Review of “Fort Henry: An Illustrated History” by Steve Mecredy

Review of Fort Henry: An Illustrated History by Steve Mecred

The Special Council of Lower Canada and the Origin of Canadian Sovereignty

Turning to Agamben’s notion of the decision of the “state of exception” as the fundamental act of the sovereign, this article traces the origin of Canadian sovereignty through a legal history of the suspension of habeas corpus in Lower Canada. Building both on the work of Canadianists engaging the political and legal theory of Giorgio Agamben and the work of Canadian historians on the Special Council of Lower Canada, this article demonstrates how Governor Colborne’s declaration of martial law in response to the 1837-1838 rebellions in Lower Canada reveals the genesis-moment of Canadian sovereignty. This historical contextualization of the Special Council fills an important gap in the historiography of the Council, as well as the continental approaches to applied theory in Canadian political science

Neotectonics of the Western Nepal Fault System: Implications for Himalayan strain partitioning

Oblique convergence at the Himalayan margin is hypothesized to be partitioned by orogen-normal thrusting and orogen-parallel strike-slip faulting. We conducted field mapping and remote sensing in the Dhaulagiri Range of Nepal, and the results reveal an active regional fault system termed the Western Nepal Fault System (WNFS). Right and normally offset Quaternary deposits and brittly deformed bedrock demarcate dextral slip along two strike-slip faults striking N40–50°W linked via an extensional right step over striking N10–20°E. The strike-slip attitudes subparallel bedrock foliation, while the step over cuts at a high angle (~70°). Fault slip data along the strike-slip segments trend N70°W with minor dip component, top to north. Fault slip data and observed kinematics along the WNFS support our interpretation that the WNFS formed via arc-parallel stress. On the basis of geometry, kinematics, and structural position we correlate the WNFS to active faults between the Karakoram and Bari Gad faults. This suggests an ~350 km long dextral fault system extending obliquely across the Western Nepal Himalaya which appears to intersect the Main Frontal Thrust (MFT) near 83°30′E, coinciding with a large gradient in the arc-parallel component of GPS velocities. We interpret the WNFS to represent a class of orogen-parallel strike-slip faults working with subduction to accommodate obliquely convergent plate motion. Our observations support the hypothesis that the region lying between the MFT and the WNFS is a continental version of a fore-arc sliver bounded at its base by the Main Himalayan Thrust

Reactive oxygen species induce virus-independent MAVS-oligomerization in systemic lupus erythematosus

The increased expression of genes induced by type I interferon (IFN) is characteristic of viral infections and systemic lupus erythematosus (SLE). We showed that mitochondrial antiviral signaling (MAVS) protein, which normally forms a complex with retinoic acid gene I (RIG-I)–like helicases during viral infection, was activated by oxidative stress independently of RIG-I helicases. We found that chemically generated oxidative stress stimulated the formation of MAVS oligomers, which led to mitochondrial hyperpolarization and decreased adenosine triphosphate production and spare respiratory capacity, responses that were not observed in similarly treated cells lacking MAVS. Peripheral blood lymphocytes of SLE patients also showed spontaneous MAVS oligomerization that correlated with the increased secretion of type I IFN and mitochondrial oxidative stress. Furthermore, inhibition of mitochondrial reactive oxygen species (ROS) by the mitochondria-targeted antioxidant MitoQ prevented MAVS oligomerization and type I IFN production. ROS-dependent MAVS oligomerization and type I IFN production were reduced in cells expressing the MAVS-C79F variant, which occurs in 30% of sub-Saharan Africans and is linked with reduced type I IFN secretion and milder disease in SLE patients. Patients expressing the MAVS-C79F variant also had reduced amounts of oligomerized MAVS in their plasma compared to healthy controls. Together, our findings suggest that oxidative stress–induced MAVS oligomerization in SLE patients may contribute to the type I IFN signature that is characteristic of this syndrome

Selective superoxide generation within mitochondria by the targeted redox cycler MitoParaquat

