The relationship between diastolic blood pressure and coronary artery calcification is dependent on single nucleotide polymorphisms on chromosome 9p21.3.

BACKGROUND: Single nucleotide polymorphisms (SNPs) within the 9p21.3 genomic region have been consistently associated with coronary heart disease (CHD), myocardial infarction, and quantity of coronary artery calcification (CAC), a marker of subclinical atherosclerosis. Prior studies have established an association between blood pressure measures and CAC. To examine mechanisms by which the 9p21.3 genomic region may influence CHD risk, we investigated whether SNPs in 9p21.3 modified associations between blood pressure and CAC quantity. METHODS: As part of the Genetic Epidemiology Network of Arteriopathy (GENOA) Study, 974 participants underwent non-invasive computed tomography (CT) to measure CAC quantity. Linear mixed effects models were used to investigate whether seven SNPs in the 9p21.3 region modified the association between blood pressure levels and CAC quantity. Four SNPs of at least marginal significance in GENOA for a SNP-by-diastolic blood pressure (DBP) interaction were then tested for replication in the Framingham Heart Study's Offspring Cohort (N = 1,140). RESULTS: We found replicated evidence that one SNP, rs2069416, in CDKN2B-AS1, significantly modified the association between DBP and CAC quantity (combined P = 0.0065; Bonferroni-corrected combined P = 0.0455). CONCLUSIONS: Our results represent a novel finding that the relationship between DBP and CAC is dependent on genetic variation in the 9p21.3 region. Thus, variation in 9p21.3 may not only be an independent genetic risk factor for CHD, but also may modify the association between DBP levels and the extent of subclinical coronary atherosclerosis.

Matrix gla protein gene polymorphism is associated with increased coronary artery calcification progression.

OBJECTIVE: Matrix gla protein (MGP) inhibits arterial and cartilaginous calcification. A threonine to alanine (Thr83Ala) polymorphism (codon 83) in MGP is associated with myocardial infarction and femoral artery calcification. We examined the association of the MGP Thr83Ala polymorphism with quantity and progression of coronary artery calcification (CAC), a noninvasive measure of subclinical coronary atherosclerosis. METHODS AND RESULTS: In 605 participants of the Epidemiology of Coronary Artery Calcification Study, generalized linear mixed models were fit to determine the association of MGP Thr83Ala with CAC quantity and progression. There was a significant additive relation between MGP Thr83Ala and CAC progression (P=0.001). In the fully adjusted model, every 1 Ala83 allele increase was associated with an estimated 1.9% (95% confidence interval, 0.7%-3.0%) per year since baseline larger increase in CAC quantity. A proxy single nucleotide polymorphism for MGP Thr83Ala (rs6488724) was similarly associated with CAC progression in an independent cohort from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. CONCLUSIONS: Increased risk of myocardial infarction associated with MGP ThrAla83 genotype observed elsewhere may be related to faster progression of subclinical coronary atherosclerosis. MGP genotype could be a potential candidate for identifying individuals at increased risk of atherosclerotic disease who would benefit from aggressive primary prevention strategies.

MicroRNA-710 regulates multiple pathways of carcinogenesis in murine metastatic breast cancer.

Prior research has shown that critical differences between non-metastatic and metastatic tumor cells are at the level of microRNA. Consequently, harnessing these molecules for the treatment of metastatic cancer could have significant clinical impact. In the present study, we set out to identify metastasis-specific microRNAs which drive metastatic colonization of distant organs. Using a murine model of metastatic breast cancer, we employed a directed approach in which we screened for microRNAs that are differentially expressed between the primary tumors and metastatic lesions but concordantly expressed in all of the metastatic lesions irrespective of the tissue that is colonized. Of the identified targets, we focused on miR-710, which was consistently and significantly downregulated in the metastatic lesions relative to the primary tumors. The level of downregulation was independent of the distant organ that is involved, suggesting that miR-710 plays a fundamental role in metastatic colonization. Computational target prediction suggested a pleiotropic role for miR-710 in apoptosis, migration and invasion, and stemness. Using a previously validated oligonucleotide delivery system, we introduced miR-710 mimics into 4T1 metastatic breast adenocarcinoma cells and assessed the resultant phenotypic effects. We demonstrated significant inhibition of cell viability, migration, and invasion. We also showed that the treatment profoundly enhanced cell senescence, reduced stemness, and influenced markers of epithelial to mesenchymal transition, as evidenced by enhanced E-cadherin and reduced vimentin expression. This knowledge represents a first step towards harnessing a similar approach to discover novel microRNA targets with therapeutic potential in metastasis.

