Assessment and Management of Atrial Fibrillation in Older Adults with Frailty.

Atrial fibrillation (AF) is a major driver of morbidity and mortality among older adults with frailty. Moreover, frailty is highly prevalent in older adults with AF. Understanding and addressing the needs of frail older adults with AF is imperative to guide clinicians caring for older adults. In this review, we summarize current evidence to support the assessment and management of older adults with AF and frailty, incorporating numerous recent landmark trials and studies in the context of the 2023 US AF guideline.

Impact of ovary-intact menopause in a mouse model of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) afflicts over half of all patients with heart failure and is a debilitating and fatal syndrome affecting postmenopausal women more than any other demographic. This bias toward older females calls into question the significance of menopause in the development of HFpEF, but this question has not been probed in detail. In this study, we report the first investigation into the impact of ovary-intact menopause in the context of HFpEF. To replicate the human condition as faithfully as possible, vinylcyclohexene dioxide (VCD) was used to accelerate ovarian failure (AOF) in female mice while leaving the ovaries intact. HFpEF was established with a mouse model that involves two stressors typical in humans: a high-fat diet and hypertension induced from the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME). In young female mice, AOF or HFpEF-associated stressors independently induced abnormal myocardial strain indicative of early subclinical systolic and diastolic cardiac dysfunction. HFpEF but not AOF was associated with elevations in systolic blood pressure. Increased myocyte size and reduced myocardial microvascular density were not observed in any group. Also, a broad panel of measurements that included echocardiography, invasive pressure measurements, histology, and serum hormones revealed no interaction between AOF and HFpEF. Interestingly, AOF did evoke a higher density of infiltrating cardiac immune cells in both healthy and HFpEF mice, suggestive of proinflammatory effects. In contrast to young mice, middle-aged "old" mice did not exhibit cardiac dysfunction from estrogen deprivation alone or from HFpEF-related stressors.NEW & NOTEWORTHY This is the first preclinical study to examine the impact of ovary-intact menopause [accelerated ovarian failure (AOF)] on HFpEF. Echocardiography of young female mice revealed early evidence of diastolic and systolic cardiac dysfunction apparent only on strain imaging in HFpEF only, AOF only, or the combination. Surprisingly, AOF did not exacerbate the HFpEF phenotype. Results in middle-aged "old" females also showed no interaction between HFpEF and AOF and, importantly, no cardiovascular impact from HFpEF or AOF.

Histopathology of the Mitral Valve Residual Leaflet in Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: Mitral valve (MV) elongation is a primary hypertrophic cardiomyopathy (HCM) phenotype and contributes to obstruction. The residual MV leaflet that protrudes past the coaptation point is especially susceptible to flow-drag and systolic anterior motion. Histopathological features of MVs in obstructive hypertrophic cardiomyopathy (OHCM), and of residual leaflets specifically, are unknown. OBJECTIVES: The purpose of this study was to characterize gross, structural, and cellular histopathologic features of MV residual leaflets in OHCM. On a cellular-level, we assessed for developmental dysregulation of epicardium-derived cell (EPDC) differentiation, adaptive endocardial-to-mesenchymal transition and valvular interstitial cell proliferation, and genetically-driven persistence of cardiomyocytes in the valve. METHODS: Structural and immunohistochemical staining were performed on 22 residual leaflets excised as ancillary procedures during myectomy, and compared with 11 control leaflets from deceased patients with normal hearts. Structural components were assessed with hematoxylin and eosin, trichrome, and elastic stains. We stained for EPDCs, EPDC paracrine signaling, valvular interstitial cells, endocardial-to-mesenchymal transition, and cardiomyocytes. RESULTS: The residual leaflet was always at A2 segment and attached by slack, elongated and curlicued, myxoid chords. MV residual leaflets in OHCM were structurally disorganized, with expanded spongiosa and increased, fragmented elastic fibers compared with control leading edges. The internal collagenous fibrosa was attenuated and there was collagenous tissue overlying valve surfaces in HCM, with an overall trend toward decreased leaflet thickness (1.09 vs 1.47 mm, P = 0.08). No markers of primary cellular processes were identified. CONCLUSIONS: MV residual leaflets in HCM were characterized by histologic findings that were likely secondary to chronic hemodynamic stress and may further increase susceptibility to systolic anterior motion.

