Subclinical atherosclerosis, cardiovascular health, and disease risk: is there a case for the Cardiovascular Health Index in the primary prevention population?

BACKGROUND: Current primary prevention guidelines for cardiovascular disease (CVD) prioritize risk identification, risk stratification using clinical and risk scores, and risk reduction with lifestyle interventions and pharmacotherapy. Subclinical atherosclerosis is an early indicator of atherosclerotic burden and its timely recognition can slow or prevent progression to CVD. Thus, individuals with subclinical atherosclerosis are a priority for primary prevention. This study takes a practical approach to answering a challenge commonly faced by primary care practitioners: in patients with no known CVD, how can individuals likely to have subclinical atherosclerosis be easily identified using existing clinical data and/or information provided by the patient? METHODS: Using NHANES (1999-2004), 6091 men and women aged ≥40 years without any CVD comprised the primary prevention population for this study. Subclinical atherosclerosis was determined via ankle-brachial index (ABI) using established cutoffs (subclinical atherosclerosis defined as ABI (0.91-0.99); normal defined as ABI (1.00-1.30)). Three common scores were calculated: the Framingham Risk Score (FRS), the Metabolic Syndrome (MetS), and the Cardiovascular Health Index (CVHI). Logistic regression analysis assessed the association between these scores and subclinical atherosclerosis. The sensitively and specificity of these scores in identifying subclinical atherosclerosis was determined. RESULTS: In eligible participants, 3.8% had subclinical atherosclerosis. Optimum and average CVHI was associated with decreased odds for subclinical atherosclerosis. High, but not intermediate-risk, FRS was associated with increased odds for subclinical atherosclerosis. MetS was not associated with subclinical atherosclerosis. Of the 3 scores, CVHI was the most sensitive in identifying subclinical atherosclerosis and had the lowest number of missed cases. The FRS was the most specific but least sensitive of the 3 scores, and had almost 10-fold more missed cases vs. the CVHI. The MetS had "middle" sensitivity and specificity, and 10-fold more missed cases vs. the CVHI. CONCLUSIONS: Results from this study suggest that routine administration of the CVHI in a primary prevention population would yield the benefits of identifying patients with existing subclinical CVD not identified through traditional CVD risk factors or scores, and bring physical activity and nutrition to the forefront of provider-patient discussions about lifestyle factors critical to maintaining and prolonging cardiovascular health.

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

KEY POINTS: 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. ABSTRACT: While research into vascular outcomes of the metabolic syndrome has focused on arterial/arteriolar and capillary levels, investigation into venular function and how this impacts responses has received little attention. Using the in situ cremaster muscle of obese Zucker rats (OZR; with lean Zucker rats (LZR) as controls), we determined indices of venular function. At ∼17 weeks of age, skeletal muscle post-capillary venular density was reduced by ∼20% in LZR vs. OZR, although there was no evidence of remodelling of the venular wall. Venular tone at ∼25 µm (post-capillary) and ∼75 µm (collecting) diameter was elevated in OZR vs. LZR. Venular dilatation to acetylcholine was blunted in OZR vs. LZR due to increased oxidant stress-based loss of nitric oxide bioavailability (post-capillary) and increased α1 - (and α2 -) mediated constrictor tone (collecting). Venular constrictor responses in OZR were comparable to LZR for most stimuli, although constriction to α1 -adrenoreceptor stimulation was elevated. In response to field stimulation of the cremaster muscle (0.5, 1, 3 Hz), venular dilator and hyperaemic responses to lower frequencies were blunted in OZR, but responses at 3 Hz were similar between strains. Venous production of TxA2 was higher in OZR than LZR and significantly higher than PGI2 production in either following arachidonic acid challenge. These results suggest that multi-faceted alterations to skeletal muscle venular function in OZR may contribute to alterations in upstream capillary pressure profiles and the transcapillary exchange of solutes and water under conditions of metabolic syndrome.

Increased peripheral vascular disease risk progressively constrains perfusion adaptability in the skeletal muscle microcirculation.