RNAi-Mediated PD-L1 Inhibition for Pancreatic Cancer Immunotherapy.

The recent past has seen impressive progress in the treatment of various malignancies using immunotherapy. One of the most promising approaches involves immune checkpoint inhibitors. However, the clinical results with these agents have demonstrated variability in the response. Pancreatic cancer, in particular, has proven resistant to initial immunotherapy approaches. Here, we describe an alternative strategy that relies on combining gemcitabine and a novel programmed death-ligand 1 (PD-L1) inhibitor, termed MN-siPDL1. MN-siPDL1 incorporates small interfering RNA against PD-L1 (siPDL1) conjugated to a magnetic nanocarrier (MN). We show that noninvasive magnetic resonance imaging (MRI) could be used to monitor therapeutic response. Combination therapy consisting of gemcitabine and MN-siPDL1 in a syngeneic murine pancreatic cancer model resulted in a significant reduction in tumor growth and an increase in survival. Following optimization, a 90% reduction in tumor volume was achieved 2 weeks after the beginning of treatment. Whereas 100% of the control animals had succumbed to their tumors by week 6 after the beginning of treatment, there was no mortality in the experimental group by week 5, and 67% of the experimental animals survived for 12 weeks. This method could provide therapeutic benefit against an intractable disease for which there are no effective treatments and which is characterized by a mere 1% 5-year survival.

Coronary artery calcification progression is heritable.

BACKGROUND: Coronary artery calcification (CAC), a marker of coronary artery atherosclerosis, can be measured accurately and noninvasively with the use of electron beam computed tomography. Serial measures of CAC quantify progression of calcified coronary artery plaque. Little is known about the role of genetic factors in progression of CAC quantity. METHODS AND RESULTS: We quantified the relative contributions of measured risk factors and unmeasured genes to CAC progression measured by 2 electron beam computed tomography examinations an average of 7.3 years apart in 877 asymptomatic white adults (46% men) from 625 families in a community-based sample. After adjustment for baseline risk factors and CAC quantity, the estimated heritability of CAC progression was 0.40 (P<0.001). Baseline risk factors and CAC quantity explained 64% of the variation in CAC progression. Thus, genetic factors explained 14% of the variation [(100-64) x (0.40)] in CAC progression. After adjustment for risk factors, the estimated genetic correlation (pleiotropy) between baseline CAC quantity and CAC progression was 0.80 and was significantly different than 0 (P<0.001) and 1 (P=0.037). The environmental correlation between baseline CAC quantity and CAC progression was 0.42 and was significantly different than 0 (P=0.006). CONCLUSIONS: Evidence was found that many but not all genetic factors influencing baseline CAC quantity also influence CAC progression. The identification of common and unique genetic influences on these traits will provide important insights into the genetic architecture of coronary artery atherosclerosis.

Determinants of coronary artery and aortic calcification in the Old Order Amish.

