Prospective study of plasma high molecular weight kininogen and prekallikrein and incidence of coronary heart disease, ischemic stroke and heart failure

Introduction: High molecular weight kininogen (HK) and prekallikrein (PK) are proteins in the kallikrein/kinin system of the coagulation cascade. They play an important role in the contact activation system of the intrinsic coagulation pathway, renin-angiotensin activation, and inflammation. Hence these proteins have been posited to affect the occurrence of cardiovascular events and thus to be potential therapeutic targets. Previous case-control studies have provided inconsistent evidence for an association of HK and PK with cardiovascular disease. Methods: In the prospective population-based Atherosclerosis Risk in Communities(ARIC) Study, we used Cox proportional hazards regression models to investigate the association in 4195 middle-aged adults of plasma HK and PK concentrations in 1993–95 (linearly and in quartiles) with incident coronary heart disease, ischemic stroke, and heart failure through 2016. Results: Over a mean of 18 years follow-up, we identified incident cardiovascular events (coronary heart disease and ischemic stroke) in 618 participants and heart failure in 667. We observed no significant relation between HK or PK and cardiovascular disease or heart failure, before and after adjusting for several potential confounding variables. Conclusions: We found no compelling evidence to support an association of plasma HK or PK concentrations with incident CHD, ischemic stroke, or heart failure

Long-term association of venous thromboembolism with frailty, physical functioning, and quality of life: The atherosclerosis risk in communities study

BACKGROUND: Relatively little is known about the long-term consequences of venous thromboembolism (VTE) on physical functioning. We compared long-term frailty status, physical function, and quality of life among survivors of VTE with survivors of coronary heart disease (CHD) and stroke, and with those without these diseases. METHODS AND RESULTS: Cases of VTE, CHD, and stroke were continuously identified since ARIC (Atherosclerosis Risk in Communities Study) recruitment during 1987 to 1989. Functional measures were objectively captured at ARIC clinic visits 5 (2011–2013) and 6 (2016–2017); quality of life was self-reported. The 6161 participants at visit 5 were, on average, 75.7 (range, 66–90) years of age. By visit 5, 3.2% had had a VTE, 6.9% CHD, and 3.4% stroke. Compared with those without any of these conditions, VTE survivors were more likely to be frail (odds ratio [OR], 3.11; 95% CI, 1.80–5.36) and have low (<10) versus good scores on the Short Physical Performance Battery (OR, 3.59; 95% CI, 2.36–5.47). They also had slower gait speed, less endurance, and lower physical quality of life. VTE survivors were similar to coronary heart disease and stroke survivors on categorical frailty and outcomes on Short Physical Performance Battery assessment. When score on the Short Physical Performance Battery instrument was modeled continuously, VTE survivors performed better than stroke survivors but worse than CHD survivors. CONCLUSIONS: VTE survivors had triple the odds of frailty and poorer physical function than those without the vascular diseases considered. Their function was somewhat worse than that of CHD survivors, but better than stroke survivors. These findings suggest that VTE patients may benefit from additional efforts to improve postevent physical functioning

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

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

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

BackgroundNo previous studies have examined the interplay among socioeconomic status, sex, and race with the risk of atrial fibrillation (AF).Methods and ResultsWe 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 $25 000 per year compared with those with$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.ConclusionsLower 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 levels of liver enzymes and incidence of atrial fibrillation: the Atherosclerosis Risk in Communities cohort

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

Race and Vitamin D Binding Protein Gene Polymorphisms Modify the Association of 25-Hydroxyvitamin D and Incident Heart Failure: The ARIC (Atherosclerosis Risk in Communities) Study

Abstract Objectives This study sought to determine if low serum 25-hydroxyvitamin D (25[OH]D) is associated with incident heart failure (HF) and if the association is: 1) partly mediated by traditional cardiovascular risk factors; 2) stronger among whites than blacks; and 3) stronger among those genetically predisposed to having high levels of vitamin D binding protein (DBP).Background Suboptimal 25(OH)D is a potential cardiovascular risk factor.Methods A total of 12,215 ARIC (Atherosclerosis Risk in Communities) study participants free of HF at baseline (1990 to 1992; median age, 56; 24% black) were followed through 2010. Total serum 25(OH)D was measured at baseline using liquid chromatography–mass spectrometry. Incident HF events were identified by a hospital discharge code of ICD9-428 and parallel International Classification of Diseases codes for HF deaths.Results During 21 years of follow-up, 1,799 incident HF events accrued. The association between 25(OH)D and HF varied by race (p-interaction = 0.02). Among whites, risk was 2-fold higher for those in the lowest (≤17 ng/ml) versus highest (≥31 ng/ml) quintile of 25(OH)D. The association was attenuated but remained significant with covariate adjustment. In blacks there was no overall association. In both races, those with low 25(OH)D and the rs7041 G allele, which predisposes to high DBP, were at greater risk (p-interaction = 0.01).Conclusions Low serum 25(OH)D was independently associated with incident HF among whites, but not among blacks. However, in both races, low 25(OH)D was associated with HF risk among those genetically predisposed to high DBP. These findings provide novel insight into metabolic differences that may underlie racial variation in the association between 25(OH)D and cardiovascular risk

Echocardiographic Measures of Cardiac Structure and Function Are Associated with Risk of Atrial Fibrillation in Blacks: The Atherosclerosis Risk in Communities (ARIC) Study

BackgroundSeveral studies have examined the link between atrial fibrillation (AF) and various echocardiographic measures of cardiac structure and function in whites and other racial groups but not in blacks. Exploring AF risk factors in blacks is important given that the lower incidence of AF in this racial group despite higher risk factors, is not completely explained.MethodsWe examined the association of echocardiographic measures with AF incidence in 2283 blacks (64.5% women, mean age 58.8 years) free of diagnosed AF and enrolled in the Jackson cohort of Atherosclerosis Risk in Communities (ARIC) study, a prospective study of cardiovascular disease. Echocardiography was performed in 1993–1995, and incident AF was determined by electrocardiograms at a follow-up study exam, hospitalization discharge codes and death certificates through the end of 2009. Cox proportional hazards regression was used to estimate hazard ratios and 95% confidence intervals for AF associated with the echocardiographic measures, adjusting for age, sex, and known AF risk factors.ResultsDuring an average follow-up of 13.5 years, 191 (8.4%) individuals developed AF. Left ventricular (LV) internal diameter 2-D (diastole) and percent fractional shortening of LV diameter displayed a U-shaped relationship with risk of AF, while left atrial diameter displayed a J-shaped nonlinear association. LV mass index was associated positively with AF. E/A ratio 1.5 and ejection fraction (EF <50%) were also associated with higher AF risk. These measures improved risk stratification for AF in addition to traditional risk factors, although not significantly {C-statistic of 0.767 (0.714–0.819) vs. 0.744 (0.691–0.797)}.ConclusionsIn a community-based population of blacks, echocardiographic measures of cardiac structure and function are significantly associated with an increased risk of AF

Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials

Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting