Baseline pro-inflammatory gene expression in whole blood is related to adverse long-term outcomes after transcatheter aortic valve replacement: a case control study.

BACKGROUND: Age-associated inflammation and immune system dysfunction have been implicated as mechanisms that increase risk for adverse long-term procedural outcomes in older adults. The purpose of this study was to investigate relationships between baseline inflammatory and innate antiviral gene expression and outcomes after transcatheter aortic valve replacement (TAVR) in older adults with severe aortic stenosis. METHODS: We performed a retrospective case-control study comparing pre-procedural pro-inflammatory and Type 1 interferon (IFN) gene expression in 48 controls with favorable outcomes (alive 1 year after TAVR with improved quality of life [QoL]) versus 48 individuals with unfavorable outcomes (dead by 1 year or alive at 1 year but with reduced QoL). Gene expression was evaluated in whole blood via (1) pre-defined composite scores of 19 inflammation-associated genes and 34 Type I IFN response genes, and (2) pro-inflammatory and antiviral transcription factor activity inferred from promotor based bioinformatics analyses of genes showing > 25% difference in average expression levels across groups. All analyses were adjusted for age, gender, body mass index, diabetes, immunosuppression, cardiovascular disease (CVD), and frailty. RESULTS: Relative to controls, those with unfavorable outcomes demonstrated higher expression of the pro-inflammatory gene composite prior to TAVR (p < 0.01) and bioinformatic indicators of elevated Nuclear Factor kB (p < 0.001) and Activator Protein 1 (p < 0.001) transcription factor activity, but no significant differences in Type I IFN-related gene expression. CONCLUSIONS: These results demonstrate that a pro-inflammatory state prior to TAVR, independent of CVD severity and frailty status, is associated with worse long-term procedural outcomes.

Metformin Treatment in Old Rats and Effects on Mitochondrial Integrity.

Metformin, a commonly used well-tolerated treatment for type 2 diabetes, is being deployed in clinical trials to ameliorate aging in older nondiabetic humans. Concerningly, some experiments in model organisms have suggested that metformin use at old ages shortens life span and is toxic to mitochondria. The demonstrated safety of metformin therapy in humans and the conflicting data from model organisms compelled us to test the hypothesis that metformin treatment would be toxic to older rats. To define an effective dose in 30-month-old hybrid rats, we evaluated two doses of metformin (0.1%, 0.75% of the diet) and treated the rats for 4 months. Body mass decreased at the 0.75% dose. Neither dose affected mortality between 30 and 34 months of age. We assessed mitochondrial integrity by measuring mitochondrial DNA (mtDNA) copy number and deletion mutation frequency, and mitochondrial respiration in skeletal muscle and the heart. In skeletal muscle, we observed no effect of metformin on quadriceps mass, mtDNA copy number, or deletion frequency. In the heart, metformin-treated rats had higher mtDNA copy number, lower cardiac mass, with no change in mtDNA deletion frequency. Metformin treatment resulted in lower mitochondrial complex I-dependent respiration in the heart. We found that, in old rats, metformin did not compromise mtDNA integrity, did not affect mortality, and may have cardiac benefits. These data provide some reassurance that a metformin intervention in aged mammals is not toxic at appropriate doses.

Perspectives on Implementing a Multidomain Approach to Caring for Older Adults With Heart Failure.