Superoxide is the proximal reactive oxygen species (ROS) produced by the mitochondrial respiratory chain and plays a major role in pathological oxidative stress and redox signaling. While there are tools to detect or decrease mitochondrial superoxide, none can rapidly and specifically increase superoxide production within the mitochondrial matrix. This lack impedes progress, making it challenging to assess accurately the roles of mitochondrial superoxide in cells and in vivo. To address this unmet need, we synthesized and characterized a mitochondria-targeted redox cycler, MitoParaquat (MitoPQ) that comprises a triphenylphosphonium lipophilic cation conjugated to the redox cycler paraquat. MitoPQ accumulates selectively in the mitochondrial matrix driven by the membrane potential. Within the matrix, MitoPQ produces superoxide by redox cycling at the flavin site of complex I, selectively increasing superoxide production within mitochondria. MitoPQ increased mitochondrial superoxide in isolated mitochondria and cells in culture ~a thousand-fold more effectively than untargeted paraquat. MitoPQ was also more toxic than paraquat in the isolated perfused heart and in Drosophila in vivo. MitoPQ enables the selective generation of superoxide within mitochondria and is a useful tool to investigate the many roles of mitochondrial superoxide in pathology and redox signaling in cells and in vivo

Noninvasive Biomarkers for Cardiovascular Dysfunction Programmed in Male Offspring of Adverse Pregnancy.

[Figure: see text]

Endogenous Transmembrane TNF-Alpha Protects Against Premature Senescence in Endothelial Colony Forming Cells

RATIONALE: Transmembrane tumor necrosis factor-α (tmTNF-α) is the prime ligand for TNF receptor 2, which has been shown to mediate angiogenic and blood vessel repair activities in mice. We have previously reported that the angiogenic potential of highly proliferative endothelial colony-forming cells (ECFCs) can be explained by the absence of senescent cells, which in mature endothelial cells occupy >30% of the population, and that exposure to a chronic inflammatory environment induced premature, telomere-independent senescence in ECFCs. OBJECTIVE: The goal of this study was to determine the role of tmTNF-α in the proliferation of ECFCs. METHODS AND RESULTS: Here, we show that tmTNF-α expression on ECFCs selects for higher proliferative potential and when removed from the cell surface promotes ECFC senescence. Moreover, the induction of premature senescence by chronic inflammatory conditions is blocked by inhibition of tmTNF-α cleavage. Indeed, the mechanism of chronic inflammation-induced premature senescence involves an abrogation of tmTNF/TNF receptor 2 signaling. This process is mediated by activation of the tmTNF cleavage metalloprotease TNF-α-converting enzyme via p38 MAP kinase activation and its concurrent export to the cell surface by means of increased iRhom2 expression. CONCLUSIONS: Thus, we conclude that tmTNF-α on the surface of highly proliferative ECFCs plays an important role in the regulation of their proliferative capacity

Targeting mitochondrial fitness as a strategy for healthy vascular aging.

