Carl D. Shrader

Cerebral Cortical Microvascular Rarefaction in Metabolic Syndrome is Dependent on Insulin Resistance and Loss of Nitric Oxide Bioavailability.

Chronic presentation of the MS is associated with an increased likelihood for stroke and poor stroke outcomes following occlusive cerebrovascular events. However, the physiological mechanisms contributing to compromised outcomes remain unclear, and the degree of cerebral cortical MVD may represent a central determinant of stroke outcomes.

Insulin enhances proliferation and viability of human umbilical vein endothelial cells

This investigation is a follow-up to our previous in vivo studies revealing that rapid stretch increases tissue insulin in murine skin flaps, coincident with the up-regulation of key angiogenic effectors and enhanced vascularization. In the present study, we used human umbilical vein endothelial cells (HUVECs) as an in vitro model system to determine the role of insulin in the chemical signals regulating the processes of proliferation and viability (survival). MTT-based colorimetric methods demonstrated that insulin enhances proliferation and survival of HUVECs. Western blot analysis revealed that protein kinase B (pAkt [Thr308]) and vascular endothelial growth factor (VEGF) were the insulin-responsive intermediates in proliferating endothelial cells (ECs). In insulin-enhanced survival, both pAkt (Thr308) and pAkt (Ser473) were activated in HUVECs. However, no change in VEGF expression accompanied pAkt activation. The beneficial effects of insulin were abrogated by insulin receptor (IR)/insulin-like growth factor receptor (IGFR) or phosphoinositide-3 kinase (PI3-K) blockade, suggesting that insulin-induced EC proliferation and viability are mediated through pIR/pIGFR and PI3-K effectors. These data provide new insights into the beneficial effects of insulin on vascularization and tissue viability, providing a mechanistic link to the enhancement of healing in acutely stretched skin.

Metabolic syndrome impairs reactivity and wall mechanics of cerebral resistance arteries in obese Zucker rats

The metabolic syndrome (MetS) is highly prevalent in the North American population and is associated with increased risk for development of cerebrovascular disease. This study determined the structural and functional changes in the middle cerebral arteries (MCA) during the progression of MetS and the effects of chronic pharmacological interventions on mitigating vascular alterations in obese Zucker rats (OZR), a translationally relevant model of MetS. The reactivity and wall mechanics of ex vivo pressurized MCA from lean Zucker rats (LZR) and OZR were determined at 7-8, 12-13, and 16-17 wk of age under control conditions and following chronic treatment with pharmacological agents targeting specific systemic pathologies. With increasing age, control OZR demonstrated reduced nitric oxide bioavailability, impaired dilator (acetylcholine) reactivity, elevated myogenic properties, structural narrowing, and wall stiffening compared with LZR. Antihypertensive therapy (e.g., captopril or hydralazine) starting at 7-8 wk of age blunted the progression of arterial stiffening compared with OZR controls, while treatments that reduced inflammation and oxidative stress (e.g., atorvastatin, rosiglitazone, and captopril) improved NO bioavailability and vascular reactivity compared with OZR controls and had mixed effects on structural remodeling. These data identify specific functional and structural cerebral adaptations that limit cerebrovascular blood flow in MetS patients, contributing to increased risk of cognitive decline, cerebral hypoperfusion, and ischemic stroke; however, these pathological adaptations could potentially be blunted if treated early in the progression of MetS.

Rates of Nonsteroidal Anti-Inflammatory Drug Use in Patients with Established Cardiovascular Disease: A Retrospective, Cross-Sectional Study from NHANES 2009–2010

PurposeNonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat pain, inflammation, and fever in the USA. Unfortunately, NSAIDs have been associated with an increased risk of adverse cardiovascular events, especially among NSAID users with established cardiovascular disease (CVD). In 2005, the Food and Drug Administration (FDA) released an initial warning regarding NSAID use and CVD risk, and recently, in July 2015, released an updated statement strengthening this initial warning. The purpose of this study is to evaluate the rates of NSAID use among patients with CVD following the 2005 FDA warning regarding NSAID use and increased CVD risk.MethodsThis was a retrospective, cross-sectional study of participants from the National Health and Nutrition Examination Survey, 2009–2010. Participants’ CVD status was determined by self-reported diagnosis. Current use of over the counter (OTC) NSAIDs was defined by self-reported use of ibuprofen or naproxen, and we identified the current use of prescription NSAIDs in the database of prescription medication.ResultsRespondents with CVD were 2.1 times more likely to use OTC NSAIDs or prescription NSAIDs than respondents without CVD. Among CVD patients, respondents with angina and myocardial infarction were 60% more likely to use any form of NSAID, and respondents with congestive heart failure were less likely to use any form of NSAID than those with other forms of CVD.ConclusionsOur results indicate that there is still a large proportion of CVD patients using NSAIDs. It is now crucial to determine the reasons why prescribers are still prescribing NSAIDs despite the FDA warning.

Altered post‐capillary and collecting venular reactivity in skeletal muscle with metabolic syndrome

With the development of the metabolic syndrome, both post‐capillary and collecting venular dilator reactivity within the skeletal muscle of obese Zucker rats (OZR) is impaired. The impaired dilator reactivity in OZR reflects a loss in venular nitric oxide and PGI2 bioavailability, associated with the chronic elevation in oxidant stress. Additionally, with the impaired dilator responses, a modest increase in adrenergic constriction combined with an elevated thromboxane A2 production may contribute to impaired functional dilator and hyperaemic responses at the venular level. For the shift in skeletal muscle venular function with development of the metabolic syndrome, issues such as aggregate microvascular perfusion resistance, mass transport and exchange within with capillary networks, and fluid handling across the microcirculation are compelling avenues for future investigation.

Evaluation of inflammatory cell biomarkers in chronic venous insufficiency

Objective Inflammation has been implicated as a factor that may contribute to chronic venous insufficiency. The purpose of this study is to compare readily available inflammatory cell biomarkers, with an emphasis on neutrophil count, lymphocyte count, and neutrophil lymphocyte ratio, in patients with chronic venous insufficiency. We hypothesized that circulating leukocyte counts would be higher in the peripheral blood of patients with severe compared to mild chronic venous insufficiency. Methods We performed a retrospective medical record review of patients discharged from Ruby Memorial Hospital (Morgantown, WV, USA) with a primary diagnosis of chronic venous insufficiency. Patients were organized into two groups—mild and severe chronic venous insufficiency—based on the Clinical, Etiologic, Anatomic, and Pathophysiological classification system, and inflammatory cell counts were compared between groups. Results We observed a significantly higher neutrophil count (p = .002) and neutrophil-lymphocyte ratio (p = .005) in patients with severe chronic venous insufficiency compared to mild. Further, the neutrophil–lymphocyte ratio may be a useful predictor of chronic venous insufficiency severity. Conclusions We reported significant differences in inflammatory cell biomarkers between mild and severe chronic venous insufficiency, as well as provided support for the use of the neutrophil–lymphocyte ratio as a predictor of chronic venous insufficiency severity. These results may provide clinicians with additional insight to manage chronic venous insufficiency in patients and provide a framework for the development of novel treatment options targeting the immune system in chronic venous insufficiency.