The Impact of Health Equity-Informed Eligibility Criteria to Increase the Delivery of Pharmacist-Delivered Comprehensive Medication Management Services for Patients with High Blood Pressure.

OBJECTIVE: Evaluate a cardiovascular care intervention intended to increase access to comprehensive medication management (CMM) pharmacy care and improve vascular health goals among socially disadvantaged patients. DESIGN: Retrospective electronic health records-based evaluation. SETTING: Thirteen health care clinics serving socially vulnerable neighborhoods within a large health system. PARTICIPANTS: Hypertensive and hyperlipidemic adult patients. INTERVENTION: CMM pharmacists increased recruitment among patients who met clinical criteria in clinics serving more diverse and socially vulnerable communities. CMM pharmacists partnered with patients to work toward meeting health goals through medication management and lifestyle modification. MAIN OUTCOME MEASURES: Changes in the engagement of socially disadvantaged patients between preintervention and intervention time periods; vascular health goals (ie, controlled blood pressure, appropriate statin and aspirin therapies, and tobacco nonuse); and the use of health system resources by CMM care group. RESULTS: The intervention indicated an overall shift in sociodemographics among patients receiving CMM care (fewer non-Hispanic Whites: N = 1988, 55.81% vs N = 2264, 59.97%, P < .001; greater place-based social vulnerability: N = 1354, 38.01% vs N = 1309, 34.68%, P = .03; more patients requiring interpreters: N = 776, 21.79% vs N = 698, 18.49%, P < .001) compared to the preintervention period. Among patients meeting intervention criteria, those who partnered with CMM pharmacists (N = 439) were more likely to connect with system resources (social work: N = 47, 10.71% vs 163, 3.74%, P < .001; medical specialists: N = 249, 56.72% vs N = 1989, 45.66%; P < .001) compared to those without CMM care (N = 4356). Intervention patients who partnered with CMM pharmacists were also more likely to meet blood pressure (N = 357, 81.32% vs N = 3317, 76.15%, P < .001) and statin goals (N = 397, 90.43% vs N = 3509, 80.56%, P < .001) compared to non-CMM patients. CONCLUSIONS: The demographics of patients receiving CMM became more diverse with the intervention, indicating improved access to CMM pharmacists. Cultivating relationships among patients with greater social disadvantage and cardiovascular disease and CMM pharmacists may improve health outcomes and connect patients to essential resources, thus potentially improving long-term cardiovascular outcomes.

Surveillance of the Initiation of, Participation in, and Completion of Cardiac Rehabilitation in Minnesota, 2017-2018.

INTRODUCTION: Cardiac rehabilitation (CR) is an evidence-based secondary prevention program designed to improve cardiovascular health after a cardiac event. The objective of our study was to identify gaps in CR use among publicly and privately insured people in Minnesota to assist in developing shared goals among public health, cardiac rehabilitation professionals, and program delivery sites to improve CR delivery. METHODS: We applied a published claims-based surveillance methodology to the Minnesota All Payer Claims Database to assess eligibility for, initiation of, participation in, and completion of CR by patients with qualifying events in 2017. We stratified results by sociodemographic and geographic factors and qualifying condition and used adjusted prevalence ratios to make statistical comparisons. RESULTS: Less than half (47.6%) of qualifying patients initiated CR within 1 year of their qualifying event; the rate was higher among men (vs women), adults aged 45 to 64 years (vs ≥65 y), and patients with commercial or Medicaid insurance coverage (vs Medicare). Among those who initiated CR, only 14.0% completed the full series of 36 sessions. Participation in at least 12 sessions and completion of 36 sessions was less likely among adults aged 18 to 64 (vs 65-74 y) and among patients covered by Medicaid (vs Medicare). Patterns of CR initiation, participation, and completion also varied geographically. CONCLUSION: This analysis expands on previous Medicare fee-for-service population CR surveillance and provides a first detailed look at the CR landscape in Minnesota, renewing attention to CR as a key secondary prevention strategy. Collaboration and sharing with partners has established the Minnesota Department of Health as a valuable partner in driving health system change to improve equitable provision of CR in Minnesota.