Cardiovascular diseases (CVD) are the leading cause of death worldwide and aging is the primary risk factor for CVD. The development of vascular dysfunction, including endothelial dysfunction and stiffening of the large elastic arteries (i.e., the aorta and carotid arteries), contribute importantly to the age-related increase in CVD risk. Vascular aging is driven in large part by oxidative stress, which reduces bioavailability of nitric oxide and promotes alterations in the extracellular matrix. A key upstream driver of vascular oxidative stress is age-associated mitochondrial dysfunction. This review will focus on vascular mitochondria, mitochondrial dysregulation and mitochondrial reactive oxygen species (ROS) production and discuss current evidence for prevention and treatment of vascular aging via lifestyle and pharmacological strategies that improve mitochondrial health. We will also identify promising areas and important considerations ('research gaps') for future investigation.REVIEW ARTICLE| JUNE 25 2020 Targeting mitochondrial fitness as a strategy for healthy vascular aging Matthew J. Rossman ; Rachel A. Gioscia-Ryan ; Zachary S. Clayton ; Michael P. Murphy ; Douglas R. Seals Crossmark: Check for Updates Clin Sci (Lond) (2020) 134 (12): 1491–1519. https://doi.org/10.1042/CS20190559 Article history Split-Screen Views Icon Views PDF Link PDF Share Icon Share Cite Icon Cite Get Permissions Abstract Cardiovascular diseases (CVD) are the leading cause of death worldwide and aging is the primary risk factor for CVD. The development of vascular dysfunction, including endothelial dysfunction and stiffening of the large elastic arteries (i.e., the aorta and carotid arteries), contribute importantly to the age-related increase in CVD risk. Vascular aging is driven in large part by oxidative stress, which reduces bioavailability of nitric oxide and promotes alterations in the extracellular matrix. A key upstream driver of vascular oxidative stress is age-associated mitochondrial dysfunction. This review will focus on vascular mitochondria, mitochondrial dysregulation and mitochondrial reactive oxygen species (ROS) production and discuss current evidence for prevention and treatment of vascular aging via lifestyle and pharmacological strategies that improve mitochondrial health. We will also identify promising areas and important considerations (‘research gaps’) for future investigation. Keywords:arterial stiffness, endothelial function, mitophagy, oxidative stress, reactive oxygen species Subjects:Aging, Cardiovascular System & Vascular Biology, Translational Science Cardiovascular diseases (CVD) remain the largest contributor to morbidity and mortality in both developed and many developing nations [1,2]. Aging is by far the strongest risk factor for CVD, with >90% of all deaths occurring in adults 50 years of age and older [1,2]. Importantly, the changing demographics of aging characterized by a shift toward older populations [3] predicts a progressive, marked increase in prevalence of CVD in the absence of effective intervention [4]. A key mechanism by which aging increases CVD risk is the development of vascular dysfunction [5,6]. A number of adverse changes to the vasculature occur with aging, but two major clinically relevant expressions are endothelial dysfunction, as assessed by reduced arterial dilation in response to endothelium-derived nitric oxide (NO), and stiffening of the large elastic arteries (i.e., the aorta and carotid arteries) [5,6]. In combination, endothelial dysfunction and arterial stiffening contribute to a ‘vascular aging’ phenotype that drives much of the adverse effects of age on CVD. Vascular endothelial dysfunction The vascular endothelium is a single-cell layer lining the lumen of blood vessels. Endothelial cells play a critical role regulating vasomotor tone, metabolism, immune function, thrombosis and many other processes via synthesis and release of a variety of vasoactive molecules [7]. A major vasodilatory and largely vasoprotective molecule released by endothelial cells is NO, which is produced in response to mechanical (i.e., blood flow) and chemical (e.g., acetylcholine [ACh]) stimuli by the enzyme nitric oxide synthase (eNOS); eNOS catalyzes the generation of NO from L-arginine and oxygen, with NO subsequently diffusing to vascular smooth muscle cells where it induces vascular smooth muscle relaxation and vasodilation [7]. Endothelial dysfunction occurs with aging and is characterized by a decline in endothelium-dependent dilation (EDD), largely as a consequence of reductions in NO, although changes in concentrations of vasoactive factors such as prostaglandins, endothelin-1, norepinephrine and angiotensin II also contribute [7]. NO-mediated EDD can be determined in pre-clinical models by assessing changes in artery diameter in response to flow in vivo [8,9] or changes in diameter of isolated artery segments ex vivo in response to mechanical or pharmacological stimuli, such as ACh [10]. In humans, the gold-standard non-invasive assessment of NO-mediated EDD is brachial artery flow-mediated dilation (FMD), in which the change in brachial artery diameter in response to increases in blood flow is determined [10,11]. Brachial artery FMD primarily assesses macrovascular (conduit artery) function. Microvascular (resistance vessel) function can be determined by measuring changes in blood flow in response to intra-arterial