BACKGROUND: Coronary artery calcification (CAC) is associated with an increased risk of cardiovascular disease; little is known, however, about thoracic aortic calcification (AC). Our goal was to characterize risk factors for CAC and AC and to estimate the genetic contribution to their variation. METHODS AND RESULTS: The presence and quantity of CAC and AC were measured with electron beam computed tomography and fasting blood tests and cardiovascular risk factors were obtained in 614 asymptomatic Amish subjects. CAC prevalence was higher in men than women (55% versus 41%; P<0.0001), although there was no sex difference in AC prevalence (51% and 56% in men and women, respectively; P=0.95). Age was more strongly associated with AC presence (odds ratio [OR], 2.7 for 5 years) than CAC presence (OR, 1.9 for 5 years) (homogeneity P=0.001). Subjects with AC had a 3.3-fold higher odds of having CAC. Heritabilities of CAC and AC presence were 0.27+/-0.17 (P=0.04) and 0.55+/-0.18 (P=0.0008), respectively, whereas the heritabilities of quantity of CAC and AC were 0.30+/-0.10 (P=0.001) and 0.40+/-0.10 (P<0.0001), respectively. The genetic correlation between CAC and AC quantity was 0.34+/-0.19, whereas the environmental correlation between these 2 traits was 0.38+/-0.09. CONCLUSIONS: CAC and AC have similar risk factors, except male gender is associated only with CAC and age is more strongly associated with AC. The patterns of correlations suggest that CAC and AC share some common sets of genes and environmental factors, although it is likely that separate genes and environmental factors also influence calcification at each site.

The association of coronary artery calcification and carotid artery intima-media thickness with distinct, traditional coronary artery disease risk factors in asymptomatic adults.

Coronary artery calcification (CAC) and common carotid artery intima-media thickness (CIMT) are measures of subclinical vascular disease. This 2000-2006 study aimed to characterize the associations among coronary artery disease risk factors, CAC quantity, and CIMT and to estimate shared genetic and environmental contributions to both CAC and CIMT among 478 asymptomatic Amish adults in Lancaster County, Pennsylvania. Heritability for CAC quantity and CIMT, adjusted for age and sex, was 0.42 (P = 0.0001) and 0.29 (P = 0.003), respectively. CAC quantity and CIMT were modestly correlated (adjusted r = 0.14, P = 0.003) but showed little evidence of shared genetic or environmental factors. However, significant genetic correlations were found for CAC quantity and total cholesterol (0.44 (standard error, 0.19); P = 0.03), for CAC quantity and low density lipoprotein cholesterol (0.55 (standard error, 0.17); P = 0.005), and for CIMT and waist circumference (0.58 (standard error, 0.25); P = 0.046), suggesting shared genes for these risk factors and measures of subclinical disease. Results suggest that some of the same genes influence variation in CAC and low density lipoprotein cholesterol, whereas a different set of genes influences variation in CIMT and waist circumference.

Aortic valve calcification: determinants and progression in the population.

BACKGROUND: Aortic valve calcification (AVC) is considered degenerative. Recent data suggested links to atherosclerosis or coronary disease (CAD). METHODS AND RESULTS: AVC and coronary artery calcifications (CAC) were prospectively assessed by Electron-Beam-Computed-Tomography in 262 population-based research participants > or = 60 years. AVC was frequent (27%) with aging (P<0.01) and in men (P<0.05). AVC was associated with diabetes, hypertension, higher body-mass-index, and serum glucose (all P<0.05). AVC was a marker of higher prevalence (P<0.01) and severity of CAD (CAC score: 441+/-802 versus 265+/-566, P<0.05) independently of age. After follow-up of 3.8+/-0.9 years, AVC score increased (94+/-271 versus 54+/-173, P<0.01, +11+/-32 U/year), faster with higher baseline AVC score (P<0.01). Compared with participants remaining free of AVC, de novo acquisition of AVC was associated with higher LDL-cholesterol (141+/-31 versus 121+/-27 mg/dL, P<0.05) and faster CAC progression (+78+/-87 versus +28+/-47 U/year, P<0.05). In multivariate analysis, LDL-cholesterol independently determined AVC acquisition while higher baseline AVC scores determined faster progression of existing AVC. CONCLUSION: In the population, AVC is frequent with aging and atherosclerotic risk factors. AVC is a marker of subclinical CAD. AVC is progressive, appearing de novo with progressive atherosclerosis whereas established AVC progresses independently of atherosclerotic risk factors and faster with increasing initial AVC loads.

