Paul V. Targonski

Coronary Endothelial Dysfunction Is Associated With an Increased Risk of Cerebrovascular Events

Background—Stroke, mainly attributable to atherothrombotic disease, represents a leading cause of disability and death in the Western world. Endothelial dysfunction, which is considered a key factor in atherogenesis, is associated with an increased risk of cardiovascular events. However, the magnitude of the association between coronary endothelial dysfunction (CED) and cerebrovascular events is unknown. This study was performed to investigate the association between CED and cerebrovascular events. Methods and Results—We studied 503 patients without obstructive coronary artery disease (CAD) who underwent coronary endothelial function testing by intracoronary acetylcholine infusion. Patients were divided according to the presence (n=305) or absence (n=198) of CED, and medical records were examined for the occurrence of ischemic or hemorrhagic stroke or transient ischemic attack either before (prevalent) or after (incident) coronary endothelial function testing. Among the study population, a total of 25 cerebrovascular events were documented, 22 in patients with CED (15 prevalent) and 3 in patients without (all prevalent) (P =0.008). Multivariable logistic regression, which included traditional cerebrovascular disease–related risk factors, identified the presence of CED as the single strongest factor associated with cerebrovascular events (OR, 4.32; 95% CI, 1.26 to 14.83). Kaplan-Meier analysis indicated that patients with CED had a significantly higher cumulative cerebrovascular event rate than those without (P =0.04). Conclusions—Presence of CED in patients without obstructive CAD is independently associated with an increased risk of cerebrovascular events. Thus, detection of this early stage of atherosclerosis may provide important information to identify patients who benefit from aggressive preventive strategies.

Preemptive genotyping for personalized medicine: design of the right drug, right dose, right time-using genomic data to individualize treatment protocol.

OBJECTIVE To report the design and implementation of the Right Drug, Right Dose, Right Time-Using Genomic Data to Individualize Treatment protocol that was developed to test the concept that prescribers can deliver genome-guided therapy at the point of care by using preemptive pharmacogenomics (PGx) data and clinical decision support (CDS) integrated into the electronic medical record (EMR). PATIENTS AND METHODS We used a multivariate prediction model to identify patients with a high risk of initiating statin therapy within 3 years. The model was used to target a study cohort most likely to benefit from preemptive PGx testing among the Mayo Clinic Biobank participants, with a recruitment goal of 1000 patients. We used a Cox proportional hazards model with variables selected through the Lasso shrinkage method. An operational CDS model was adapted to implement PGx rules within the EMR. RESULTS The prediction model included age, sex, race, and 6 chronic diseases categorized by the Clinical Classifications Software for International Classification of Diseases, Ninth Revision codes (dyslipidemia, diabetes, peripheral atherosclerosis, disease of the blood-forming organs, coronary atherosclerosis and other heart diseases, and hypertension). Of the 2000 Biobank participants invited, 1013 (51%) provided blood samples, 256 (13%) declined participation, 555 (28%) did not respond, and 176 (9%) consented but did not provide a blood sample within the recruitment window (October 4, 2012, through March 20, 2013). Preemptive PGx testing included CYP2D6 genotyping and targeted sequencing of 84 PGx genes. Synchronous real-time CDS was integrated into the EMR and flagged potential patient-specific drug-gene interactions and provided therapeutic guidance. CONCLUSION This translational project provides an opportunity to begin to evaluate the impact of preemptive sequencing and EMR-driven genome-guided therapy. These interventions will improve understanding and implementation of genomic data in clinical practice.