The impact of prolonged lower limb ischemia on amputation, mortality, and functional status: the FRIENDS registry.

BACKGROUND: Peripheral artery disease (PAD) is a major cause of cardiovascular ischemic events and amputation. Knowledge gaps exist in defining and measuring key factors that predict these events. The objective of this study was to assess whether duration of limb ischemia would serve as a major predictor of limb and patient survival. METHODS: The FReedom from Ischemic Events: New Dimensions for Survival (FRIENDS) registry enrolled consecutive patients with limb-threatening peripheral artery disease at a single tertiary care hospital. Demographic information, key clinical care time segments, functional status and use of revascularization, and pharmacotherapy data were collected at baseline, and vascular ischemic events, cardiovascular mortality, and all-cause mortality were recorded at 30 days and 1 year. RESULTS: A total of 200 patients with median (interquartile range) age of 76 years (65-84 years) were enrolled in the registry. Median duration of limb ischemia was 0.75 days for acute limb ischemia (ALI) and 61 days for chronic critical limb ischemia (CLI). Duration of limb ischemia of <12, 12 to 24, and >24 hours in patients with ALI was associated with much higher rates of first amputation (P = .0002) and worse amputation-free survival (P = .037). No such associations were observed in patients with CLI. CONCLUSIONS: For individuals with ischemic symptoms <14 days, prolonged limb ischemia is associated with higher 30-day and 1-year amputation, systemic ischemic event rates, and worse amputation-free survival. No such associations are evident for individuals with chronic CLI. These data imply that prompt diagnosis and revascularization might improve outcomes for patients with ALI.

Blood glucose screening rates among Minnesota adults with hypertension, Behavioral Risk Factor Surveillance System, 2011.

INTRODUCTION: Many US adults have multiple chronic conditions, and hypertension and diabetes are among the most common dyads. Diabetes and prediabetes prevalence are increasing, and both conditions negatively affect cardiovascular health. Early diagnosis and treatment of diabetes and prediabetes can benefit people with hypertension by preventing cardiovascular complications. METHODS: We analyzed 2011 Minnesota Behavioral Risk Factor Surveillance System data to describe the proportion of adults with hypertension screened for diabetes according to US Preventive Services Task Force Recommendations for blood glucose testing. Covariates associated with lower odds of recent screening among adults without diabetes were determined using weighted logistic regression. RESULTS: Of Minnesota adults with self-reported hypertension, 19.6% had a diagnosis of diabetes and 10.7% had a diagnosis of prediabetes. Nearly one-third of adults with hypertension without diabetes had not received blood glucose screening in the past 3 years. Factors associated with greater odds of not being screened in multivariable models included being aged 18 to 44 years (adjusted odds ratio [AOR], 1.77; 95% confidence interval [CI], 1.23-2.55); being nonobese, with stronger effects for normal body mass index; having no check-up in the past 2 years (AOR, 2.49; 95% CI, 1.49-4.17); having hypertension treated with medication (AOR, 2.01; 95% CI, 1.49-2.71); and completing less than a college degree (AOR, 1.45; 95% CI, 1.14-1.84). Excluding respondents with prediabetes or those not receiving a check-up did not change the results. CONCLUSIONS: Failure to screen among providers and failure to understand the importance of screening among individuals with hypertension may mean missed opportunities for early detection, clinical management, and prevention of diabetes.

Acute stroke reperfusion therapy trends in the expanded treatment window era.