The fundamental role of miR-10b in metastatic cancer.

Small, non-coding strands of RNA have been identified as a significant player in the pathology of cancer. One of the first miRNAs to be shown as having aberrant expression in cancer was miR-10b. Since the inaugural study on miR-10b, its role as a metastasis promoting factor has been extensively validated. To date, more than 100 studies have been completed on miR-10b and metastasis across 18 cancer types. This immense set of information holds possibilities for novel methods to improve the lives of many. This review outlines what is currently understood of miR-10b's clinical significance, its molecular regulation, and the possible diagnostic and therapeutic methods leveraging miR-10b as a fundamental target in metastatic cancer. Such methods would move us closer to developing a truly individualized therapeutic strategy against cancer and will likely provide unique information about cancer staging, disease outcome, metastatic potential, and ultimately survival.

Associations of serum uric acid with markers of inflammation, metabolic syndrome, and subclinical coronary atherosclerosis.

BACKGROUND: We examined the associations of serum uric acid (UA) with indices of coronary heart disease (CHD) risk, including the 10-year probability of CHD (10y-CHDr), metabolic syndrome (MS), inflammation (C-reactive protein [CRP] and fibrinogen), and the presence and quantity of coronary artery calcium (CAC). METHODS: Subjects (n = 1107, mean age 58 years, 59% women) belonged to sibships with > or =2 individuals with hypertension diagnosed before age 60 years. UA was measured by a colorimetric method, CAC by electron beam computed tomography, and CAC score calculated using the method of Agatston. The correlation of UA with 10y-CHDr, MS components, log CRP, and fibrinogen was assessed after adjustment for age and gender. Multivariable regression was used to assess whether UA was associated with CAC presence and quantity after (1) adjustment for age and gender, and (2) additional adjustment for CHD risk factors. RESULTS: Most subjects (71%) had hypertension and 14% had diabetes. Mean (+/- SD) UA level was 5.97 +/- 1.6 mg/dL, and CAC was detectable in 63% of patients. After adjustment for age and gender, UA was significantly correlated with 10y-CHDr, number of MS components, log CRP, and fibrinogen. UA was associated with CAC presence and quantity after adjustment for age and gender but not after further adjustment for systolic blood pressure (BP), diabetes, total and HDL-cholesterol, smoking, and body mass index (BMI). CONCLUSIONS: Serum UA was significantly correlated with several indices of CHD risk. UA was associated with presence and quantity of CAC, but not independently of conventional risk factors.

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.

Progression of subclinical coronary atherosclerosis: does obesity make a difference?

BACKGROUND: Obesity is associated with coronary artery calcification (CAC), a marker of the presence and extent of subclinical coronary atherosclerosis. Obesity adds incremental information in identifying those at higher risk of coronary heart disease to traditional risk factor assessment. The present study examined associations between obesity measures and progression of CAC in those at higher (> or =10%) and lower (<10%) 10-year coronary heart disease risk according to the Framingham risk equation. METHODS AND RESULTS: In this study, 443 asymptomatic white individuals >30 years of age (243 men) had baseline and follow-up CAC measurements an average of 8.9 years apart. Multivariable linear regression models were fit to determine associations of obesity measures at baseline with progression of CAC defined as log(e) of the difference between follow-up and baseline CAC area plus 1 divided by time (in years) between examinations, adjusting for baseline CAC quantity, age, sex, baseline hypertension status, and baseline cholesterol level. Among 329 participants (74.3%) in the lower-risk group, waist circumference (P=0.024), waist-to-hip ratio (P<0.001), body mass index (P=0.036), and being overweight compared with being underweight or of normal weight (P=0.008) were each significantly positively associated with progression of CAC. Among those at higher coronary heart disease risk, no baseline obesity measures were associated with CAC progression. CONCLUSIONS: Various measures of obesity were associated with increased progression of CAC in those at lower risk of coronary heart disease. Future studies examining the effectiveness of weight reduction strategies in reducing CAC progression among those with an otherwise favorable risk factor profile may be warranted.