infusions of ACh and is primarily assessed in the forearm [10,11]. These experimental approaches all demonstrate reduced endothelial function with aging in pre-clinical models and humans [12–17]. Endothelial dysfunction is the major antecedent of atherosclerosis [5,18] and both reduced brachial artery FMD and lower forearm blood flow responses to ACh are independent predictors of CV events and CVD in middle-aged and older adults free from clinical disease in large, community-based cohort studies [19–21]. Large elastic artery stiffening The aorta and carotid arteries expand and recoil as blood is ejected into the arterial system by the left ventricle during systole [22]. This action limits arterial pulsatile pressures by providing a dampening function and protects the downstream microvasculature from potentially damaging fluctuations in blood pressure and flow [23]. Moreover, the elastic recoil of the aorta aids in the propulsion of blood to the periphery and maintains perfusion of the heart during diastole [22]. With aging, aortic stiffening results in blood being ejected into a stiffer aorta, which augments central systolic blood pressure because the ejected pressure wave travels at a higher velocity in stiffer arteries and is reflected by points of impedance such that the returning pressure wave reaches the heart at mid-to-late systole [22,24]. In addition, the greater forward moving pressure wave amplitude (from systolic ejection, prior to the return of wave reflections) is a major contributor to the age-related increase in central systolic blood pressure after age 60, particularly in women, as a consequence of a plateau or decrease in reflected wave amplitude [25,26]. The augmented systolic blood pressure, in turn, contributes to isolated systolic hypertension and results in a loss of diastolic pressure augmentation, such that aortic pulse pressure is widened [22,24]. Aortic stiffening therefore increases left ventricular afterload during systole, promoting left ventricular hypertrophy and dysfunction, and compromises coronary perfusion during diastole because of the reduced augmentation of diastolic pressure [24,27]. The loss of pulsatility-dampening effects of the aorta and the carotid artery also allows for transmission of high pulsatile pressures to the delicate small vessels in the microcirculation, which is particularly harmful for high-flow, low-resistance organs such as the brain and kidney, and a potential causative factor in target organ damage [23]. Structural changes to arteries, functional influences (i.e., factors influencing vascular smooth muscle tone) and the stiffness of vascular smooth muscle cells contribute to large elastic artery stiffening with aging [28,29]. The primary structural changes mediating arterial stiffening occur in the extracellular matrix and include degradation/fragmentation of elastin (e.g., by matrix metalloproteinases), an increase in the deposition of collagen and formation of advanced glycation end products (AGEs), which cross-link collagen fibers, increasing their stiffness [5,30,31]. Increased vascular smooth muscle tone is a consequence of changes such as reductions in NO and increased sympathetic nervous system, endothelin-1 and renin–angiotensin aldosterone system activity [32–34]. These factors also influence the intrinsic stiffness of the vascular smooth muscle cells, which adds to the stiffness of the arterial wall [29]. The mechanical stiffness of the large elastic arteries can be determined ex vivo in pre-clinical models by directly measuring properties such as compliance by creating stress-strain curves [35,36]. In vivo, arterial stiffness can be assessed in pre-clinical settings and humans with pulse wave velocity (PWV), which is a measure of the (regional) speed of the pulse wave generated by the heart when blood is ejected into the arterial system [22]. Aortic PWV is the predominant measure in rodents and carotid-femoral PWV is the reference standard measure of aortic stiffness in humans [10,22]. Carotid-femoral PWV increases with aging and is a strong, independent predictor of CVD risk in older adults [37,38]. Moreover, consistent with aortic stiffness-associated end organ damage, growing evidence supports an association between elevated carotid-femoral PWV and other age-related clinical disorders such as cognitive decline, dementia, including Alzheimer’s disease, and decreases in renal function/chronic kidney disease [39–43]. The local distensibility of the carotid artery can also be determined in humans by measuring carotid artery compliance (the change in artery diameter for a given change in arterial pressure) and determining the carotid distensibility coefficient (i.e., changes in artery diameter normalized to diastolic lumen diameter) and/or carotid beta-stiffness index, which is largely independent of blood pressure [10,22]. Carotid artery compliance is associated with incident stroke, independent of aortic stiffness [44]. Mechanisms of vascular dysfunction with aging The primary molecular mechanisms of vascular aging are oxidative stress and chronic, low grade inflammation [45,46] (Figure 1). Excessive production of reactive oxygen species (ROS) in combination with unchanged or decreased abundance/activity of antioxidant enzymes (e.g., superoxide dismutase, SOD) results in the development of oxidative stress in arteries with aging [24,45]. Excess superoxide rapidly reacts with NO to