BACKGROUND: The American Heart Association/American Stroke Association (AHA/ASA) recommended an expansion of the time window for acute ischemic stroke (AIS) reperfusion with intravenous (IV) recombinant tissue plasminogen activator (rt-PA) from 3 to 4.5 hours after symptom onset. We examine rates of IV and intra-arterial (IA) reperfusion before and after the recommendations to track guideline adoption in community practice. METHODS: Patients with AIS in the Paul Coverdell National Acute Stroke Registry spanning years 2007-2012 were identified. Trends in rates of IV rt-PA versus IA therapy were examined. Outcomes included symptomatic intracerebral hemorrhage (sICH), in-hospital mortality, ability to ambulate at discharge, and discharge destination. RESULTS: From 2007 to 2012, there were 182,235 AIS patients (median age, 72 years; 51.5% women) in the database at the time of analysis. AIS patients receiving IV rt-PA increased significantly from 3.7% in 2007 to 5.1% in 2012 in the ≤3 hours time window and from .2% in 2007 to 1.3% in 2012 in the 3-4.5 hours time window (P < .001 for both). There was also a significant increase in the rate of IA therapy between 2007 and 2012 (P < .001). There was a significant decrease in the rate of sICH among patients who received any reperfusion between 2007 and 2012. CONCLUSIONS: There was a trend for increased utilization of IV rt-PA in the 0-3 hours and the 3-4.5 hours time windows, which began around the same time as the publication of AHA/ASA recommendations in 2009. This increase was associated with an increase in IA treatment rates along with a decrease in overall sICH rates for patients receiving any reperfusion.

Serum and dietary magnesium and incidence of atrial fibrillation in whites and in African Americans--Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: Low serum magnesium (Mg) has been associated with an increased risk of cardiovascular disease (CVD), including ventricular arrhythmias, but the association between serum or dietary Mg and atrial fibrillation (AF) has not been investigated. METHODS AND RESULTS: A total of 14,290 men and women (75% white; 53% female; mean age, 54 years) free of AF at baseline participating in the Atherosclerosis Risk in Communities study in the United States, were studied. Incident AF cases through 2009 were ascertained from electrocardiograms, hospital discharge codes, and death certificates. Multivariate Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for AF associated with serum and dietary Mg quintiles. Over a median follow-up time of 20.6 years, 1,755 incident AF cases were identified. In multivariate models, lower serum Mg was associated with higher AF risk: compared to individuals in the middle quintile (≥ 0.80-0.83 mmol/L), the HR (95% CI) of AF in quintiles 1, 2, 4, and 5 were 1.34 (1.16-1.54), 0.99 (0.85-1.16), 1.04 (0.90-1.22), and 1.06 (0.91-1.23), respectively. There was no evidence of significant interactions between serum Mg and sex or race. No association between dietary Mg and AF risk was observed. CONCLUSIONS: Lower serum Mg was associated with a higher AF risk, and this association was not different between whites and African Americans. Dietary Mg was not associated with AF risk.

The FReedom from Ischemic Events-New Dimensions for Survival (FRIENDS) registry: design of a prospective cohort study of patients with advanced peripheral artery disease.

BACKGROUND: Advanced lower extremity peripheral artery disease (PAD), whether presenting as acute limb ischemia (ALI) or chronic critical limb ischemia (CLI), is associated with high rates of cardiovascular ischemic events, amputation, and death. Past research has focused on strategies of revascularization, but few data are available that prospectively evaluate the impact of key process of care factors (spanning pre-admission, acute hospitalization, and post-discharge) that might contribute to improving short and long-term health outcomes. METHODS/DESIGN: The FRIENDS registry is designed to prospectively evaluate a range of patient and health system care delivery factors that might serve as future targets for efforts to improve limb and systemic outcomes for patients with ALI or CLI. This hypothesis-driven registry was designed to evaluate the contributions of: (i) pre-hospital limb ischemia symptom duration, (ii) use of leg revascularization strategies, and (iii) use of risk-reduction pharmacotherapies, as pre-specified factors that may affect amputation-free survival. Sequential patients would be included at an index "vascular specialist-defined" ALI or CLI episode, and patients excluded only for non-vascular etiologies of limb threat. Data including baseline demographics, functional status, co-morbidities, pre-hospital time segments, and use of medical therapies; hospital-based use of revascularization strategies, time segments, and pharmacotherapies; and rates of systemic ischemic events (e.g., myocardial infarction, stroke, hospitalization, and death) and limb ischemic events (e.g., hospitalization for revascularization or amputation) will be recorded during a minimum of one year follow-up. DISCUSSION: The FRIENDS registry is designed to evaluate the potential impact of key factors that may contribute to adverse outcomes for patients with ALI or CLI. Definition of new "health system-based" therapeutic targets could then become the focus of future interventional clinical trials for individuals with advanced PAD.