To determine the impact of progressive elevations in peripheral vascular disease (PVD) risk on microvascular function, we utilized eight rat models spanning "healthy" to "high PVD risk" and used a multiscale approach to interrogate microvascular function and outcomes: healthy: Sprague-Dawley rats (SDR) and lean Zucker rats (LZR); mild risk: SDR on high-salt diet (HSD) and SDR on high-fructose diet (HFD); moderate risk: reduced renal mass-hypertensive rats (RRM) and spontaneously hypertensive rats (SHR); high risk: obese Zucker rats (OZR) and Dahl salt-sensitive rats (DSS). Vascular reactivity and biochemical analyses demonstrated that even mild elevations in PVD risk severely attenuated nitric oxide (NO) bioavailability and caused progressive shifts in arachidonic acid metabolism, increasing thromboxane A2 levels. With the introduction of hypertension, arteriolar myogenic activation and adrenergic constriction were increased. However, while functional hyperemia and fatigue resistance of in situ skeletal muscle were not impacted with mild or moderate PVD risk, blood oxygen handling suggested an increasingly heterogeneous perfusion within resting and contracting skeletal muscle. Analysis of in situ networks demonstrated an increasingly stable and heterogeneous distribution of perfusion at arteriolar bifurcations with elevated PVD risk, a phenomenon that was manifested first in the distal microcirculation and evolved proximally with increasing risk. The increased perfusion distribution heterogeneity and loss of flexibility throughout the microvascular network, the result of the combined effects on NO bioavailability, arachidonic acid metabolism, myogenic activation, and adrenergic constriction, may represent the most accurate predictor of the skeletal muscle microvasculopathy and poor health outcomes associated with chronic elevations in PVD risk.

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.

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

OBJECTIVE: 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. METHODS: This study used the OZR model of MS and clinically relevant, chronic interventions to determine the impact on cerebral cortical microvascular rarefaction via immunohistochemistry with a parallel determination of cerebrovascular function to identify putative mechanistic contributors. RESULTS: OZR exhibited a progressive rarefaction (to ~80% control MVD) of the cortical microvascular networks vs. lean Zucker rats. Chronic treatment with antihypertensive agents (captopril/hydralazine) had limited effectiveness in blunting rarefaction, although treatments improving glycemic control (metformin/rosiglitazone) were superior, maintaining ~94% control MVD. Chronic treatment with the antioxidant TEMPOL severely blunted rarefaction in OZR, although this ameliorative effect was prevented by concurrent NOS inhibition. CONCLUSIONS: Further analyses revealed that the maintenance of glycemic control and vascular NO bioavailability were stronger predictors of cerebral cortical MVD in OZR than was prevention of hypertension, and this may have implications for chronic treatment of CVD risk under stroke-prone conditions.

Seronegative immunity to SARS-CoV-2: a case study.

BACKGROUND: COVID-19 presents with a variable clinical course from asymptomatic to severe respiratory distress with nearly 25% mortality in mechanically-ventilated patients. As such, there is uncertainty regarding how host factors modulate the disease course. CASE PRESENTATION: This report examines these factors in two geriatric patients with multiple comorbid conditions who were residents of the long-term care facility in West Virginia that was the epicenter of COVID-19 in the state. Each patient had substantial, unprotected exposure to SARS-CoV-2 with subsequent negative PCR and antibody testing. CONCLUSIONS: These cases could represent an important step in understanding host factors that modulate the disease course and susceptibility of patients exposed to SARS-CoV-2, and illustrate the need for further research into host resistance relating to this pandemic.

Responding to a COVID-19 Outbreak at a Long-Term Care Facility.

This article describes an outbreak of COVID-19 in a long-term care facility (LTCF) in West Virginia that was the epicenter of the state's pandemic. Beginning with the index case, we describe the sequential order of procedures undertaken by the facility including testing, infection control, treatment, and communication with facility residents, staff, and family members. We also describe the lessons learned during the process and provide recommendations for handling an outbreak at other LTCFs.

Palliative Opioids May Be a Bridge to Care for Rural Long-Term Care Facility Residents with Severe COVID-19 Symptoms.