Identification of genetic loci affecting mouse-adapted bovine spongiform encephalopathy incubation time in mice

Abstract. Prion diseases are fatal neurodegenerative disorders of humans and animals, which include bovine spongiform encephalopathy (BSE) and its human form, variant Creutzfeldt-Jakob disease (vCJD). They are characterized by a prolonged incubation period, which is known to be influenced by polymorphisms in the prion protein gene. Previous studies of inbred mice have demonstrated that additional genetic loci also contribute to the observed variation in incubation period. However, a substantial transmission barrier between cow and mouse complicates studies using BSE. As a result, primary transmissions display large variations in incubation period and not all animals develop clinical signs of disease. To identify quantitative trait loci for BSE without the presence of a transmission barrier, we analysed 124 animals from an F2 intercross between CAST/Ei and NZW/OlaHsd mice and challenged them intracerebrally with a strain of BSE that was passaged twice through C57BL/6OlaHsd mice. Interval mapping identified two highly significant linked regions on chromosomes 2 and 11 with peak lod scores of 6.34 and 4.77, respectively. Composite interval mapping suggests that chromosome 2 includes three linked quantitative trait loci. Loci in the same position on chromosomes 2 and 11 were also identified in a previous study using the same mouse cross but infected with Chandler/RML scrapie prions. If these are the same loci, it suggests that these loci may be influencing incubation time independently of prion strain. This provides hope that it may be possible to identify human quantitative trait loci for prion incubation time using mouse models that may allow identification of at-risk individuals and the discovery of novel therapeutic targets.

Referral to Autopsy: Effect of Antemortem Cardiovascular Disease: A Population-Based Study in Olmsted County, Minnesota

PURPOSE Autopsy studies can provide insight into disease trends and their determinants, including data on the prevalence of atherosclerosis. However, such studies are subject to autopsy bias, which limits their generalizability to the source population. The impact of this bias on autopsy based estimates of time trends in heart disease prevalence is unknown. To report on the trends over time in autopsy rates in Olmsted County, MN, to examine the association between clinical diagnoses of cardiovascular diseases (CVDs) and referral to autopsy and how this association may have changed over time. METHODS We examined the trends in autopsy rates between 1979 and 1994 in Olmsted County, and the association between antemortem characteristics including cardiovascular diagnoses and autopsy referral. RESULTS From 1979 to 1994, a total of 9110 residents died in Olmsted County. The average annual autopsy rate was 30%. Autopsy rates declined from 36% in 1979 to 23% in 1994, corresponding to an average decline of 0.6%/year (p < 0.01). Referral to autopsy was positively associated with younger age, male sex, in-hospital place of death, antemortem diagnoses of myocardial infarction (MI) or peripheral vascular disease (PVD), and earlier calendar period. There was no evidence of an interaction between calendar period and any of these predictor variables. Antemortem diagnosis of heart failure was associated with a decrease in the odds of referral to autopsy over time as compared to persons without such diagnosis. CONCLUSIONS In Olmsted County, autopsy rates, although declining over time, have remained on average approximately 30%. Antemortem diagnoses of MI or PVD are associated with autopsy referral but this association did not change over time. While the greater decline overtime in the use of autopsy observed among decedents with an antemortem diagnosis of congestive heart failure (CHF) deserves further studies, the present findings reduce the concern for bias of time trends in the prevalence of atherosclerosis by changes in the clinical characteristics of decedents referred to autopsy.

A cross-sectional survey of the relationship between walking, biking, and the built environment for adults aged over 70 years.

Purpose Determine the relationship between walkability scores (using the Walk Score®) and activity levels (both bicycle and walking) in adults aged between 70 and 85 years in Rochester, Minnesota. Patients and methods This was a self-reported cross-sectional survey in adults aged over 70 years living in Rochester, Minnesota. Analysis used t-tests or chi-square analysis as appropriate. The primary endpoint was bicycle use or walking. The predictor variables were the Walk Score® as determined by their address, Charlson index, Duke Activity Status Index (DASI), and a 12-item short-form survey (SF-12) scores. Secondary analysis used an outcome of functional status (using the DASI) and walkability scores. Results Fifty-three individuals completed the surveys (48% return rate). The average age in the overall cohort was 77.02 years. Eighty-nine percent of individuals could walk at least a block and 15.1% rode their bicycles. The Walk Scores® did not differ between those who walked (38.9 ± 27.4) and those that did not (40.0 ± 36.08; P = 0.93). In a similar fashion, the Walk Scores® were not different for those who biked (36.38 ± 27.68) and those that did not (39.44 ± 28.49; P = 0.78). There was no relationship between Walk Scores® and DASI; however, a decreased DASI score was associated with increased age and comorbid illness (Charlson Score). Conclusion In this small pilot survey, there was no difference in Walk Scores® between those older adults who walked or biked, compared to those that did not. The Walk Scores® were low in both groups, which may indicate the lack of accessibility for all older adults living in Rochester, Minnesota. The functional status seemed to be more related to age or comorbid conditions than the built environment.