form the secondary reactive species peroxynitrite (ONOO−), decreasing the bioavailability of NO [24,45], causing endothelial dysfunction. Peroxynitrite is also the primary molecule that reacts with and oxidizes tetrahydrobiopterin (BH4), an essential co-factor for NO production by eNOS [47]. Loss of BH4 leads to eNOS uncoupling, whereby eNOS produces more superoxide and less NO, exacerbating oxidative stress and decreasing bioavailable NO and endothelial cell function [47]. Excess ROS also can activate pro-inflammatory networks such as those regulated by the transcription factor nuclear factor kappa B (NF-kB), which up-regulates the production of pro-inflammatory cytokines that can impair vascular function and activate other ROS producing systems and enzymes, creating an adverse feed-forward (vicious) cycle of inflammation and oxidative stress [24,45]. Figure 1 Aging is associated with mitochondrial dysfunction-induced increases in reactive oxygen species (ROS) and oxidative stress and increases in pro-inflammatory cytokine signaling and chronic low-grade inflammation. Together, these processes induce vascular dysfunction, featuring: (lower left) large elastic artery stiffening mediated by degradation of elastin fibers (blue), increased deposition of collagen (brown), and greater cross-linking of structural proteins by advanced glycation end-products (dashed connecting lines); and (right) vascular endothelial dysfunction characterized by reduced nitric oxide (NO) bioavailability and endothelium-dependent dilation. These and other changes to arteries, in turn, increase the risk of developing cardiovascular diseases, chronic kidney disease, and Alzheimer’s disease and related dementias. VIEW LARGEDOWNLOAD SLIDE Mechanisms of age-associated vascular dysfunction and related clinical disorders Aging is associated with mitochondrial dysfunction-induced increases in reactive oxygen species (ROS) and oxidative stress and increases in pro-inflammatory cytokine signaling and chronic low-grade inflammation. Together, these processes induce vascular dysfunction, featuring: (lower left) large elastic artery stiffening mediated by degradation of elastin fibers (blue), increased deposition of collagen (brown), and greater cross-linking of structural proteins by advanced glycation end-products (dashed connecting lines); and (right) vascular endothelial dysfunction characterized by reduced nitric oxide (NO) bioavailability and endothelium-dependent dilation. These and other changes to arteries, in turn, increase the risk of developing cardiovascular diseases, chronic kidney disease, and Alzheimer’s disease and related dementias. This overall state of oxidative stress and inflammation also contributes to arterial stiffening with aging by altering the structural properties of the arterial wall. Production of collagen by fibroblasts is stimulated by superoxide-related oxidative stress [30,48,49]. Matrix metalloproteinases are up-regulated and elastin content is lower in aorta of SOD-deficient mice, consistent with the concept that elastin degradation is induced by oxidative stress [50]. Vascular oxidative stress also promotes transforming growth factor β signaling and this, in turn, stimulates inflammation, which further reinforces arterial stiffness via activation of the pro-oxidant enzyme, NADPH oxidase [48]. AGEs interact with the receptor for AGEs to activate NFkB-regulated pro-inflammatory pathways and oxidative stress, which ultimately perpetuates arterial stiffening and further increases production of AGEs [51]. Mitochondrial dysfunction is emerging as a key source of vascular oxidative stress and contributor to age-related vascular dysfunction. The remaining sections of this article will focus on mitochondrial dysfunction as a driver of vascular aging and review current evidence for prevention/treatment of age-associated vascular dysfunction via lifestyle and pharmacological strategies that improve mitochondrial health. We will also discuss current ‘research gaps’ and future directions for the field. Vascular mitochondria, mitochondrial dysregulation and ROS Mitochondria are cytoplasmic organelles that are present in the majority of cell types in the human body, including vascular endothelial and smooth muscle cells. Mitochondria are often referred to as the ‘powerhouse’ of the cell for their role in ATP production by oxidative phosphorylation, which occurs via a series of electron transfers through the respiratory chain in the mitochondrial inner membrane that is coupled to ATP synthesis by the FoF1-ATP synthase by the protonmotive force across the inner membrane. However, mitochondria are also vital for a number of additional cellular processes, including regulation of metabolism, calcium homeostasis, immune function, cell growth and stem cell function, and cell death pathways. Although mitochondrial density in vascular tissues is considerably lower than other tissues such as skeletal muscle, liver and heart [52,53], increasing evidence indicates that these organelles are critical for maintenance of cellular and tissue homeostasis in the vasculature. This topic has been reviewed in detail elsewhere [54–61], but below we briefly summarize some of the key roles of mitochondria in the vasculature. A first important distinction is to consider the vascular cell type in question, as the density and subcellular distribution of mitochondria vary between endothelial and