF and DM (n = 134; mean age 57.4 ± 11 years, 66% men, 69% minority) were randomized to usual care (control) or intervention. The control group received standard HF and DM educational brochures with follow-up telephone contact. The intervention group received education and counseling on combined HF and DM self-care (diet, medications, self-monitoring, symptoms, and PA) with follow-up home visit and telephone counseling. Measures included questionnaires for HF- and DM-specific and overall QOL, PA frequency, and physical function (6-min walk test [6MWT]) and were obtained at baseline and 3 and 6 months. Analysis included mixed models with a priori post hoc tests. Adjusting for age, body mass index, and comorbidity, the intervention group improved in HF total (P = .002) and physical (P < .001) QOL scores at 3 months with retention of improvements at 6 months, improved in emotional QOL scores compared with control at 3 months (P = .04), and improved in health status ratings (P = .04) at 6 months compared with baseline. The intervention group improved in 6MWT distance (924 ft to 952 ft; P = .03) whereas the control group declined (834 ft to 775 ft; F1,63 = 6.86; P = .01). The intervention group increased self-reported PA between baseline and 6 months (P = .01). CONCLUSIONS: An integrated HF and DM self-care intervention improved perceived HF and general QOL but not DM QOL. Improved physical functioning and self-reported PA were also observed with the integrated self-care intervention. Further study of the HF and DM integrated self-care intervention on other outcomes, such as hospitalization and cost, is warranted.

An economic evaluation of a self-care intervention in persons with heart failure and diabetes.

BACKGROUND: Persons with concomitant heart failure (HF) and diabetes mellitus constitute a growing population whose quality of life is encumbered with worse clinical outcomes as well as high health resource use (HRU) and costs. METHODS AND RESULTS: Extensive data on HRU and costs were collected as part of a prospective cost-effectiveness analysis of a self-care intervention to improve outcomes in persons with both HF and diabetes. HRU costs were assigned from a Medicare reimbursement perspective. Patients (n = 134) randomized to the self-care intervention and those receiving usual care/attention control were followed for 6 months, revealing significant differences in the number of hospitalization days and associated costs between groups. The mean number of inpatient days was 3 with bootstrapped bias-corrected (BCa) confidence intervals (CIs) of 1.8-4.4 d for the intervention group and 7.3 d (BCa CI 4.1-10.9 d) in the control group: P = .044. Total direct HRU costs per participant were an estimated $9,065 (BCa CI $6,496-$11,936) in the intervention and $16,712 (BCa CI 8,200-$26,621) in the control group, for a mean difference of -$7,647 (BCa CI -$17,588 to $809; P = .21) in favor of the intervention, including intervention costs estimated to be $130.67 per patient. CONCLUSIONS: The self-care intervention demonstrated dominance in lowering costs without sacrificing quality-adjusted life-years.

Coexisting Frailty, Cognitive Impairment, and Heart Failure: Implications for Clinical Care.

OBJECTIVE: To review some of the proposed pathways that increase frailty risk in older persons with heart failure and to discuss tools that may be used to assess for changes in physical and cognitive functioning in this population in order to assist with appropriate and timely intervention. METHODS: Review of the literature. RESULTS: Heart failure is the only cardiovascular disease that is increasing by epidemic proportions, largely due to an aging society and therapeutic advances in disease management. Because heart failure is largely a cardiogeriatric syndrome, age-related syndromes such as frailty and cognitive impairment are common in heart failure patients. Compared with age-matched counterparts, older adults with heart failure 4 to 6 times more likely to be frail or cognitively impaired. The reason for the high prevalence of frailty and cognitive impairment in this population is not well known but may likely reflect the synergistic effects of heart failure and aging, which may heighten vulnerability to stressors and accelerate loss of physiologic reserve. Despite the high prevalence of frailty and cognitive impairment in the heart failure population, these conditions are not routinely screened for in clinical practice settings and guidelines on optimal assessment strategies are lacking. CONCLUSION: Persons with heart failure are at an increased risk for frailty, which may worsen symptoms, impair self-management, and lead to worse heart failure outcomes. Early detection of frailty and cognitive impairment may be an opportunity for intervention and a key strategy for improving clinical outcomes in older adults with heart failure.

A pilot test of an integrated self-care intervention for persons with heart failure and concomitant diabetes.