Impact of an electronic medical record-based clinical decision support tool for dysphagia screening on care quality.

BACKGROUND AND PURPOSE: Dysphagia screening (DS) before oral intake in patients with acute stroke is a hospital-level performance measure. We report outcomes of an initiative to improve compliance to this quality measure. METHODS: The design was a pre- versus postintervention comparison study. The Intervention was an electronic medical record-based clinical DS system embedded within stroke admission orders. The clinical DS was designed to facilitate DS in patients with stroke. The primary outcome was compliance to a process measure in patients with ischemic stroke: performance of a swallow screen before oral intake. RESULTS: DS measure compliance increased from 36% to 74% (P=0.001). Chart audits found screened patients were more likely to have clinical DS-embedded admission orders initiated or stroke unit admission. CONCLUSIONS: The electronic medical record offers a ready platform for clinical DS implementation. DS is a difficult performance measure to improve. The described clinical DS has the potential for improving performance on this challenging care quality measure.

Utilization of intravenous thrombolysis in 3-4.5 hours: analysis of the Minnesota stroke registry.

BACKGROUND: The American Heart Association and the American Stroke Association recommend intravenous (IV) thrombolysis up to 4.5 h from acute ischemic stroke symptom onset based on its proven benefit in improving patient outcomes. We analyzed data from the Minnesota Stroke Registry to assess the rates of IV thrombolytic utilization and the process of care in this expanded window. METHODS: We identified patients who had received IV recombinant tissue plasminogen activator (rt-PA) at any of the 19 participating hospitals from January 1, 2008 till December 31, 2010. Treatment groups were those actually treated by IV rt-PA in 0-3 h and those treated by IV rt-PA in 3-4.5 h. Duration from symptom onset to arrival in the emergency department (ED) was dichotomized to cohorts of 0-2 and 2-3.5 h. We determined the overall utilization of IV rt-PA in the expanded window and calculated door-to-needle times for the two treatment windows. We also ascertained the rates of symptomatic intracerebral hemorrhage between the two treatment groups. RESULTS: Out of the total 519 patients who received IV rt-PA for acute ischemic stroke, 433 (83%) were treated within 0-3 h and 86 (17%) within 3-4.5 h. Of all the patients who received IV rt-PA within 3-4.5 h, 45% arrived at the ED within 2 h of symptom onset. Median door-to-needle time for the 0- to 3-hour window was 74.5 min [interquartile range (IQR) 57-90] and 54 min (IQR 43.5-70.5) for the 3- to 4.5-hour window. Based on arrival time to the ED, door-to-needle time of ≤60 min was achieved by only 31% (142/458) of patients who arrived within 0-2 h of their symptom onset compared to 61% (37/61) of those who arrived at the ED within 2-3.5 h of their symptom onset. Fifty-nine (14%) patients in the 0- to 3-hour group and 17 (20%) patients in the 3- to 4.5-hour group received a combination of IV rt-PA and endovascular treatments. Among patients with documented admission National Institutes of Health Stroke Scale scores, the values (median with IQR) were different between the 0- to 3- and the 3- to 4.5-hour group, i.e. 10 (IQR 5-18) and 7 (IQR 4-14), respectively. CONCLUSION: Patients who received IV rt-PA within the 3- to 4.5-hour window comprised 17% of all IV rt-PA cases treated in the Minnesota Stroke Registry hospitals after the new guidelines recommended a time window expansion. Almost half of these patients would have qualified for treatment within the 0- to 3-hour window as they presented within 0-2 h of symptom onset. Patients arriving 2-3.5 h after symptom onset received thrombolysis on average 20 min faster than patients arriving within 2 h of symptom onset.

The incidence and health economic burden of ischemic amputation in Minnesota, 2005-2008.

