Jeffrey R. Misialek

Use of coronary artery calcium testing to guide aspirin utilization for primary prevention: estimates from the multi-ethnic study of atherosclerosis

Background—Aspirin for the primary prevention of coronary heart disease (CHD) is only recommended for individuals at high risk for CHD although the majority of CHD events occur in individuals who are at low to intermediate risk. Methods and Results—To estimate the potential of coronary artery calcium (CAC) scoring to guide aspirin use for primary prevention of CHD, we studied 4229 participants from the Multi-Ethnic Study of Atherosclerosis who were not on aspirin at baseline and were free of diabetes mellitus. Using data from median 7.6-year follow-up, 5-year number-needed-to-treat estimations were calculated by applying an 18% relative CHD reduction to the observed event rates. This was contrasted to 5-year number-needed-to-harm estimations based on the risk of major bleeding reported in an aspirin meta-analysis. Results were stratified by a 10% 10-year CHD Framingham Risk Score (FRS). Individuals with CAC≥100 had an estimated net benefit with aspirin regardless of their traditional risk status (estimated 5-year number needed to treat of 173 for individuals <10% FRS and 92 for individuals ≥10% FRS, estimated 5-year number needed to harm of 442 for a major bleed). Conversely, individuals with zero CAC had unfavorable estimations (estimated 5-year number needed to treat of 2036 for individuals <10% FRS and 808 for individuals ≥10% FRS, estimated 5-year number needed to harm of 442 for a major bleed). Sex-specific and age-stratified analyses showed similar results. Conclusions—For the primary prevention of CHD, Multi-Ethnic Study of Atherosclerosis participants with CAC≥100 had favorable risk/benefit estimations for aspirin use while participants with zero CAC were estimated to receive net harm from aspirin.

Measurement by a Novel LC-MS/MS Methodology Reveals Similar Serum Concentrations of Vitamin D–Binding Protein in Blacks and Whites

BACKGROUND Vitamin D deficiency is associated with poor bone health and other adverse health outcomes; however, the associations are greatly attenuated in black vs white individuals. One possible explanation for this attenuation is different concentrations of bioavailable vitamin D metabolites in plasma, which are estimated with equations that include the total concentration of vitamin D binding globulin (VDBG) and haplotype-specific dissociation constants. METHODS We developed a method to quantify VDBG with LC-MS/MS that could also identify the haplotypes/isoforms of VDBG present. We validated the method according to recent recommendations for publications of biomarker studies. We determined serum VDBG concentrations in samples from the Atherosclerosis Risk in Communities cohort and compared the results with a widely used monoclonal immunoassay. RESULTS With 10 μL of serum or plasma, the lower limit of quantification for the assay (<20% CV) was 71 μg/mL. The assay was linear from 62 to 434 μg/mL, with total imprecision of 7.3-9.0% CV at approximately 250 μg/mL. Significant hemolysis interfered with quantification. The identification of isoforms was 97% concordant with genotyping (κ coefficient). Method comparison with immunoassay revealed significant isoform-specific effects in the immunoassay. Mean concentrations (SD) of VDBG by mass spectrometry were similar in whites and blacks [262 (25) vs 266 (35) μg/mL, respectively; P = 0.43]. CONCLUSIONS Validated mass spectrometric methods for the quantification of proteins in human samples can provide additional information beyond immunoassay. Counter to prior observations by immunoassay, VDBG concentrations did not vary by race.

Physical activity, obesity, weight change, and risk of atrial fibrillation: the Atherosclerosis Risk in Communities study.

Background—Physical activity (PA) has previously been suggested to attenuate the risk of atrial fibrillation (AF) conferred by excess body weight and weight gain. We prospectively examined the relationship between body size, weight change, and level of PA in a biracial cohort of middle-aged men and women. Methods and Results—Baseline characteristics on risk factor levels were obtained on 14 219 participants from the Atherosclerosis Risk in Communities Study. AF incidence was ascertained from 1987 to 2009. Adjusted Cox proportional hazards models were used to estimate the associations between body mass index, waist circumference, relative weight change, and PA level with incident AF. During follow-up, there were 1775 cases of incident AF. Body mass index and waist circumference were positively associated with AF as was weight loss/gain of >5% initial body weight. An ideal level of PA had a small protective effect on AF risk and partially attenuated the risk of AF associated with excess weight in men but not women: compared with men with a normal body mass index, the risk of AF in obese men with an ideal, intermediate, and poor level of PA at baseline was increased by 37%, 129%, and 156% (Pinteraction=0.04). During follow-up, PA did not modify the association between weight gain and risk of AF. Conclusions—Obesity and extreme weight change are risk factors for incident AF, whereas being physically active is associated with a small reduction in risk. In men only, being physically active offset some, but not all, of the risk incurred with excess body weight.Background— Physical activity (PA) has previously been suggested to attenuate the risk of atrial fibrillation (AF) conferred by excess body weight and weight gain. We prospectively examined the relationship between body size, weight change, and level of PA in a biracial cohort of middle-aged men and women. Methods and Results— Baseline characteristics on risk factor levels were obtained on 14 219 participants from the Atherosclerosis Risk in Communities Study. AF incidence was ascertained from 1987 to 2009. Adjusted Cox proportional hazards models were used to estimate the associations between body mass index, waist circumference, relative weight change, and PA level with incident AF. During follow-up, there were 1775 cases of incident AF. Body mass index and waist circumference were positively associated with AF as was weight loss/gain of >5% initial body weight. An ideal level of PA had a small protective effect on AF risk and partially attenuated the risk of AF associated with excess weight in men but not women: compared with men with a normal body mass index, the risk of AF in obese men with an ideal, intermediate, and poor level of PA at baseline was increased by 37%, 129%, and 156% ( P interaction=0.04). During follow-up, PA did not modify the association between weight gain and risk of AF. Conclusions— Obesity and extreme weight change are risk factors for incident AF, whereas being physically active is associated with a small reduction in risk. In men only, being physically active offset some, but not all, of the risk incurred with excess body weight.

Circulating levels of liver enzymes and incidence of atrial fibrillation: the Atherosclerosis Risk in Communities cohort

Background Elevated levels of circulating liver enzymes have been associated with increased risk of cardiovascular disease. Their possible association with atrial fibrillation (AF) has received little attention. Methods We studied 9333 men and women, aged 53–75 years, free of AF, participating in the Atherosclerosis Risk in Communities Study followed-up from 1996 to 2010. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ glutamyl transpeptidase (GGT) were measured in stored plasma samples. Incident AF was ascertained from hospitalisations and death certificates. Associations between liver enzymes and AF incidence were assessed using multivariable Cox proportional hazards models. Results During a mean follow-up of 12 years, 1021 incident AF events were identified. Levels of AST, and to a lesser extent ALT, showed a U-shaped association with AF risk, with higher AF risk among individuals in the two extremes of the distribution in minimally adjusted models. The associations were weakened after adjustment for potential confounders. By contrast, GGT, modelled as log base 2, was linearly associated with AF risk after multivariable adjustment: a doubling of GGT levels was associated with a 20% increased risk of AF (95% CI 10% to 30%). Additional adjustment for inflammatory markers did not appreciably affect the results. Associations were not different in men and women, in whites and blacks, among never drinkers of alcohol, and among those without prevalent heart failure. Conclusions In this community-based prospective study, higher levels of liver enzymes, mainly GGT, were associated with an increased risk of AF. The mechanisms underlying this association deserve further scrutiny.

Reference ranges of PR duration and P-wave indices in individuals free of cardiovascular disease: The Multi-Ethnic Study of Atherosclerosis (MESA)

In this brief report, we provide normal reference ranges for PR duration [unadjusted and heart rate adjusted] and P-wave indices [duration, amplitude and terminal force in V1] in individuals free of cardiovascular disease and its risk factors. We used automatically processed digital ECG data from 1252 US participants [mean age 59 (± 10) years, 738 women, 588 whites, 207 African-Americans, 217 Hispanics, 240 Chinese] from the Multi-Ethnic Study of Atherosclerosis [MESA]. In multivariable adjusted linear regression models with PR and each P-wave variable as a separate outcome, significant age, sex and race differences in these markers were observed. Subsequently, we report reference ranges for abnormal [2nd and 98th percentiles], borderline abnormal [5th and 95th percentiles] and mean [SD] values of PR and P-wave indices stratified by age [middle age (45-64 years) and seniors (65-84 years)], sex [men and women] and race [whites, African Americans, Hispanics and Chinese].