Studies show 30% to 47% of people with heart failure (HF) have concomitant diabetes mellitus (DM). Self-care for persons with both of these chronic conditions is conflicting, complex, and often inadequate. This pilot study tested an integrated self-care program for its effects on HF and DM knowledge, self-care efficacy, self-care behaviors, and quality of life (QOL). Hospitalized HF-DM participants (N = 71) were randomized to usual care or intervention using a 1:2 allocation and followed at 30 and 90 days after intervention. Intervention was an integrated education and counseling program focused on HF-DM self-care. Variables included demographic and clinical data, knowledge about HF and DM, HF- and DM-specific self-efficacy, standard HF and DM QOL scales, and HF and DM self-care behaviors. Analysis included descriptive statistics, multilevel longitudinal models for group and time effects, post hoc testing, and effect size calculations. Sidak adjustments were used to control for type 1 error inflation. The integrated HF-DM self-care intervention conferred effects on improved HF knowledge (30 days, p = .05), HF self-care maintenance (30 and 90 days, p < .001), HF self-care management (90 days, p = .05), DM self-efficacy (30 days, p = .03; 90 days, p = .004), general diet (30 days, p = .05), HF physical QOL (p = .04), and emotional QOL scores (p = .05) at 90 days within the intervention group. The participants in the usual care group also reported increased total and physical QOL. Greater percentages of participants in the intervention group improved self reported exercise between 0 and 30 days (p = .005 and moderate effect size ES = .47) and foot care between 0 and 90 days (p = .03, small ES = .36). No group differences or improvements in DM-specific QOL were observed. An integrated HF-DM self-care intervention was effective in improving essential components of self-care and had sustained (90 day) effects on selected self-care behaviors. Future studies testing HF-DM integrated self-care interventions in larger samples with longer follow-up and on other outcomes such as hospitalization and clinical markers are warranted.

Hitting the (bio)mark part 1: selecting and measuring biomarkers in cardiovascular research.

Cardiovascular studies, including nursing research, frequently integrate biomarkers for diagnostic, prognostic, monitoring and therapeutic insights. However, effective utilization of biomarker data demands careful consideration. In the study design phase, researchers must select biomarkers that align with study objectives while considering resources and logistical factors. Additionally, a nuanced understanding of disease pathophysiology and biomarker characteristics is needed. During data collection, suitable experimental conditions and assays need to be defined. Whether researchers opt to manage these steps internally or outsource some, a comprehensive understanding of biomarker selection and experiments remains crucial. In this article, part 1 of 2, we provide an overview of considerations for the design to measurement phases of biomarker studies.

Hitting the (bio)mark part 2: analyzing, interpreting, and reporting biomarker data in cardiovascular research.

Incorporating biomarkers into cardiovascular studies, including nursing research, is a common approach when identifying underlying mechanisms and providing targets for intervention. However, effective utilization of biomarker data demands careful consideration. In the analysis, interpretation, and reporting phase, there are many facets to consider, including non-normality of the data, normalization procedures, and potential confounding influences of other clinical data. Furthermore, as many studies focus on patient-reported outcomes, it is important that the analysis and interpretation of biomarkers in relation to patient-reported outcomes is rigorous and reproducible. In this article, part 2 of 2, we provide an overview of considerations for the analysis, interpretation, and reporting phases of biomarker studies. We also provide an example of these steps.

Heart failure symptom burden, dietary intake, and inflammation: An integrative review of the literature.

Heart failure (HF) is characterized by high symptom burden including, but not limited to fatigue, dyspnea, and edema. Up to 21.5% of HF patients experience significant depressive symptoms, much higher than 7.1% in adults without HF. Diet, metabolites, and other inflammatory mechanisms have gained notable attention in recent studies for contributions to symptoms in HF. Symptoms for black adults (B/As) with HF are often influenced by lifestyle factors, which may influence their higher mortality rates; few studies address these factors. Distinguishing the links between key elements with diet, inflammation, and symptoms may bring clarity for new dietary strategies in HF clinical care. The purpose of this integrative review is to examine the existing literature regarding relationships among physiologic pathways in HF along with physical and emotional symptoms in the context of inflammation, dietary intake, tumor necrosis factor-alpha (TNF-α), a biomarker of inflammation, and trimethylamine-N-Oxide (TMAO). Based on available evidence, inflammation may be a key link between physical symptoms, diet, depression, TMAO, and TNF-α in persons with HF and warrants further examination to clarify pathological links to solidify evidence for better guidance with dietary modifications. The literature reviewed in this study demonstrates that more work is needed to examine dietary planning, social support, and differences between men and women in the B/A community. Results of this literature review call attention to the essential, personalized care needs related to symptom monitoring and dietary planning which is expected to decrease symptom burden in the HF population.