PURPOSE: Long term care facility (LTCF) residents are at high risk for severe COVID-19 symptoms, but those in rural and resource-limited areas, such as West Virginia (WV) and the larger Appalachian region, may experience delays in obtaining higher levels of medical care due to isolated geography and limited transportation. The study examined the outcomes between residents from 1 LCTF in WV who were moved to a hospital as compared to those remaining in the facility. METHODS: This cohort study compares mortality outcomes among severely symptomatic residents desiring hospitalization and those electing to stay at the facility receiving palliative opioids with supplemental oxygen. FINDINGS: Forty residents tested positive for COVID-19 with 11 developing severe respiratory symptoms. Eight residents elected to receive care at the LTCF while 3 desired hospitalization. Mortality was assessed at 4 time points and was not statistically different between those who were hospitalized versus those who received palliative opioids at the LTCF. Although not significant, the difference in mortality between those hospitalized (66.7%) and those receiving opioids at the LTCF (12.5%) in the acute phase trended toward significance (P = .072). Overall mortality at the 6-month time point among all residents who developed severe respiratory symptoms at this LTCF was 54.5%. CONCLUSIONS: LTCF residents choosing different levels of therapeutic intervention for severe COVID-19 symptoms had no mortality difference. Palliative opioids may be an effective treatment for LTCF residents with severe COVID-19 and also a bridge to care in rural areas with limited resources until more advanced treatments can be accessed.

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.

Physician wellness in rural America: a review.

OBJECTIVE: The primary purpose of this article is to review the unique wellness factors that affect physicians practicing in rural communities. Research has indicated that rural communities often struggle to attract and retain primary care physicians and numerous wellness factors impact these attraction/ retention rates. METHOD: Articles selected for inclusion in this review were determined based upon their relevance to rural physicians, overall wellness factors of physicians, and recruitment and retention of physicians in rural communities. Articles were included from peer-reviewed journals focusing upon both medical and psychological perspectives of rural physician wellness factors. RESULTS: Results indicated that rural physicians often have fewer resources, an increased workload, and longer hours when compared to their urban counterparts. These factors contribute to lower job satisfaction, poor retention rates, and decreased physician wellness. Research also demonstrates that physicians who are unwell are more likely to experience substance abuse, depression, relationship difficulties, and general psychological distress. These issues are particularly prominent in rural practice settings and may have significant impact upon rural patients. CONCLUSION: To date, there are few assessment measures available to assess physician wellness and no evidence-based treatments to address wellness deficits in rural physicians' medical or psychological health. Such resources would have the potential to benefit individual rural physicians and the quality of healthcare they deliver to rural communities. Future research should focus upon the assessment and promotion of rural physician well being, which may improve recruitment and retention of quality physicians to provide optimal care in rural communities.

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 [Thr(308)]) and vascular endothelial growth factor (VEGF) were the insulin-responsive intermediates in proliferating endothelial cells (ECs). In insulin-enhanced survival, both pAkt (Thr(308)) and pAkt (Ser(473)) 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.

Acute stretch promotes endothelial cell proliferation in wounded healing mouse skin.

We have developed a novel in vivo model utilizing acute stretch to investigate endothelial cell proliferation as a marker of vascular growth in healing mouse skin. This study is a follow-up to ones revealing immediate stretch improves blood flow, decreases total tissue necrosis, and induces tissue insulin transcription. Dorsal distally based flaps of skin were stretched for 3 min using linear (skin hook) plus hemispherical load cycling (inflated subcutaneous silicone catheter). Unstretched, wounded skin along the back and sternum served as postoperative controls. Laser Doppler flowmetry demonstrated a threefold increase in flap perfusion at postoperative day 7. A stretch-induced sixfold increase in endothelial cell mitogenesis accompanied enhancements in blood flow and extracorporal wound healing over the sternum. Western blots revealed up-regulation/activation of insulin and mitogenic signaling intermediates in stretched skin. Activated insulin and insulin growth factor receptors (pIR/pIGFR), protein kinase B (Akt, pAkt), vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (flk-1) were among the identified stretch-responsive intermediates. These results indicate the benefits of acute stretch are mediated through enhanced vascularity as evidenced by endothelial cell mitogenesis and up-regulation/activation of insulin and key angiogenic effectors in dorsal distally based skin flaps.