The Return of Actionable Variants Empirical (RAVE) Study,a Mayo Clinic Genomic Medicine Implementation Study: Design and Initial Results

Objectives

To identify clinically actionable genetic variants from targeted sequencing of 68 disease-related genes, estimate their penetrance, and assess the impact of disclosing results to participants and providers.

Brachial artery diameter and vasodilator response to nitroglycerine, but not flow-mediated dilatation, are associated with the presence and quantity of coronary artery calcium in asymptomatic adults

In the present study, we investigated whether measures of brachial artery reactivity were associated with the presence and extent of subclinical coronary atherosclerosis in asymptomatic adults. Electron beam computed tomography was employed to assess the presence and quantity of CAC (coronary artery calcium) in 441 participants (mean age, 61 years; 49% men) without prior history of CHD (coronary heart disease) or stroke, and CAC score was calculated using the method described by Agatston and co-workers [(1990) J. Am. Coll. Cardiol. 15, 827-832] High-resolution ultrasound was employed to measure BAD (brachial artery diameter), FMD (flow-mediated dilatation) and NMD (nitroglycerine-mediated dilatation). CAC score and FMD were log-transformed after adding 1 to reduce skewness. Multivariable logistic and linear regression models based on generalized estimating equations were used to assess whether BAD, FMD and NMD were each independently associated with the presence and quantity of CAC after adjustment for CHD risk factors and use of statin and hypertension medication. CAC was detectable in 64% of participants. After adjustment for age and sex, FMD was not correlated (r=-0.06; P=0.27), BAD was positively correlated (r=0.16; P=0.004) and NMD was inversely correlated in a borderline significant manner (r=-0.10; P=0.084) with log(CAC+1). In multivariable logistic regression analyses, FMD was not associated, whereas higher BAD (P=0.021) and lower NMD (P=0.030) were independently associated with the presence of CAC. In multivariable linear regression analyses, higher BAD (P=0.004) and lower NMD (P=0.016), but not FMD, were independently associated with log(CAC+1). We conclude that greater diameter of the brachial artery and lower vasodilator response to nitroglycerine, but not FMD, are associated with subclinical coronary atherosclerosis.     

Lack of association between lipoprotein(a) and coronary artery calcification in the Genetic Epidemiology Network of Arteriopathy (GENOA) study

OBJECTIVE: To investigate the relationship between lipoprotein(a) [Lp(a)] levels and the extent of coronary atherosclerosis in a cohort that consisted predominantly of hypertensive patients. PATIENTS AND METHODS: Patients were ascertained through sibships that contained at least 2 individuals with essential hypertension diagnosed before the age of 60 years. The 10-year coronary heart disease (CHD) risk was estimated on the basis of the Framingham risk equation. Serum Lp(a) was measured by an immunoturbidimetric assay. Coronary artery calcification (CAC) was measured noninvasively by electron beam computed tomography and CAC score calculated using the Agatston score. RESULTS: Patients included 765 non-Hispanic, white individuals (59% women) participating in the Genetic Epidemiology Network of Arteriopathy study. The mean +/- SD age of the patients was 62 +/- 8 years, and 77% had hypertension. The prevalence of detectable CAC was 87% in men and 60% in women. The CAC scores did not differ significantly across quintiles of Lp(a) levels in either men or women. In a multiple regression model that included conventional risk factors, Lp(a) levels were not related to CAC quantity in either sex. No significant interactions were noted between Lp(a) levels and the conventional risk factors in the prediction of CAC quantity. When stratified on the basis of the 10-year CHD risk, 26.5% of the patients were low risk (< 6%), 60.5% were intermediate risk (6%-20%), and 12.9% were high risk (> 20%). Lipoprotein(a) was not associated with CAC quantity within subgroups based on 10-year CHD risk. CONCLUSION: In this cohort enriched with hypertensive patients, the estimated 10-year CHD risk did not appear to modify the lack of an association between Lp(a) levels and CAC.     

