Is the peripheral microcirculation a window into the human coronary microvasculature?

An increasing body of evidence suggests a pivotal role for the microvasculature in the development of cardiovascular disease. A dysfunctional coronary microvascular network, specifically within endothelial cells-the inner most cell layer of vessels-is considered a strong, independent risk factor for future major adverse cardiac events. However, challenges exist with evaluating this critical vascular bed, as many of the currently available techniques are highly invasive and cost prohibitive. The more easily accessible peripheral microcirculation has surfaced as a potential surrogate in which to study mechanisms of coronary microvascular dysfunction and likewise may be used to predict poor cardiovascular outcomes. In this review, we critically evaluate a variety of prognostic, physiological, and mechanistic studies in humans to answer whether the peripheral microcirculation can add insight into coronary microvascular health. A conceptual framework is proposed that the health of the endothelium specifically may link the coronary and peripheral microvascular beds. This is supported by evidence showing a correlation between human coronary and peripheral endothelial function in vivo. Although not a replacement for investigating and understanding coronary microvascular function, the microvascular endothelium from the periphery responds similarly to (patho)physiological stress and may be leveraged to explore potential therapeutic pathways to mitigate stress-induced damage.

Role of Adiponectin Receptor 1 in Promoting Nitric Oxide-Mediated Flow-Induced Dilation in the Human Microvasculature.

Chronic administration of exogenous adiponectin restores nitric oxide (NO) as the mediator of flow-induced dilation (FID) in arterioles collected from patients with coronary artery disease (CAD). Here we hypothesize that this effect as well as NO signaling during flow during health relies on activation of Adiponectin Receptor 1 (AdipoR1). We further posit that osmotin, a plant-derived protein and AdipoR1 activator, is capable of eliciting similar effects as adiponectin. Human arterioles (80-200 µm) collected from discarded surgical adipose specimens were cannulated, pressurized, and pre-constricted with endothelin-1 (ET-1). Changes in vessel internal diameters were measured during flow using videomicroscopy. Immunofluorescence was utilized to compare expression of AdipoR1 during both health and disease. Administration of exogenous adiponectin failed to restore NO-mediated FID in CAD arterioles treated with siRNA against AdipoR1 (siAdipoR1), compared to vessels treated with negative control siRNA. Osmotin treatment of arterioles from patients with CAD resulted in a partial restoration of NO as the mediator of FID, which was inhibited in arterioles with decreased expression of AdipoR1. Together these data highlight the critical role of AdipoR1 in adiponectin-induced NO signaling during shear. Further, osmotin may serve as a potential therapy to prevent microvascular endothelial dysfunction as well as restore endothelial homeostasis in patients with cardiovascular disease.

Vascular endothelial adiponectin signaling across the life span.

Cardiovascular disease risk increases with age regardless of sex. Some of this risk is attributable to alterations in natural hormones throughout the life span. The quintessential example of this being the dramatic increase in cardiovascular disease following the transition to menopause. Plasma levels of adiponectin, a "cardioprotective" adipokine released primarily by adipose tissue and regulated by hormones, also fluctuate throughout one's life. Plasma adiponectin levels increase with age in both men and women, with higher levels in both pre- and postmenopausal women compared with men. Younger cohorts seem to confer cardioprotective benefits from increased adiponectin levels yet elevated levels in the elderly and those with existing heart disease are associated with poor cardiovascular outcomes. Here, we review the most recent data regarding adiponectin signaling in the vasculature, highlight the differences observed between the sexes, and shed light on the apparent paradox regarding increased cardiovascular disease risk despite rising plasma adiponectin levels over time.

COVID-19 and science advice on the 'Grand Stage': the metadata and linguistic choices in a scientific advisory groups' meeting minutes.

Science advice for governments attracted great scrutiny during the COVID-19 pandemic, with the public spotlight on institutions and individual experts-putting science advice on the 'Grand Stage'. A review of the academic literature identified transparency, a plurality of expertise, the science and policy 'boundary', and consensus whilst addressing uncertainty as key themes. The Scientific Advisory Group for Emergencies (SAGE) has been the primary provider of coordinated scientific and technical advice to the UK Government during emergencies since 2009. Using the first 89 of SAGE's meeting minutes (study period: 22 January 2020-13 May 2021), the 'metadata' and linguistic choices are analysed to identify how SAGE's role and protocols are communicated. This includes understanding which experts were regularly taking part in discussions, the role of scientific experts in the science advisory system and their influence on policy choices, and the degree of consensus and uncertainty within this group of experts-all of which relate to the degree of transparency with the public. In addition, a temporal analysis examines how these practices, such as linguistically marking uncertainty, developed over the period studied. Linguistic markers indexing certainty and uncertainty increased, demonstrating a commitment to precise and accurate communication of the science, including ambiguities and the unknown. However, self-references to SAGE decreased over the period studied. The study highlights how linguistic analysis can be a useful approach for developing an understanding of science communication practices and scientific ambiguity. By considering how SAGE presents to those outside the process, the research calls attention to what remains 'behind the scenes' and consequently limits the public's understanding of SAGE's role in the COVID-19 response.

Sweat the small stuff: The human microvasculature and heart disease.

Traditionally thought of primarily as the predominant regulator of myocardial perfusion, it is becoming more accepted that the human coronary microvasculature also exerts a more direct influence on the surrounding myocardium. Coronary microvascular dysfunction (CMD) not only precedes large artery atherosclerosis, but is associated with other cardiovascular diseases such as heart failure with preserved ejection fraction and hypertrophic cardiomyopathy. It is also highly predictive of cardiovascular events in patients with or without atherosclerotic cardiovascular disease. This review focuses on this recent paradigm shift and delves into the clinical consequences of CMD. Concepts of how resistance arterioles contribute to disease will be discussed, highlighting how the microvasculature may serve as a potential target for novel therapies and interventions. Finally, both invasive and non-invasive methods with which to assess the coronary microvasculature both for diagnostic and risk stratification purposes will be reviewed.

Crossing signals: bioactive lipids in the microvasculature.

The primary function of the arterial microvasculature is to ensure that regional perfusion of blood flow is matched to the needs of the tissue bed. This critical physiological mechanism is tightly controlled and regulated by a variety of vasoactive compounds that are generated and released from the vascular endothelium. Although these substances are required for modulating vascular tone, they also influence the surrounding tissue and have an overall effect on vascular, as well as parenchymal, homeostasis. Bioactive lipids, fatty acid derivatives that exert their effects through signaling pathways, are included in the list of vasoactive compounds that modulate the microvasculature. Although lipids were identified as important vascular messengers over three decades ago, their specific role within the microvascular system is not well defined. Thorough understanding of these pathways and their regulation is not only essential to gain insight into their role in cardiovascular disease but is also important for preventing vascular dysfunction following cancer treatment, a rapidly growing problem in medical oncology. The purpose of this review is to discuss how biologically active lipids, specifically prostanoids, epoxyeicosatrienoic acids, sphingolipids, and lysophospholipids, contribute to vascular function and signaling within the endothelium. Methods for quantifying lipids will be briefly discussed, followed by an overview of the various lipid families. The cross talk in signaling between classes of lipids will be discussed in the context of vascular disease. Finally, the potential clinical implications of these lipid families will be highlighted.

Strengthening and Expanding Child Services in Low Resource Communities: The Role of Task-Shifting and Just-in-Time Training.

In the United States, the demand for child mental health services is increasing, while the supply is limited by workforce shortages. These shortages are unlikely to be corrected without significant structural changes in how mental health services are provided. One strategy for bridging this gap is task-shifting, defined as a process by which services that are typically delivered by professionals are moved to individuals with less extensive qualifications or training. Although task-shifting can increase the size of the workforce, there are challenges related to training new workers. In this paper, we propose Just-In-Time Training (JITT) as one strategy for improving task-shifting efforts. We define JITT as on-demand training experiences that only include what is necessary, when it is necessary, to promote competent service delivery. We offer a proof of concept from our own work shifting counseling and academic support tasks from school mental health professionals to pre-baccalaureate mentors, citing lessons learned during our iterative process of JITT development. We conclude with a series of key considerations for scaling up the pairing of task-shifting and JITT, including expanding the science of JITT and anticipating how task-shifting and JITT would work within the context of dynamic mental health service systems.

Pediatric Skin Failure.

