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1. Chronic statin therapy is associated with enhanced cutaneous vascular responsiveness to sympathetic outflow during passive heat stress

   https://doi.org/10.1113/JP278237  

   Greaney, Jody L. ; Stanhewicz, Anna E. ; Kenney, W. Larry ( August 2019 , The Journal of Physiology)

   Impairments in both central sympathetic and peripheral microvascular function contribute to blunted reflex cutaneous vasodilatation during heat stress in healthy older adults.

   Hypercholesterolaemia is associated with decrements in neurovascular function; however, little is known about the impact of hypercholesterolaemia on the integrated responses to heat stress. Further, whether chronic statin therapy alters skin sympathetic outflow or its relation to cutaneous vascular conductance during heat stress is unknown.

   We demonstrate that reflex cutaneous vasodilatation is impaired in older hypercholesterolaemic adults but not in formerly hypercholesterolaemic adults currently treated with a statin compared to age‐matched controls.

   Additionally, chronic statin treatment‐induced improvements in reflex vasodilatation are mediated, in part, by increases in end‐organ responsiveness to efferent sympathetic outflow during whole‐body heating.

   These data add to the growing body of literature substantiating the beneficial pleiotropic neurovascular effects of chronic statin treatment and provide further support for the use of statins to confer additional cardioprotective benefits in older adults.

   Attenuated reflex cutaneous vasodilatation in healthy human ageing is mediated by alterations in both central (sympathetic outflow) and peripheral (microvascular endothelial) function. Hypercholesterolaemia is associated with further impairments in neurovascular function. HMG‐CoA reductase inhibitors (statins) improve cutaneous endothelium‐dependent dilatation; however, whether statin therapy alters skin sympathetic nervous system activity (SSNA) or its relation to cutaneous vascular conductance (CVC) during passive heat stress is unknown. We hypothesized that (1) hypercholesterolaemic older adults would demonstrate blunted increases in both SSNA and CVC during passive heating and (2) chronic statin treatment would improve the response range and sensitivity of the SSNA:CVC relation. Reflex vasodilatation in response to a 1.0°C rise in oral temperature (T_or; water perfused suit) was induced in 13 healthy normocholesterolaemic adults (62 ± 2 years; LDL = 113 ± 7 mg/dl), 10 hypercholesterolaemic adults (60 ± 1 years; LDL = 183 ± 2 mg/dl), and 10 previously hypercholesterolaemic adults (64 ± 1 years; LDL = 102 ± 2 mg/dl) treated with lipophilic statin (10–40 mg daily). SSNA (peroneal microneurography) and red cell flux (laser‐Doppler flowmetry) in the innervated dermatome (dorsum of foot) were continuously measured. Reflex vasodilatation was blunted in hypercholesterolaemic adults, but not in statin‐treated adults, compared to normocholesterolaemic adults (at ∆T_or = 1.0°C: normal = 36 ± 1%CVC_max, high = 32 ± 1%CVC_max, statin = 38 ± 1%CVC_max;P < 0.01). ∆SSNA was not different (at ∆T_or = 1.0°C: normal: ∆ = 393 ± 96%, high: ∆ = 311 ± 120%, statin: ∆ = 256 ± 90%;P = 0.11). The slope of the SSNA:CVC relation was blunted in hypercholesterolaemic adults (0.02 ± 0.03%CVC_max/%_baseline) compared to both normocholesterolaemic (0.09 ± 0.02%CVC_max/%_baseline;P = 0.024) and statin‐treated (0.12 ± 0.05%CVC_max/%_baseline;P = 0.03) adults. Chronic statin treatment improves reflex cutaneous vasodilatation in formerly hypercholesterolaemic older adults by increasing end‐organ responsiveness to sympathetic outflow during passive heat stress.

    

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2. Sex differences in the incidence and mode of death in rats with heart failure with preserved ejection fraction

   https://doi.org/10.1113/EP089163  

   Elkholey, Khaled ; Morris, Lynsie ; Niewiadomska, Monika ; Houser, Jeremy ; Ramirez, Michelle ; Tang, Mulan ; Humphrey, Mary Beth ; Stavrakis, Stavros ( January 2021 , Experimental Physiology)

   What is the central question of this study?