vascular smooth muscle cells, and indeed even among the same cell types in different vascular beds [54,60]. In general, unlike in highly metabolically active tissues with greater ATP demand, the principal role of mitochondria in the vasculature appears to be cellular signaling rather than energy provision [54]. Cellular energy demand is quite low in endothelial cells, and ATP demand is met primarily via glycolysis. However, endothelial mitochondria are critical in the regulation of calcium homeostasis, apoptosis/necrosis, cellular response to stress, and immune and inflammatory pathways. An essential feature of these roles is the regulated production of signaling molecules including redox-active molecules (reactive oxygen, nitrogen and other species; mtROS), mitochondrial DNA, mitochondria-derived peptides and damage-associated molecular pattern molecules (DAMPs), which exert effects intra- and extra-cellularly [62]. Importantly, there is cross-talk between mitochondrial and nuclear signaling pathways, whereby mitochondria-derived signaling is both influenced by and can influence nuclear events including gene expression [63]. Similarly, in vascular smooth muscle cells, mitochondria have an important role in cellular signaling. Mitochondria are involved in signaling pathways for regulation of vascular smooth muscle cell growth and proliferation (e.g., TGF-β activity) [64], as well as maintenance of the dynamic balance among synthesis and breakdown of extracellular structural proteins, including collagen and elastin (e.g., matrix metalloproteinase enzyme activities) [65]. There is also emerging evidence demonstrating interplay between mtROS signaling and inflammatory pathways known to be important for regulating vascular smooth muscle cell function, including those involving NFkB and the NLRP3-inflammasome [66–69], further highlighting the crucial role of mtROS in vascular homeostasis. Mitochondrial ROS The signaling functions of vascular mitochondria are thought to be mediated in large part by the production of ROS at low, physiological levels. However, the dysregulation of this mtROS production also has the potential to lead to pathophysiological sequelae that disrupt other mitochondrial functions, cellular homeostasis, and ultimately vascular function. The production of ROS by mitochondria can occur at several sites (Figure 2), including but not limited to the electron transport proteins, and this topic has been reviewed in detail elsewhere [54,60,70]. The most important sites for ROS production within mitochondria appear to be complexes I and III. These ROS are thought to be critical transducers of signaling mediated by mitochondria, leading to post-transcriptional modification of proteins and interactions with immune and inflammatory cellular pathways, although the mechanistic details are still uncertain. In the vasculature, the proximal mtROS species is superoxide, which is generated primarily at the electron transport chain in the mitochondrial inner membrane via interaction between oxygen and unpaired electrons, influenced by the proton motive force and the redox state of the coenzyme Q pool and integrity of intrinsic electron transport chain proteins [54,58,60,70]. Superoxide is released into the matrix (complex I) or into both the matrix and intermembrane space (complex III); it can also undergo dismutation to hydrogen peroxide by the antioxidant enzyme manganese superoxide dismutase (MnSOD) [59,60,62,70]. Hydrogen peroxide is also generated de novo on the surface of the mitochondrial outer membrane or in the intermembrane space mitochondria by p66SHC, a growth factor adapter protein referred to as a sensor/marker and ‘master regulator’ of mitochondrial redox signaling whose activity is indicative of the rate of mtROS production [71]. In addition, NADPH oxidase 4 (NOX4) is viewed as a primarily mitochondrial isoform of the NOX monoamine oxidase family of enzymes that contributes to mitochondrial hydrogen peroxide generation [72], although more research is needed to confirm the mitochondrial specificity of NOX4. Figure 2 Aging is associated with dysregulated mitochondrial quality control featuring reduced mitochondrial biogenesis (upper left) and reduced mitophagy (upper right), increased mitochondrial fission (upper middle right), reduced mitochondrial fusion (lower middle right), reduced mitochondrial stress resistance (lower right), increased mitochondrial DNA damage (middle left of mitochondria image) and increased bioactivity of mitochondrial reactive oxygen species (e.g., superoxide and other reactive oxygen species [ROS], middle of mitochondria image) relative to antioxidant defenses (e.g., manganese superoxide dismutase [SOD], lower right of mitochondria). VIEW LARGEDOWNLOAD SLIDE Mechanisms of age-associated mitochondrial dysfunction Aging is associated with dysregulated mitochondrial quality control featuring reduced mitochondrial biogenesis (upper left) and reduced mitophagy (upper right), increased mitochondrial fission (upper middle right), reduced mitochondrial fusion (lower middle right), reduced mitochondrial stress resistance (lower right), increased mitochondrial DNA damage (middle left of mitochondria image) and increased bioactivity of mitochondrial reactive oxygen species (e.g., superoxide and other reactive oxygen species [ROS], middle of mitochondria image) relative to antioxidant defenses (e.g., manganese superoxide dismuta

Perioperative Outcomes are Adversely Affected by Poor Pretransfer Adherence to Acute Limb Ischemia Practice Guidelines

Objectives The accepted treatment for acute limb ischemia (ALI) is immediate systemic anticoagulation and timely reperfusion to restore blood flow. In this study, we describe the retrospective assessment of pretransfer management decisions by referring hospitals to an academic tertiary care facility and its impact on perioperative adverse events. Methods A retrospective analysis of ALI patients transferred to us via our Level I Vascular Emergency program from 2010 to 2013 was performed. Patient demographics, comorbidities, Rutherford ischemia classification, time to anticoagulation, and time to reperfusion were tabulated and analyzed for correlation to incidence of major adverse limb events (MALE), mortality, and bypass patency in the perioperative period (30-day postoperative). All time intervals were calculated from the onset of symptoms and categorized into three subcohorts (48 hrs). Results Eighty-seven patients with an average age of 64.0 (± 16.2) years presented to outlying hospitals and was transferred to us with lower extremity ALI. The mean delay from symptom onset to initial referring physician evaluation was 18.3 hrs. At that time of evaluation, 53.8% had Rutherford class IIA ischemia and 36.3% had class IIB ischemia. Seventy-six (87.4%) patients were started on heparin previous to transfer. However, only 44 (57.9%) patients reached therapeutic levels as measured by activated partial thromboplastin time (aPTT) prior to definitive revascularization. A delay of anticoagulation initiation >48 hrs from symptom onset was associated with increased 30-day reintervention rates compared with the <6 hrs group (66.7% vs. 23.5%; p<0.05). However, time to reperfusion had no statistically significant impact on MALE, 30-day mortality, or 30-day interventional patency in our small cohorts. Additionally, patients with a previous revascularization had a higher 30-day reintervention rate (46.5%; p<0.05). Conclusions The practice of timely therapeutic anticoagulation of patients referred for ALI from community facilities occurs less frequently than expected and is associated with an increased perioperative reintervention rate