Initiation of oral anticoagulation in US older adults newly diagnosed with atrial fibrillation during hospitalization.

BACKGROUND: Atrial fibrillation is a common cause of stroke among older adults and is often first detected during hospitalization, given frequent use of cardiac telemetry. METHODS: In a 20% national sample of Medicare fee-for-service beneficiaries, we identified patients aged 65-or-older newly diagnosed with atrial fibrillation while hospitalized in 2016. Our primary outcome was an oral anticoagulant claim within 7-days of discharge. Multivariable logistic regression analyses assessed relationships between anticoagulation initiation and thromboembolic and bleeding risk scores while controlling for demographics, frailty, comorbidities, and hospitalization characteristics. RESULTS: Among 38,379 older adults newly diagnosed with atrial fibrillation while hospitalized (mean age 78.2 [SD 8.4]; 51.8% female; 83.3% white), 36,633 (95.4%) had an indication for anticoagulation and 24.6% (9011) of those initiated an oral anticoagulant following discharge. Higher CHA2 DS2 -VASc score was associated with a small increase in oral anticoagulant initiation (predicted probability 20.5% [95% CI, 18.7%-22.3%] for scores <2 and 24.9% [CI, 24.4%-25.4%] for ≥4). Elevated HAS-BLED score was associated with a small decrease in probability of anticoagulant initiation (25.4% [CI, 24.4%-26.4%] for score <2 and 23.1% [CI, 22.5%-23.8%] for ≥3). Frailty was associated with decreased likelihood of oral anticoagulant initiation (24.7% [CI, 23.2%-26.2%] for non-frail and 18.1% [CI, 16.6%-19.6%] for moderately-severely frail). Anticoagulant initiation varied by primary reason for hospitalization, with predicted probability highest among patients with a primary diagnosis of atrial fibrillation (46.1% [CI, 45.0%-47.3%]) and lowest among those with non-cardiovascular conditions (13.8% [CI, 13.3%-14.3%]) and bleeds (3.6% [CI, 2.4%-4.8%]). CONCLUSIONS: Oral anticoagulant initiation is uncommon among older adults newly diagnosed with atrial fibrillation during hospitalization, even among patients hospitalized primarily for atrial fibrillation and patients with high thromboembolic risk. Clinicians should discuss risks and benefits of oral anticoagulants with all inpatients found to have atrial fibrillation.

Human microvascular reactivity: a review of vasomodulating stimuli and non-invasive imaging assessment.

The microvasculature serves an imperative function in regulating perfusion and nutrient exchange throughout the body, adaptively altering blood flow to preserve hemodynamic and metabolic homeostasis. Its normal functioning is vital to tissue health, whereas its dysfunction is present in many chronic conditions, including diabetes, heart disease, and cognitive decline. As microvascular dysfunction often appears early in disease progression, its detection can offer early diagnostic information. To detect microvascular dysfunction, one uses imaging to probe the microvasculature's ability to react to a stimulus, also known as microvascular reactivity (MVR). An assessment of MVR requires an integrated understanding of vascular physiology, techniques for stimulating reactivity, and available imaging methods to capture the dynamic response. Practical considerations, including compatibility between the selected stimulus and imaging approach, likewise require attention. In this review, we provide a comprehensive foundation necessary for informed imaging of MVR, with a particular focus on the challenging endeavor of assessing microvascular function in deep tissues.

National Trends in Use of and Spending on Oral Anticoagulants Among US Medicare Beneficiaries From 2011 to 2019.