BACKGROUND/OBJECTIVES: The American College of Cardiology (ACC) Geriatric Cardiology Section Leadership Council recently outlined 4 key domains (which are composed of 14 subdomains) that are important to assess in older adults with heart failure (HF). We sought to determine which geriatric domains/subdomains are routinely assessed, how they are assessed, and how they impact clinical management in the care of ambulatory older adults with HF. DESIGN: Survey. SETTING: Ambulatory. PARTICIPANTS: Fifteen active ACC member physicians from the geriatric cardiology community. MEASUREMENTS: Electronic survey assessing which domains/subdomains are currently assessed in these selected real-world practices, how they are assessed, and how they are incorporated into clinical management. RESULTS: Of 15 clinicians, 14 responded to the survey. The majority routinely assess 3 to 4 domains (median, 3; interquartile range, 3-4) and a range of 4 to 12 subdomains (median, 8; interquartile range, 6-11). All respondents routinely assess the medical and physical function domains, 71% routinely assess the mind/emotion domain, and 50% routinely assess the social domain. The most common subdomains included comorbidity burden (100%), polypharmacy (100%), basic function (93%), mobility (86%), falls risk (71%), frailty (64%), and cognition (57%). Sensory impairment (50%), social isolation (50%), nutritional status (43%), loneliness (7%), and financial means (7%) were least frequently assessed. There was significant heterogeneity with regard to the tools used to assess subdomains. Common themes for how the subdomains influenced clinical care included informing prognosis, informing risk-benefit of pharmacologic therapy and invasive procedures, and consideration for palliative care. CONCLUSIONS: While respondents routinely assess multiple domains and subdomains and view these as important to clinical care, there is substantial heterogeneity regarding which subdomains are assessed and the tools used to assess them. These observations provide a foundation that inform a research agenda with regard to providing holistic and patient-centered care to older adults with HF. J Am Geriatr Soc 67:2593-2599, 2019.

Is Posthospital Syndrome a Result of Hospitalization-Induced Allostatic Overload?

After discharge from the hospital, patients face a transient period of generalized susceptibility to disease as well as an elevated risk for adverse events, including hospital readmission and death. The term posthospital syndrome (PHS) has been used to describe this time of enhanced vulnerability. Based on data from bench to bedside, this narrative review examines the hypothesis that hospitalrelated allostatic overload is a plausible etiology of PHS. Resulting from extended exposure to stress, allostatic overload is a maladaptive state driven by overuse and dysregulation of the hypothalamic-pituitary-adrenal axis and the autonomic nervous system that ultimately generates pathophysiologic consequences to multiple organ systems. Markers of allostatic overload, including elevated levels of cortisol, catecholamines, and inflammatory markers, have been associated with adverse outcomes after hospital discharge. Based on the evidence, we suggest a possible mechanism for postdischarge vulnerability, encourage critical contemplation of traditional hospital environments, and suggest interventions that might improve outcomes.

Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting.

Stressful life events have been implicated clinically in the pathogenesis of mental illness, but the neural substrates that may account for this observation remain poorly understood. Attentional impairments symptomatic of these psychiatric conditions are associated with structural and functional abnormalities in a network of prefrontal cortical structures. Here, we examine whether chronic stress-induced dendritic alterations in the medial prefrontal cortex (mPFC) and orbital frontal cortex (OFC) underlie impairments in the behaviors that they subserve. After 21 d of repeated restraint stress, rats were tested on a perceptual attentional set-shifting task, which yields dissociable measures of reversal learning and attentional set-shifting, functions that are mediated by the OFC and mPFC, respectively. Intracellular iontophoretic injections of Lucifer yellow were performed in a subset of these rats to examine dendritic morphology in layer II/III pyramidal cells of the mPFC and lateral OFC. Chronic stress induced a selective impairment in attentional set-shifting and a corresponding retraction (20%) of apical dendritic arbors in the mPFC. In stressed rats, but not in controls, decreased dendritic arborization in the mPFC predicted impaired attentional set-shifting performance. In contrast, stress was not found to adversely affect reversal learning or dendritic morphology in the lateral OFC. Instead, apical dendritic arborization in the OFC was increased by 43%. This study provides the first direct evidence that dendritic remodeling in the prefrontal cortex may underlie the functional deficits in attentional control that are symptomatic of stress-related mental illnesses.

Frailty in Advanced Heart Failure: A Consequence of Aging or a Separate Entity?

There are over 5 million Americans with heart failure (HF), the majority of whom are over age 65. Frailty is a systemic syndrome associated with aging that produces subclinical dysfunction across multiple organ systems and leads to an increased risk for morbidity and mortality. The prevalence of frailty is about 10% in community-dwelling elderly and 20% in those with advanced HF, and increases in both cohorts with age. Yet the relationship between the primary frailty of aging and frailty secondary to HF remains poorly defined. Whether the frailty of these two populations share similar etiologies or exist as separate entities is unknown. Teasing apart potential molecular, cellular, and functional differences between the frailty of aging and that of advanced HF has implications for risk stratification, quality of life, and pharmacological and therapeutic interventions for advanced HF patients.