Genomic loci with pleiotropic effects on coronary artery calcification.

We measured 381 genomewide markers and performed genetic linkage analyses in search of loci influencing coronary artery calcification (CAC), a measure of atherosclerosis determined by electron beam computed tomography, in 948 non-Hispanic white siblings (mean age [+/-standard deviation] = 59.6 +/- 9.9 years; 73.7% hypertensive). Measured risk factors for atherosclerosis included body mass index, pulse pressure, and high-density lipoprotein (HDL)-cholesterol. After adjustment for sex and age, the logarithm transformed measure of CAC was heritable (0.40 +/- 0.08, P < 0.0001) and genetically correlated with body mass index (0.28, P < 0.001), pulse pressure (0.36, P < 0.001), and HDL-cholesterol (-0.19, P < 0.001). Univariate linkage analysis demonstrated evidence of linkage for CAC, defined by maximum LOD scores (MLS) >or= 1.30, on chromosomes 1p, 4p, 5q, 7p, 13q, and 14q. Bivariate linkage analyses of CAC with each risk factor provided evidence of two regions with pleiotropic effects on CAC and HDL-cholesterol on chromosomes 4p16 (MLS=3.03, P = 0.00084) and 9q12 (MLS = 3.21, P = 0.00056), and of a region with pleiotropic effects on CAC and body mass index on chromosome 17p11 (MLS = 3.04, P = 0.00082). Inasmuch as the chromosome 9 and 17 regions were not detected in the univariate linkage analysis for CAC, multivariate linkage analyses of CAC and genetically correlated risk factors may help localize genes for coronary atherosclerosis.

Association of plasma homocysteine with coronary artery calcification in different categories of coronary heart disease risk.

OBJECTIVE: To Investigate the association of plasma homocystelne with coronary artery calcification (CAC) in strata based on 10-year risk of coronary heart disease (CHD) in a cohort enriched in persons with hypertension. PARTICIPANTS AND METHODS: Fasting plasma homocystelne was measured by liquid chromatography electrospray tandem mass spectrometry. Coronary artery calcification was measured noninvasively by electron beam computed tomography and CAC score calculated using the method of Agatston et al. The 10-year CHD risk was calculated based on the Framingham risk score. The association of homocysteine with log-transformed CAC score was assessed in the pooled sample and within each risk stratum by linear regression after adjustment for conventional risk factors. RESULTS: In the 1071 participants studied, homocysteine was associated with CAC quantity (P = .01) after adjustment for CHD risk factors (age, male sex, total and high-density lipoproteln cholesterol, diabetes, history of smoking, body mass Index, and systolic blood pressure), serum creatinine, and statin and hypertension medication use. When the association was assessed in strata based on 10-year CHD risk, homocysteine was significantly (P = .003) associated with CAC quantity in participants at Intermediate 10-year risk of CHD (6%-20%) independent of other risk factors but not in those at lower risk or higher risk. CONCLUSION: Plasma homocysteine is associated with quantity of CAC Independent of CHD risk factors. When studied in categories of 10-year CHD risk, the association was significant in participants at intermediate risk but not in those at low or high risk. Plasma homocysteine levels may have clinical utility as a marker of CHD risk in such individuals.

Heritability of coronary artery calcium quantity measured by electron beam computed tomography in asymptomatic adults.