This cross-sectional study examines patterns of use of direct oral anticoagulants and their association with Medicare spending.

Development of a Conceptual Map of Negative Consequences for Patients of Overuse of Medical Tests and Treatments.

Importance: Overuse of medical tests and treatments is an increasingly recognized problem across health systems; best practices for reducing overuse are not clear. Framing the problem in terms of the spectrum of potential patient harm is likely to be an effective strategy for clinician and patient engagement in efforts to reduce overuse, but the scope of negative consequences of overuse for patients has not been well described. Observations: We sought to generate a comprehensive conceptual map documenting the processes through which overused tests and treatments lead to multiple domains of negative consequences for patients. For map development, an iterative consensus process was informed by structured review of the literature on overuse using PubMed and input from a panel of 6 international experts. For map verification, a systematic review was performed of case reports involving overused services, identified through literature review and manual review of relevant article collections. The conceptual map documents that overused tests and treatments and resultant downstream services generate 6 domains of negative consequences for patients: physical, psychological, social, financial, treatment burden, and dissatisfaction with health care. Negative consequences can result from overused services and from downstream services; they can also trigger further downstream services that in turn can lead to more negative consequences, in an ongoing feedback loop. Case reports on overuse confirmed the processes and domains of the conceptual map. Cases also revealed strengths and weaknesses in published communication about overuse: they were dominated by physical harms, with other negative consequences receiving far less attention. Conclusions and Relevance: This evidence-based conceptual map clarifies the processes by which overused tests and treatments result in negative consequences for patients; it also documents multiple domains of negative consequences experienced by patients. The map will be useful for facilitating comprehensive communication about overuse, estimating harms and costs associated with overused services, and informing health system efforts to reduce overuse.

Human adipose cells in vitro are either refractory or responsive to insulin, reflecting host metabolic state.

While intercellular communication processes are frequently characterized by switch-like transitions, the endocrine system, including the adipose tissue response to insulin, has been characterized by graded responses. Yet here individual cells from adipose tissue biopsies are best described by a switch-like transition between the basal and insulin-stimulated states for the trafficking of the glucose transporter GLUT4. Two statistically-defined populations best describe the observed cellular heterogeneity, representing the fractions of refractive and responsive adipose cells. Furthermore, subjects exhibiting high systemic insulin sensitivity indices (SI) have high fractions of responsive adipose cells in vitro, while subjects exhibiting decreasing SI have increasing fractions of refractory cells in vitro. Thus, a two-component model best describes the relationship between cellular refractory fraction and subject SI. Since isolated cells exhibit these different response characteristics in the presence of constant culture conditions and milieu, we suggest that a physiological switching mechanism at the adipose cellular level ultimately drives systemic SI.

Insulin regulates Glut4 confinement in plasma membrane clusters in adipose cells.

Insulin-stimulated delivery of glucose transporter-4 (GLUT4) to the plasma membrane (PM) is the hallmark of glucose metabolism. In this study we examined insulin's effects on GLUT4 organization in PM of adipose cells by direct microscopic observation of single monomers tagged with photoswitchable fluorescent protein. In the basal state, after exocytotic delivery only a fraction of GLUT4 is dispersed into the PM as monomers, while most of the GLUT4 stays at the site of fusion and forms elongated clusters (60-240 nm). GLUT4 monomers outside clusters diffuse freely and do not aggregate with other monomers. In contrast, GLUT4 molecule collision with an existing cluster can lead to immediate confinement and association with that cluster. Insulin has three effects: it shifts the fraction of dispersed GLUT4 upon delivery, it augments the dissociation of GLUT4 monomers from clusters ∼3-fold and it decreases the rate of endocytic uptake. All together these three effects of insulin shift most of the PM GLUT4 from clustered to dispersed states. GLUT4 confinement in clusters represents a novel kinetic mechanism for insulin regulation of glucose homeostasis.