INTRODUCTION: Critical limb ischemia (CLI) is the most severe manifestation of peripheral artery disease (PAD), is associated with high rates of myocardial infarction, stroke, and amputation, and has a high health economic cost. The objective of this study was to estimate the incidence of lower limb amputation, the most serious consequence of CLI, and to create a surveillance methodology for the incidence of ischemic amputation in Minnesota. METHODS: We assessed the incidence of ischemic amputation using all inpatient hospital discharge claims in Minnesota from 2005 through 2008. We identified major and minor ischemic amputations via the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) procedure codes for lower limb amputation not due to trauma or cancer and assessed geographic and demographic differences in the incidence of ischemic amputation. RESULTS: The age-adjusted annual incidence of lower limb ischemic amputation in Minnesota during the 4-year period was 20.0 per 100,000 (95% confidence interval, 19.4-20.6). Amputations increased significantly with age, were more common in men and in people with diabetes, and were slightly more common in rural residents. The number of amputation-related hospitalizations was steady over 4 years. The median total charge for each amputation was $32,129, and cumulative inpatient hospitalization charges were $56.5 million in 2008. CONCLUSION: The incidence of ischemic amputation is high and results in major illness and health economic costs. These data represent the first population-based estimate of ischemic amputation at the state level and provide a national model for state-based surveillance.

Utility of dysphagia screening results in predicting poststroke pneumonia.

BACKGROUND AND PURPOSE: Dysphagia screening before oral intake (DS) is a stroke care quality indicator. The value of DS is unproven. Quality adherence and outcome data from the Paul Coverdell National Acute Stroke Registry were examined to establish value of DS. METHODS: Adherence to the DS quality indicator was examined in patients with stroke discharged from Paul Coverdell National Acute Stroke Registry hospitals between March 1 and December 31, 2009. Patients were classified as unscreened (US), screened and passed (S/P), and screened and failed. Associations between screening status and pneumonia rate were assessed by logistic regression models after adjustment for selected variables. RESULTS: A total of 18 017 patients with stroke discharged from 222 hospitals in 6 states were included. A total of 4509 (25%) were US; 8406 (47%) were S/P, and 5099 (28%) were screened and failed. Compared with US patients, screened patients were significantly more impaired. Pneumonia rates were: US 4.2%, S/P 2.0%, and screened and failed 6.8%. After adjustment for demographic and clinical features, US patients were at a higher risk of pneumonia (OR, 2.2; 95% CI, 1.7 to 2.7) compared with S/P patients. CONCLUSIONS: Data suggest that patients are selectively screened based on stroke severity. Pneumonia rate was higher in US patients compared with S/P patients. Clinical judgment regarding who should be screened is imperfect. S/P patients have a lower pneumonia rate indicating that DS adds accuracy in predicting pneumonia risk. The Joint Commission recently retired DS as a performance indicator for Primary Stroke Center certification. These results suggest the need to implement a DS performance measure for patients with acute stroke.

Serum magnesium and risk of sudden cardiac death in the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: We hypothesized that serum magnesium (Mg) is associated with increased risk of sudden cardiac death (SCD). METHODS: The Atherosclerosis Risk in Communities Study assessed risk factors and levels of serum Mg in a cohort of 45- to 64-year-old subjects in 1987-1989 (n = 14,232). After an average of 12 years of follow-up, we observed 264 cases of SCD, as determined by physician review of all suspected cases. We used proportional hazards regression to evaluate the association of serum Mg with risk of SCD. RESULTS: Individuals in the highest quartile of serum Mg were at significantly lower risk of SCD in all models. This association persisted after adjustment for potential confounding variables, with an almost 40% reduced risk of SCD (hazard ratio 0.62, 95% CI 0.42-0.93) in quartile 4 versus 1 of serum Mg observed in the fully adjusted model. CONCLUSIONS: This study suggests that low levels of serum Mg may be an important predictor of SCD. Further research into the effectiveness of Mg supplementation for those considered to be at high risk for SCD is warranted.

Serum and dietary magnesium and risk of ischemic stroke: the Atherosclerosis Risk in Communities Study.