BACKGROUND: Electron beam computed tomography is an accurate, noninvasive method to detect and quantify coronary artery calcification (CAC), a marker of subclinical and clinical coronary artery atherosclerosis. CAC quantity predicts future coronary artery disease end points in asymptomatic adults, but measured risk factors explain less than half the variability in CAC quantity. Although several candidate genes for CAC have been identified, the relative importance of genetic influences on CAC quantity has not been assessed in asymptomatic adults in a community. METHODS AND RESULTS: We quantified the relative contributions of measured risk factors and genetic influences on CAC quantity measured by electron beam computed tomography in 698 asymptomatic white adults from 302 families. Before adjusting for any risk factors, 43.5% of the variation in CAC quantity was attributable to genetic factors (P=0.0007). Independent predictors of CAC quantity were identified with stepwise linear regression. After adjusting for these risk factors, including age, sex, fasting glucose level, systolic blood pressure, pack-years of smoking, and LDL cholesterol, 41.8% of the residual variation in CAC quantity was attributable to genetic factors (P=0.0003). CONCLUSIONS: These results demonstrate the importance of genetic factors in subclinical coronary atherosclerosis variation as measured by CAC quantity. The presence of genetic effects suggests that unknown genes that influence CAC quantity are yet to be identified.

Evaluation and clinical implications of aortic valve calcification measured by electron-beam computed tomography.

BACKGROUND: Electron-beam computed tomography (EBCT) is used to measure coronary calcification but not for aortic valve calcification (AVC). Its accuracy, association with aortic stenosis (AS) severity, and diagnostic and prognostic value with respect to AVC are unknown. METHODS AND RESULTS: In 30 explanted aortic valves, the AVC score by EBCT (1125+/-1294 Agatston units [AU]) showed a strong linear correlation (r=0.96, P<0.0001) with valvular calcium weight (653+/-748 mg) by pathology that allowed estimation of calcium weight as AVC score/1.7, with a small standard error of the estimate (53 mg). In 100 consecutive clinical patients, we measured AVC by EBCT and AS severity by echocardiographic aortic valve area (AVA). The AVC score was 1316+/-1749 AU (range 0 to 7226 AU). Intraobserver and interobserver variabilities were excellent (4+/-4% and 4+/-10%, respectively). AVC and AVA were strongly associated (r=0.79, P<0.0001) but had a curvilinear relationship that suggested that AVC and AVA provide complementary information. AVC score > or =1100 AU provided 93% sensitivity and 82% specificity for diagnosis of severe AS (AVA <1 cm2), with a receiver operator characteristic curve area of 0.89. AVC assessment by echocardiography was often more severe than by EBCT (P<0.0001). During follow-up, 22 patients either died, developed heart failure, or required surgery. With adjustment for age, sex, symptoms, ejection fraction, and AVA, the AVC score was independently predictive of event-free survival (risk ratio 1.06 per 100-AU increment [1.02 to 1.10], P<0.001), even after adjustment for echocardiographic calcifications. CONCLUSIONS: AVC is accurately and reproducibly measured by EBCT and shows a strong association and diagnostic value for severe AS. The curvilinear relationship between AVC and AVA suggests these measures are complementary, and indeed, AVC provides independent outcome information. Thus, AVC is an important measurement in the evaluation of patients with AS.

C-reactive protein is related to arterial wave reflection and stiffness in asymptomatic subjects from the community.