Parathyroid hormone concentration and risk of cardiovascular diseases: the Atherosclerosis Risk in Communities (ARIC) Study

BACKGROUND According to a recent meta-analysis, parathyroid hormone (PTH) excess is associated with increased cardiovascular disease (CVD) risk, but existing studies are limited. We examined in a prospective study the association of PTH with the incidence of CVD, taking into account vitamin D and other confounding variables. METHODS The ARIC study measured PTH using a second-generation assay (Roche, Indianapolis, IN) in stored serum samples from 1990 to 1992 and related levels in 10,392 adults to incident cardiovascular outcomes (coronary heart disease [n = 808], heart failure [n = 1,294], stroke [n = 586], peripheral artery disease [n = 873], atrial fibrillation [n = 1,190], and CVD mortality [n = 647]) through 2010 (median follow-up 19 years). RESULTS Contrary to the hypothesis, PTH level was not associated positively with any CVD outcome. The associations of incident heart failure, peripheral artery disease, and CVD mortality with PTH actually were weakly inverse (P trend = .02-.04) in the most fully adjusted models. For example, the hazard ratios across PTH quartiles were 1.00, 1.07, 1.07, and 0.96 (P trend = .74) for coronary heart disease incidence and were 1.00, 0.69, 0.74, and 0.74 (P trend = .02) for CVD mortality. Patterns were similar when restricted to participants with normal baseline kidney function. CONCLUSIONS This large prospective study failed to support the hypothesis that elevated PTH is an independent risk marker for incident CVD. When our data were added to the previous meta-analysis, the pooled hazard ratio remained statistically significant but weakened.

Socioeconomic Status and the Incidence of Atrial Fibrillation in Whites and Blacks: The Atherosclerosis Risk in Communities (ARIC) Study

Background No previous studies have examined the interplay among socioeconomic status, sex, and race with the risk of atrial fibrillation (AF). Methods and Results We prospectively followed 14 352 persons (25% black, 75% white, 55% women, mean age 54 years) who were free of AF and participating in the Atherosclerosis Risk in Communities (ARIC) study. Socioeconomic status was assessed at baseline (1987–1989) through educational level and total family income. Incident AF through 2009 was ascertained from electrocardiograms, hospitalizations, and death certificates. Cox regression was used to estimate hazard ratios and 95% CIs of AF for education and family income. Interactions were tested between socioeconomic status and age, race, or sex. Over a median follow‐up of 20.6 years, 1794 AF cases occurred. Lower family income was associated with higher AF risk (hazard ratio 1.45, 95% CI 1.27 to 1.67 in those with income less than

Association of Dietary Protein Consumption With Incident Silent Cerebral Infarcts and Stroke The Atherosclerosis Risk in Communities (ARIC) Study

25 000 per year compared with those with

Genetic Obesity and the Risk of Atrial Fibrillation- Causal Estimates from Mendelian Randomization

50 000 or more per year). The association between education and AF risk varied by sex (P=0.01), with the lowest education group associated with higher AF risk in women (hazard ratio 1.88, 95% CI 1.55 to 2.28) but not in men (hazard ratio 1.15, 95% CI 0.97 to 1.36) compared with the highest education group. Adjustment for cardiovascular risk factors attenuated the associations. There were no interactions with race or age. Blacks had lower AF risk than whites in all income and education groups. Conclusions Lower family income was associated with a higher AF risk overall, whereas the impact of education on AF risk was present only in women. Differences in socioeconomic status do not explain the lower risk of AF in blacks compared with whites.

Circulating fibroblast growth factor-23 and the incidence of atrial fibrillation: the Atherosclerosis Risk in Communities study.

Background and Purpose— The effect of dietary protein on the risk of stroke has shown inconsistent results. We aimed to evaluate the relationship of dietary protein sources with the risk of stroke and silent cerebral infarcts in a large community-based cohort. Methods— We studied 11601 adults (age, 45–64 years at baseline in 1987–1989) enrolled in the Atherosclerosis Risk in Communities (ARIC) Study, free of diabetes mellitus and cardiovascular disease. Dietary protein intake was assessed with validated food frequency questionnaires at baseline and after 6 years of follow-up. Incident stroke events were identified through hospital discharge codes and stroke deaths and physician-adjudicated through December 31, 2011. A subset of participants (n=653) underwent brain magnetic resonance imaging in 1993 to 1995 and in 2004 to 2006. Cox proportional hazard models and logistic regression were used for statistical analyses. Results— During a median follow-up of 22.7 years, there were 699 stroke events. In multivariable analyses, total, animal, and vegetable protein consumption was not associated with risk of stroke. Red meat consumption was associated with increased stroke risk, particularly ischemic events. The hazard ratios (95% confidence interval) for risk of ischemic stroke across ascending quintiles of red meat consumption were 1 (ref), 1.13 (0.85–1.49), 1.44 (1.09–1.90), 1.33 (0.99–1.79), and 1.47 (1.06–2.05); Ptrend=0.01. No association of major dietary protein sources with silent cerebral infarcts was detected. Conclusions— This study supports the notion that consumption of red meat may increase the risk of ischemic stroke. No association between dietary protein intake and silent cerebral infarcts was found.