The authors sought to examine the relation between serum or dietary magnesium and the incidence of ischemic stroke among blacks and whites. Between 1987 and 1989, 14,221 men and women aged 45-64 years took part in the first examination of the Atherosclerosis Risk in Communities Study cohort. The incidence of stroke was ascertained from hospital records. Higher serum magnesium levels were associated with lower prevalence of hypertension and diabetes mellitus at baseline. During the 15-year follow-up, 577 ischemic strokes occurred. Serum magnesium was inversely associated with ischemic stroke incidence. The age-, sex-, and race-adjusted rate ratios of ischemic stroke for those with serum magnesium levels of or=1.8 mEq/L were 1.0, 0.78 (95% confidence interval (CI): 0.62, 0.96), 0.70 (95% CI: 0.56, 0.88), and 0.75 (95% CI: 0.59, 0.95) (P(trend) = 0.005). After adjustment for hypertension and diabetes, the rate ratios were attenuated to nonsignificant levels. Dietary magnesium intake was marginally inversely associated with the incidence of ischemic stroke (P(trend) = 0.09). Low serum magnesium levels could be associated with increased risk of ischemic stroke, in part, via effects on hypertension and diabetes.

Suggestion for linkage of chromosome 1p35.2 and 3q28 to plasma adiponectin concentrations in the GOLDN Study.

BACKGROUND: Adiponectin is inversely associated with obesity, insulin resistance, and atherosclerosis, but little is known about the genetic pathways that regulate the plasma level of this protein. To find novel genes that influence circulating levels of adiponectin, a genome-wide linkage scan was performed on plasma adiponectin concentrations before and after 3 weeks of treatment with fenofibrate (160 mg daily) in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study. We studied Caucasian individuals (n = 1121) from 190 families in Utah and Minnesota. Of these, 859 individuals from 175 families had both baseline and post-fenofibrate treatment measurements for adiponectin. Plasma adiponectin concentrations were measured with an ELISA assay. All participants were typed for microsatellite markers included in the Marshfield Mammalian Genotyping Service marker set 12, which includes 407 markers spaced at approximately 10 cM regions across the genome. Variance components analysis was used to estimate heritability and to perform genome-wide scans. Adiponectin was adjusted for age, sex, and field center. Additional models also included BMI adjustment. RESULTS: Baseline and post-fenofibrate adiponectin measurements were highly correlated (r = 0.95). Suggestive (LOD > 2) peaks were found on chromosomes 1p35.2 and 3q28 (near the location of the adiponectin gene). CONCLUSION: Two candidate genes, IL22RA1 and IL28RA, lie under the chromosome 1 peak; further analyses are needed to identify the specific genetic variants in this region that influence circulating adiponectin concentrations.

The genetic architecture of fasting plasma triglyceride response to fenofibrate treatment.

Metabolic response to the triglyceride (TG)-lowering drug, fenofibrate, is shaped by interactions between genetic and environmental factors, yet knowledge regarding the genetic determinants of this response is primarily limited to single-gene effects. Since very low-density lipoprotein (VLDL) is the central carrier of fasting TG, identifying factors that affect both total TG and VLDL-TG response to fenofibrate is critical for predicting individual fenofibrate response. As part of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, 688 individuals from 161 families were genotyped for 91 single-nucleotide polymorphisms (SNPs) in 25 genes known to be involved in lipoprotein metabolism. Using generalized estimating equations to control for family structure, we performed linear modeling to investigate whether single SNPs, single covariates, SNP-SNP interactions, and/or SNP-covariate interactions had a significant association with the change in total fasting TG and fasting VLDL-TG after 3 weeks of fenofibrate treatment. A 10-iteration fourfold cross-validation procedure was used to validate significant associations and quantify their predictive abilities. More than one-third of the significant, cross-validated SNP-SNP interactions predicting each outcome involved just five SNPs, showing that these SNPs are of key importance to fenofibrate response. Multiple variable models constructed using the top-ranked SNP--covariate interactions explained 11.9% more variation in the change in TG and 7.8% more variation in the change in VLDL than baseline TG alone. These results yield insight into the complex biology of fenofibrate response, which can be used to target fenofibrate therapy to individuals who are most likely to benefit from the drug.

Fenofibrate effect on triglyceride and postprandial response of apolipoprotein A5 variants: the GOLDN study.