BACKGROUND: The phenomenon of skin failure as distinct from pressure ulcers has been documented in the adult literature. However, in the pediatric population, skin injury continues to be grouped indiscriminately as various types of pressure ulcers. OBJECTIVE: To identify and describe the phenomenon of skin failure in critically ill children. METHODS: Retrospective chart review of 19 patients who had serious skin injuries develop. Organ dysfunction scores, medications, pressure ulcer prevention techniques used, and laboratory values in the 7 days leading up to the development of a skin lesion were evaluated. RESULTS: At the start of the evaluation period, all patients (N = 19) had pressure ulcer prevention measures in place before the development of a serious skin injury. All of the skin lesions were full-thickness injuries on the day they were identified (as opposed to the more gradual progression from simple to complex skin injuries typically seen in pressure ulcers). As predicted, 18 of 19 patients had multiple organ dysfunction syndrome (MODS) in the week leading up to the skin injury. All patients with MODS had at least 2 dysfunctional systems, and 12 patients had 4 or more dysfunctional systems. Of the 19 patients, 8 (42%) progressed to death, compared with 1.8% in our general pediatric intensive care unit population. CONCLUSION: Although the traditional paradigm is that pressure ulcers are preventable, a subset of pressure ulcers in critically ill children may actually represent acute skin failure as a consequence of MODS.

Forced vital capacity predicts morbidity and mortality in adults with repaired tetralogy of Fallot.

OBJECTIVE: Abnormal lung function characterized by a reduced forced vital capacity (FVC) is common in adults with repaired tetralogy of Fallot (TOF) and is associated with previous thoracotomies and sternotomies. The impact of abnormal lung function on clinical outcomes in adult patients with repaired TOF is unclear. The aim of this study was to determine the impact of abnormal lung function on the outcome of hospitalization and death in adults with repaired TOF when analyzed with other traditional cardiac risk factors. DESIGN: Retrospective study of adults with repaired TOF, who underwent spirometry between 2000 and 2014. FVC < 60% of predicted was categorized as moderate-to-severely reduced lung function. Primary outcome measure was the combined clinical endpoint of death, cardiac transplantation, or nonelective hospitalization for primary cardiac or respiratory indication. RESULTS: A total of 122 patients were included. Average age at spirometry testing was 31 ± 10.1 years. FVC was < 60% predicted in 23 (19%) patients. During a mean follow-up period of 3.97 ± 2.65 years, 23 (19%) patients reached the combined clinical outcome of nonelective hospitalization and/or death. FVC < 60% predicted was independently associated with the risk for the combined clinical outcome (RR 6.68 (95% CI 2.49-17.94), P < .001). CONCLUSIONS: Abnormal pulmonary function characterized by reduced FVC is common in adults with repaired TOF. Patients with FVC < 60% predicted had a 6 times higher rate of hospitalization and/or death compared to those with FVC ≥ 60%.

Impact of prenatal diagnosis in survivors of initial palliation of single ventricle heart disease: analysis of the National Pediatric Cardiology Quality Improvement Collaborative database.

Among infants with single ventricle congenital heart disease (SVD) requiring Stage I palliation (S1P), the impact of prenatal diagnosis (PD) on outcomes has been variably characterized. We investigated the impact of PD in a large multi-center cohort of survivors of S1P in the National Pediatric Cardiology Quality Improvement Collaborative (NPCQIC) registry. Retrospective analysis of demographic and outcomes data among infants enrolled in the NPCQIC database; eligibility includes SVD requiring S1P and survival to discharge. From 43 contributing surgical centers, 591 infants had data available through time of BDG (519) or interstage death (55). Median gestational age was 39 weeks (31-46), and 66% had variants of hypoplastic left heart syndrome. PD was made in 445 (75%), with significant variation by center (p = 0.004). While infants with PD had slightly lower gestational age at birth (p < 0.001), there were no differences in birth weight, the presence of major syndromes or other organ system anomalies. Those without PD were more likely to have atrioventricular valve regurgitation (p = .002), ventricular dysfunction (p = 0.06), and pre-operative risk factors including acidosis (p < 0.001), renal insufficiency (p = 0.007), and shock (p = 0.05). Post-operative ventilation was shorter in the PD group (9 vs. 12 d, p = 0.002). Other early post-operative outcomes, interstage course, and outcomes at BDG were similar between groups. In a large cohort of infants with SVD surviving to hospital discharge after S1P, PD showed significant inter-site variation and was associated with improved pre-operative status and shorter duration of mechanical ventilation. The significance of such associations merits further study.