Effect of alcohol and tobacco use on vascular dementia: A matched case control study

Background Vascular dementia is the second most common type of dementia in the United States. The underlying association of tobacco and alcohol with vascular dementia is not completely understood. Purpose Determine the relationship of tobacco and alcohol use with the development of vascular dementia (VaD). Methods This was a matched case-control study of subjects living in Olmsted County, MN. Cases of VaD were identified through medical record abstraction using conventionally accepted definitions of VaD, using the National Institute of Neurological Disorders and Stroke and the Association Internationale pour la Recherche et l’Ensignement en Neurosicences ( NINDS-AIRENS) criteria and were matched to controls by gender and age within 3 years among persons free of dementia on the index date. Exposure data for alcohol and tobacco use were abstracted by trained nurses, along with demographic, lifestyle, cerebrovascular, cardiovascular, and vascular comorbid disease characteristics. Matched conditional logistic regression for univariate and multivariate evaluation of the association of tobacco and alcohol use with VaD was utilized. Results Current alcohol exposure was associated with a decreased risk of VaD with an odds ratio of 0.48 (95% confidence interval: 0.31–0.74). This protective effect of alcohol was seen in men, women, and subjects under 80 years of age. Tobacco use was not associated with VaD in univariate and multivariate analysis, and stratified analysis did not reveal any subgroup-specific associations between tobacco use and VaD in the study population. Conclusion Current alcohol use appears to have protective effects against the development of vascular dementia. The effects are more pronounced in subjects under age 80. This may reflect the direct vascular effects of alcohol on the vascular system or may represent a surrogate for better social or functional status. Previous alcohol use was not protective. Tobacco use was not a risk factor for VaD status, which was possibly an indication of survivorship bias in the cohort.

Intranasal cold-adapted influenza virus vaccine combined with inactivated influenza virus vaccines an extra boost for the elderly?

Although influenza vaccine delivery strategies have improved coverage rates to unprecedented levels nationally among persons aged 65 years and older, influenza remains one of the greatest vaccine-preventable threats to public health among elderly in the US. A new, intranasal live attenuated influenza vaccine (LAIV) was recently approved by the US FDA for use in persons aged 5–49 years, which excludes the elderly population. Limitations of immune response to inactivated influenza vaccine (IAIV) and effectiveness of current influenza vaccination strategies among the elderly suggest that a combined approach using LAIV and/or the IAIV in various permutations might benefit this group. We explore characteristics of the LAIV, data regarding its utility in protecting against influenza in the elderly, and challenges and opportunities regarding potential combined inactivated/live attenuated vaccination strategies for the elderly. Although LAIV appears to hold promise either alone or in combination with IAIV, large well conducted randomised trials are necessary to define further the role of LAIV in preventing influenza morbidity and mortality among the elderly. We also suggest that innovative vaccine coverage strategies designed to optimise prevention and control of influenza and minimise viral transmission in the community must accompany, in parallel, the acquisition of clinical trials data to best combat morbidity and mortality from influenza.

The Association of Transient Ischemic Attack Symptoms With Memory Impairment Among Elderly Participants of the Third US National Health and Nutrition Examination Survey