OBJECTIVE: Apolipoprotein A5 (APOA5) is a key determinant of plasma triglyceride (TG) concentrations. Genetic variation at the APOA5 locus could be responsible for some of the observed differences in response to fenofibrate therapy. METHODS AND RESULTS: We examined the association between tag SNPs (-1131T>C and 56C>G) at APOA5 and TG and HDL-C response to fenofibrate and a postprandial lipid challenge in 791 men and women participating in the GOLDN study. After 3-week drug treatment, APOA5 56G carriers displayed significant decrease in TG (P=0.006), and increase in HDL-C (P=0.002) levels relative to their basal values in the fasting state when compared with noncarriers (a TG reduction of -35.8+/-2.8% versus -27.9+/-0.9% and a HDL-C increase of 11.8+/-1.3% versus 6.9+/-0.5%, respectively). In the postprandial lipemia after a fat load, the 56G carriers showed a significant decrease in the area under curve for TG and increase for HDL-C than the noncarriers. These diverse beneficial responses of 56G carriers to fenofibrate were further characterized by a higher increase in large LDL-C concentrations and LDL size. On the other hand, subjects with different APOA5-1131T>C genotypes showed no significant response to fenofibrate intervention. CONCLUSION: This study suggests that the APOA5 56G carriers benefited more from the fenofibrate treatment than noncarriers in lowering plasma TG and increasing HDL-C levels.

Sequence variation in proprotein convertase subtilisin/kexin type 9 serine protease gene, low LDL cholesterol, and cancer incidence.

Some prospective epidemiologic studies have suggested that a low plasma cholesterol level may be associated with increased risk of cancer. Certain sequence variants in the proprotein convertase subtilisin/kexin type 9 serine protease gene (PCSK9) are associated with lifelong low total and LDL cholesterol. We therefore analyzed the association of PCSK9 variation with incidence of cancer between 1987 and 2000 in a prospective study (n=13,250). The frequency of the PCSK9 variants studied was 2.4% in blacks and 3.2% in whites. Neither was associated with increased cancer incidence: age- and sex-adjusted hazard ratios were 0.66 [95% confidence interval (95% CI), 0.31-1.39] in blacks and 0.77 (95% CI, 0.54-1.09) in whites. Low baseline total or LDL cholesterol levels in 1987 to 1989 were also not statistically significantly associated with incident cancer: multivariable-adjusted hazard ratios for the lowest compared with the highest quartiles of LDL cholesterol were 1.05 (95% CI, 0.78-1.40) in blacks and 1.16 (95% CI, 0.99-1.36) in whites. These data suggest that a lifelong low cholesterol concentration, as reflected by these PCSK9 variants, does not increase risk of cancer.

Evidence for a gene influencing fasting LDL cholesterol and triglyceride levels on chromosome 21q.

High levels of low-density lipoprotein (LDL) cholesterol, low levels of high-density lipoprotein (HDL) cholesterol, and high levels of triglycerides (TG) are strong predictors of cardiovascular disease risk. Motivated by previous evidence for pleiotropy between cholesterol and TG levels, we conducted bivariate linkage analysis of LDL cholesterol and TG concentration among participants of the Hypertension Genetic Epidemiolgy Network (HyperGEN), one of four networks in the NHLBI sponsored Family Blood Pressure Program Project. All available hypertensive siblings and their first-degree relatives were recruited. Both phenotypes were similarly adjusted for ethnicity, study center, sex, age, age-by-sex interactions, smoking, alcohol consumption, hormone use, diabetes medication use, and waist circumference. Variance component linkage analysis was performed as implemented in SOLAR, using ethnicity-specific marker allele frequencies derived from founders and multipoint IBDs calculated in MERLIN. A maximum genome-wide empirical LOD score of 3.9 was detected on chromosome 21 at 54cM, between markers D21S2055 and D21S1446. This signal overlaps with suggestive and/or significant linkages for total cholesterol, LDL cholesterol, and apolipoprotein B in three other studies and is suggestive of one or more genes on chromosome 21q jointly regulating LDL cholesterol and TG concentration.