Intersectionality in Alzheimer's Disease: The Role of Female Sex and Black American Race in the Development and Prevalence of Alzheimer's Disease.

It is well known that vascular factors and specific social determinants of health contribute to dementia risk and that the prevalence of these risk factors differs according to race and sex. In this review, we discuss the intersection of sex and race, particularly female sex and Black American race. Women, particularly Black women, have been underrepresented in Alzheimer's disease clinical trials and research. However, in recent years, the number of women participating in clinical research has steadily increased. A greater prevalence of vascular risk factors such as hypertension and type 2 diabetes, coupled with unique social and environmental pressures, puts Black American women particularly at risk for the development of Alzheimer's disease and related dementias. Female sex hormones and the use of hormonal birth control may offer some protective benefits, but results are mixed, and studies do not consistently report the demographics of their samples. We argue that as a research community, greater efforts should be made to not only recruit this vulnerable population, but also report the demographic makeup of samples in research to better target those at greatest risk for the disease.

Impact of early pericardial fluid chymase activation after cardiac surgery.

Introduction: Chymase is a highly destructive serine protease rapidly neutralized in the circulation by protease inhibitors. Here we test whether pericardial fluid (PCF) chymase activation and other inflammatory biomarkers determine intensive care unit length of stay, and explore mechanisms of chymase delivery by extracellular vesicles to the heart. Methods: PCF was collected from adult patients (17 on-pump; 13 off-pump) 4 h after cardiac surgery. Extracellular vesicles (EVs) containing chymase were injected into Sprague-Dawley rats to test for their ability to deliver chymase to the heart. Results: The mean intensive care unit (ICU) stay and mean total length of stay was 2.17 ± 3.8 days and 6.41 ± 1.3 days respectively. Chymase activity and 32 inflammatory markers did not differ in on-pump vs. off-pump cardiac surgery. Society of Thoracic Surgeons Predicted Risk of Morbidity and Mortality Score (STS-PROM), 4-hour post-surgery PCF chymase activity and C-X-C motif chemokine ligand 6 (CXCL6) were all independent predictors of ICU and total hospital length of stay by univariate analysis. Mass spectrometry of baseline PCF shows the presence of serine protease inhibitors that neutralize chymase activity. The compartmentalization of chymase within and on the surface of PCF EVs was visualized by immunogold labeling and transmission electron microscopy. A chymase inhibitor prevented EV chymase activity (0.28 fmol/mg/min vs. 14.14 fmol/mg/min). Intravenous injection of PCF EVs obtained 24 h after surgery into Sprague Dawley rats shows diffuse human chymase uptake in the heart with extensive cardiomyocyte damage 4 h after injection. Discussion: Early postoperative PCF chymase activation underscores its potential role in cardiac damage soon after on- or off-pump cardiac surgery. In addition, chymase in extracellular vesicles provides a protected delivery mechanism from neutralization by circulating serine protease inhibitors.

Exercise and Cognitive Training Intervention Improves Self-Care, Quality of Life and Functional Capacity in Persons With Heart Failure.

This study evaluated a 12-week, home-based combined aerobic exercise (walking) and computerized cognitive training (EX/CCT) program on heart failure (HF) self-care behaviors (Self-care of HF Index [SCHFI]), disease specific quality of life (Kansas City Cardiomyopathy Questionnaire [KCCQ]), and functional capacity (6-minute walk distance) compared to exercise only (EX) or a usual care attention control (AC) stretching and flexibility program. Participants (N = 69) were older, predominately female (54%) and African American (55%). There was significant improvement in self-care management, F(2, 13) = 5.7, p < .016; KCCQ physical limitation subscale, F(2, 52) = 3.4, p < .039; and functional capacity (336 ± 18 vs 388 ± 20 m, p < .05) among the EX/CCT participants. The underlying mechanisms that EX and CCT targets and the optimal dose that leads to improved outcomes are needed to design effective interventions for this rapidly growing population.