   Prior studies failed to address the role of sex in modifying the pathophysiology and response to therapy in heart failure with preserved ejection fraction (HFpEF), potentially introducing bias into translational findings. We aimed to explore sex differences in outcomes and sought to identify the underlying mechanisms in a well‐established rat model of HFpEF.

   What is the main finding and its importance?

   Male rats with HFpEF exhibited worse survival compared with females and were at a higher risk for sudden death, attributable in part to QT prolongation, autonomic dysregulation and enhanced inflammation. These data might provide the basis for the development of sex‐specific interventions in HFpEF targeting these abnormalities.

   Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of heart failure, and sudden death is the leading cause of mortality. We aimed to explore sex differences in outcomes in rats with HFpEF and sought to identify the underlying mechanisms. Dahl salt‐sensitive rats of either sex were randomized into high‐salt diet (HS diet; 8% NaCl,n = 46, 50% female) or low‐salt diet (LS diet; 0.3% NaCl;n = 24, 50% female) at 7 weeks of age. After 6 and 10 weeks of LS or HS diets, the ECG, heart rate variability, cytokines and echocardiographic parameters were measured. The animals were monitored daily for development of HFpEF and survival. Over 6 weeks of HS diet, rats developed significant hypertension and signs of HFpEF. Compared with female HS diet‐fed rats, males exhibited more left ventricular dilatation, a longer QT interval, and worse autonomic tone, as assessed by heart rate variability and elevated inflammatory cytokines. Ten of 23 (46%) male rats died during follow‐up, compared with two of 23 (9%) female rats (P = 0.01). There were four sudden deaths in males (with ventricular tachycardia documented in one rat), whereas the females died of heart failure. In conclusion, male rats with HFpEF exhibit worse survival compared with females and are at a higher risk for sudden death, attributable in part to QT prolongation, autonomic dysregulation and enhanced inflammation. These data might provide the basis for the development of sex‐specific interventions in HFpEF targeting these abnormalities.

    

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3. Advanced age protects resistance arteries of mouse skeletal muscle from oxidative stress through attenuating apoptosis induced by hydrogen peroxide

   https://doi.org/10.1113/JP278255  

   Norton, Charles E. ; Sinkler, Shenghua Y. ; Jacobsen, Nicole L. ; Segal, Steven S. ( July 2019 , The Journal of Physiology)

   Vascular oxidative stress increases with advancing age.

   We hypothesized that resistance vessels develop resilience to oxidative stress to protect functional integrity and tested this hypothesis by exposing isolated pressurized superior epigastric arteries (SEAs) of old and young mice to H₂O₂.

   H₂O₂‐induced death was greater in smooth muscle cells (SMCs) than endothelial cells (ECs) and lower in SEAs from oldvs. young mice; the rise in vessel wall [Ca²⁺]_iinduced by H₂O₂was attenuated with ageing, as was the decline in noradrenergic vasoconstriction; genetic deletion of IL‐10 mimicked the effects of advanced age on cell survival.

   Inhibiting NO synthase or scavenging peroxynitrite reduced SMC death; endothelial denudation or inhibiting gap junctions increased SMC death; delocalization of cytochrome C activated caspases 9 and 3 to induce apoptosis.

   Vascular cells develop resilience to H₂O₂during ageing by preventing Ca²⁺overload and endothelial integrity promotes SMC survival.