Association between lipoprotein-associated phospholipase A2 and cardiovascular disease: a systematic review

OBJECTIVE: To estimate the association between plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) levels and cardiovascular disease (CVD). METHODS: We searched MEDLINE (January 1, 1985, through September 30, 2006), the Cochrane library (from inception through 2006), conference proceedings, and reference sections of obtained articles and contacted experts for unpublished studies. Eligible studies were cohorts with 1 year or more of follow-up or case-control designs that provided risk estimates for CVD according to blood levels of Lp-PLA2 that were unadjusted or adjusted for conventional CVD risk factors. We used random-effects meta-analysis to estimate the association between Lp-PLA2 and CVD risk and conducted preplanned subgroup analyses to identify risk-subgroup interactions that could explain between-study differences. RESULTS: We found 14 eligible studies (N = 20,549 patients) that reported either Lp-PLA2 plasma activity (n = 5) or an immunoassay that measured the plasma concentration (n = 9). The meta-analytic estimate from the unadjusted odds ratio for the association between elevated Lp-PLA2 levels and CVD risk was 1.51 (95% confidence interval, 1.30-1.75) and from the odds ratio adjusted for conventional CVD risk factors was 1.60 (95% confidence interval, 1.36-1.89). Differences in study methods explained differences in results across studies. CONCLUSIONS: Lipoprotein-associated phospholipase A2 is significantly associated with CVD. The risk estimate appears to be relatively unaffected by adjustment for conventional CVD risk factors. Measurement of Lp-PLA2 may be useful in CVD risk stratification. In addition, Lp-PLA2 may represent a potential therapeutic target for CVD risk reduction.     

Multiple cardiovascular complications in a patient with relapsing polychondritis

Relapsing polychondritis is an uncommon disease of unknown etiology, usually manifested by inflammatory changes of cartilaginous tissues. Cardiovascular complications are rare but have been associated with adverse prognosis. Aortitis, vasculitis of large- and medium-sized arteries with aneurysm formation, valvulitis, pericarditis, and atrioventricular conduction disturbances have been reported as late complications of relapsing polychondritis. We describe a 42-year-old man who developed all the known cardiovascular complications of relapsing polychondritis except for clinically evident pericarditis. This case illustrates the multiple, varied, and potentially fatal cardiovascular complications that can occur with this disorder. Patients with relapsing polychondritis should be monitored closely for development of such complications.     

Association of novel risk factors with the ankle brachial index in African American and non-Hispanic white populations

OBJECTIVES: To investigate whether novel risk factors, including C-reactive protein (CRP), fibrinogen, lipoprotein(a) [Lp(a)], and homocysteine levels, are associated with the ankle brachial index (ABI) in African American and non-Hispanic white populations and whether novel risk factors account for ethnic differences in peripheral arterial disease (PAD). PARTICIPANTS AND METHODS: Between December 2000 and October 2004, original participants in the Genetic Epidemiology Network of Arteriopathy study returned for a second study visit to undergo measurement of risk factors and ABI. The CRP, Lp(a), and homocysteine levels were log transformed to reduce skewness. Multivariable regression analyses were used to assess whether a novel risk factor was associated with ABI after adjustment for conventional risk factors and whether ethnicity was associated with PAD (ABI, 相似文献   

Intracardiac leiomyomatosis: echocardiographic features

Intravenous leiomyomatosis is a histologically benign smooth-muscle tumor arising from either a uterine myoma or the walls of a uterine vessel with extension into veins. Echocardiographic features of two cases of intravenous leiomyomatosis with extensive spread into the right-sided cardiac chambers and pulmonary arteries are described. Both patients were middle-aged women, with prior history of hysterectomy 12 and 10 years earlier who presented with cardiac symptoms and signs. Distinctive echocardiographic features include 1) elongated mobile masses extending from the veins of the lower body, including inferior vena cava and azygos vein; 2) multiple venous attachments or metastases; and 3) filling of venous vessels and right-heart chambers. Intracardiac leiomyomatosis should be considered in a female patient presenting with an extensive mass in the right-sided cardiac chambers.