Background and Purpose: Stroke is a well-known risk factor for vascular dementia. However, the association of transient ischemic attacks with cognitive impairment is less well-established. Methods: Records from Third National Health and Nutrition Examination Survey were abstracted for demographic and medical information for participants with an age !60 years who reported being free of stroke. Five self-reported symptoms (weakness, numbness, loss of vision, inability to speak, and severe dizziness) were used as surrogates representing transient ischemic attacks. Information on conventional risk factors for vascular dementia was also obtained. Multivariable logistic regression was used to examine risk factors for memory impairment. Results: 4617 participants were included with a sample-weighted prevalence of memory impairment of 6.6% (1417 participants). The final multivariable analysis revealed a significant association between transient weakness and memory impairment (odds ratio 1.52, 95% CI 1.11-2.07). The other 4 transient ischemic attacks symptoms were not significantly associated with memory impairment in the final model. Systolic blood pressure >140 was most strongly associated with prevalent memory impairment (odds ratio, 9.78, 95% CI 1.49-64.3). Other associated risk factors included non-white race, male gender, age, education ≤12 years, and history of any alcohol use. Conclusion: Among transient ischemic attacks symptoms, self-reported weakness in the face, arm, or leg was significantly associated with memory impairment. This study indicates that transient ischemic attacks symptoms are, even in the absence of stroke, associated with memory impairment. Aggressive risk factor modification in patients with TIA symptoms may be warranted to prevent potential future memory loss.

Does the “Office Nurse” Level of Training Matter in the Family Medicine Office?

Background: The “office nurse” or clinical associate (registered nurse [RN], licensed practical nurse[LPN], or medical assistant [MA]) is a key member of the family medicine care team, but little is known about the influence of their level of training on team performance. Methods: The performance of the clinical dyad (clinician and associate) was studied in relation to the level of training of the nurse. The dyads performance was measured by the performance indicators of diabetes scores, patient satisfaction, and productivity. Results: Dyads with a RN scored higher in meeting all 5 of the diabetes quality indicators (27.8%) than those with a LPN (19.3%) or an MA (14.7%). For patient satisfaction, the RN dyads also scored higher than the other dyad groups (positive responses: RN, 96.8%; LPN, 95.5%; MA, 94.6%). Productivity was the same in all groups. Better diabetes performance was seen in those practices with fewer competing demands: nonrural versus rural (22.2% vs 15.1%, respectively), and those not doing obstetrics versus those doing obstetrics (20.3% vs 15.1%, respectively), and for physicians versus associate providers (18.8% vs 15.1%, respectively). Higher patient satisfaction was observed in those dyads who were nonrural verus rural (96.6 vs 94.1%), among those doing obstetrics (96.0% vs 94.9%), and in physicians verus associate providers (95.7% vs 93.2%). The number of years working with the same clinician was twice as high for RNs (6.63) and LPNs (6.57) than for MAs (3.29). Conclusions: A higher level of education of the clinical associate seems to confer skills that enhance the care teams management of chronic illness such as diabetes. This could potentially decrease the practice burden on other team members while facilitating the teams objectives in meeting quality indicators.

Effect of vascular burden as measured by vascular indexes upon vascular dementia: a matched case-control study.

Background Vascular dementia (VaD) is a challenging illness that affects the lives of older adults and caregivers. It is unclear how multiple vascular risk factor exposures (polyvascular disease) affect VaD. Purpose To determine the relationship between multiple vascular risk exposures, as counted on an index in cases with VaD, compared with healthy age-/gender-matched controls. Methods This was a matched case-control study of subjects living in Olmsted County, MN with documented VaD. Controls were selected by gender and age within 3 years from those who did not have dementia. The exposures included a total index (eleven exposure factors) added together, along with indexes for cerebrovascular disease (two exposures), cardiovascular disease (four exposures), vascular disease (three exposures), and lifestyle (two exposures). Analysis used matched conditional univariable logistic regression for each index. Results A total of 1736 potential subjects were identified, and 205 subjects were diagnosed with VaD. There was a significant association of the total score index with an odds ratio of 1.45 (95% confidence interval 1.21–1.74). The cerebrovascular index was also associated with VaD with an odds ratio of 12.18 (95% confidence interval 6.29–23.61). The cardiovascular and vascular indexes were also associated with VaD status. The lifestyle index was not associated with VaD. Conclusion The cumulative role of multiple vascular risk factors or diseases increased the risk of VaD, as noted by the total vascular index. The lifestyle index did not reveal any significant differences. Further work is required for evaluation of these indexes.