   Advanced age is associated with elevated oxidative stress and can protect the endothelium from cell death induced by H₂O₂. Whether such protection occurs for intact vessels or differs between smooth muscle cell (SMC) and endothelial cell (EC) layers is unknown. We tested the hypothesis that ageing protects SMCs and ECs during acute exposure to H₂O₂(200 µm, 50 min). Mouse superior epigastric arteries (SEAs; diameter, ∼150 µm) were isolated and pressurized to 100 cmH₂O at 37˚C. For SEAs from young (4 months) mice, H₂O₂killed 57% of SMCs and 11% of ECs in malesvs. 8% and 2%, respectively, in females. Therefore, SEAs from males were studied to resolve the effect of ageing and experimental interventions. For old (24 months) mice, SMC death was reduced to 10% with diminished accumulation of [Ca²⁺]_iin the vessel wall during H₂O₂exposure. In young mice, genetic deletion of IL‐10 mimicked the protective effect of ageing on cell death and [Ca²⁺]_iaccumulation. Whereas endothelial denudation or gap junction inhibition (carbenoxolone; 100 µm) increased SMC death, inhibiting NO synthase (l‐NAME, 100 µm) or scavenging peroxynitrite (FeTPPS, 5 µm) reduced SMC death along with [Ca²⁺]_i. Despite NO toxicity via peroxynitrite formation, endothelial integrity protects SMCs. Caspase inhibition (Z‐VAD‐FMK, 50 µm) attenuated cell death with immunostaining for annexin V, cytochrome C, and caspases 3 and 9 pointing to induction of intrinsic apoptosis during H₂O₂exposure. We conclude that advanced age reduces Ca²⁺influx that triggers apoptosis, thereby promoting resilience of the vascular wall during oxidative stress.

    

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4. Cross-Domain Text Mining to Predict Adverse Events from Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia

   https://doi.org/10.3390/cancers14194686  

   Mehra, Nidhi ; Varmeziar, Armon ; Chen, Xinyu ; Kronick, Olivia ; Fisher, Rachel ; Kota, Vamsi ; Mitchell, Cassie S. ( October 2022 , Cancers)

   Tyrosine kinase inhibitors (TKIs) are prescribed for chronic myeloid leukemia (CML) and some other cancers. The objective was to predict and rank TKI-related adverse events (AEs), including under-reported or preclinical AEs, using novel text mining. First, k-means clustering of 2575 clinical CML TKI abstracts separated TKIs by significant (p < 0.05) AE type: gastrointestinal (bosutinib); edema (imatinib); pulmonary (dasatinib); diabetes (nilotinib); cardiovascular (ponatinib). Next, we propose a novel cross-domain text mining method utilizing a knowledge graph, link prediction, and hub node network analysis to predict new relationships. Cross-domain text mining of 30+ million articles via SemNet predicted and ranked known and novel TKI AEs. Three physiology-based tiers were formed using unsupervised rank aggregation feature importance. Tier 1 ranked in the top 1%: hematology (anemia, neutropenia, thrombocytopenia, hypocellular marrow); glucose (diabetes, insulin resistance, metabolic syndrome); iron (deficiency, overload, metabolism), cardiovascular (hypertension, heart failure, vascular dilation); thyroid (hypothyroidism, hyperthyroidism, parathyroid). Tier 2 ranked in the top 5%: inflammation (chronic inflammatory disorder, autoimmune, periodontitis); kidney (glomerulonephritis, glomerulopathy, toxic nephropathy). Tier 3 ranked in the top 10%: gastrointestinal (bowel regulation, hepatitis, pancreatitis); neuromuscular (autonomia, neuropathy, muscle pain); others (secondary cancers, vitamin deficiency, edema). Results suggest proactive TKI patient AE surveillance levels: regular surveillance for tier 1, infrequent surveillance for tier 2, and symptom-based surveillance for tier 3. 

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5. Age-Related Collagen Remodeling Occurs in the Absence of Hypertension in Aortas of NOS3 Heterozygous Mice

   Du, Liya ; Azar, Dara ; Eliadorani, Dorsa ; Shazly, Tarek ; Lessner, Susan M. ( June 2020 , Summer Biomechanics, Bioengineering, and Biotransport Conference (SB3C))

   The endothelium, composed of a single layer of endothelial cells, is the innermost lining of vessels, acting as the interface between blood and the arterial wall. “Endothelial dysfunction” is defined as reduction or loss of bioavailability of endothelial-derived nitric oxide (NO), a condition that precedes or accompanies several cardiovascular pathologies associated with aging, such as atherosclerosis. [1] [2] NO plays an important role in regulating vascular tone and maintaining vascular homeostasis as a vasodilator. Thus, we hypothesize that decreased NO production may induce collagen fiber reorientation and increased collagen production, to shift load from smooth muscle cells to the extracellular matrix, eventually leading to vascular remodeling. The aim of this project is to study the impact of NO deficiency on hemodynamic parameters, collagen content, and collagen fiber orientation during age-related vascular remodeling using a mouse model. 

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