BACKGROUND: Emerging data suggest that C-reactive protein (CRP), a marker of inflammation, is associated with functional properties of arteries. We investigated the relationship of CRP to measures of arterial wave reflection and stiffness (aortic augmentation index [AIX], carotid-femoral pulse wave velocity [PWV], and pulse pressure) in asymptomatic individuals from the community. METHODS: Subjects (n = 214) had a mean age of 59 years and 53% were men. CRP was measured by a high-sensitivity assay and values were log-transformed to reduce skewness. Radial artery waveforms were obtained by applanation tonometry, a validated transfer function was used to derive an ascending aortic pressure waveform, and AIX calculated. PWV was calculated from electrocardiogram-gated waveforms of the right carotid and right femoral artery obtained by applanation tonometry. RESULTS: Log CRP was correlated with AIX (r = 0.24, P = .0005), PWV (r = 0.25, P = .0002), and pulse pressure (r = 0.29, P < or = .0001). In separate backward elimination multiple regression analyses, log CRP was significantly associated with AIX (P = .038) and pulse pressure (P = .036), and marginally significantly associated with PWV (P = .054), after adjustment for heart rate, height, and coronary heart disease (CHD) risk factors (age, sex, body mass index, mean arterial pressure, total cholesterol, HDL cholesterol, diabetes, hypertension, and history of smoking). CONCLUSIONS: These results suggest that CRP, a marker of systemic inflammation, is related to measures of arterial wave reflection and stiffness in asymptomatic subjects from the community. Further studies are needed to understand the mechanisms underlying this association and the implications for assessment and management of CHD risk.

Autosomal genome-wide scan for coronary artery calcification loci in sibships at high risk for hypertension.

Coronary artery disease (CAD) is the leading cause of mortality in the developed world. Although several CAD risk factors, including measures of lipid metabolism, obesity, and blood pressure, have a genetic basis, many genes for CAD susceptibility have yet to be identified. Coronary atherosclerosis is the major cause of CAD, but many with coronary atherosclerosis lack symptoms. Thus, a major limitation of using symptomatic CAD endpoints (eg, sudden coronary death, myocardial infarction) as a study outcome is substantial disease misclassification. Coronary artery calcification (CAC) is part of the atherosclerotic process and is an independent predictor of CAD endpoints. In the present study, CAC was noninvasively quantified by electron beam computed tomography. We performed genome-wide multipoint mode-of-inheritance-free linkage analysis on affected sib pairs, defined as being > or = the 70th sex- and age-specific percentile for CAC quantity, in a sample of 29 families enriched for hypertension. Almost 95% of participants were asymptomatic for CAD. Our LOD score (log10 odds in favor of linkage) results provide evidence that chromosomal regions 6p21.3 (maximum LOD score=2.22, P=0.00070) and 10q21.3 (maximum LOD score=3.24, P=0.000057) may harbor genes associated with subclinical coronary atherosclerosis.

Intramyocardial blood volume, perfusion and transit time in response to embolization of different sized microvessels.

OBJECTIVE: To study the role of the coronary microcirculation in response to different-sized microemboli, we measured changes in intramyocardial microvascular blood volume (Bv), perfusion (F) and transit time (TT) and also microvascular patterns of injury. METHODS: Bv, F and TT were quantitated in 24 pigs at baseline and again 2 min after repeat injections of 10- or 100-microm microspheres at rest or during intracoronary adenosine infusion. The association of Bv and TT was assessed in the microsphere pigs and in nine control pigs. Microvascular injury was studied on gross-pathologic and histologic samples. RESULTS: At rest, initial injection of 10-microm microspheres led to increases in Bv and F, but progressively decreased with additional injections. In contrast, even small numbers of 100-microm microspheres always led to decreases in Bv and F. Injection of microspheres during adenosine-induced vasodilation always resulted in decreases in peak Bv and F irrespective of their diameters, but microvascular TTs remained unaltered. In control pigs, however, TTs were inversely related to adenosine-induced changes in Bv. Histologically, 100-microm microspheres resulted in patchy distribution of microcirculatory plugging, while 10-microm microspheres induced contiguous hemorrhagic myocardial injury. CONCLUSION: Microsphere-induced changes in intramyocardial Bv and F and the associated pattern of myocardial injury are related to the size of embolized microvessels and the initial perfusion state. Microvascular functional volume reserve mechanisms appear to play a key role accompanying flow- and TT-preservation.

Prevalence and predictors of coronary artery calcification in women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS), a common endocrine disorder of reproductive-aged women, is associated with multiple risk factors for coronary heart disease (CHD), such as diabetes mellitus, dyslipidemia, visceral obesity, and hypertension. However, premature coronary atherosclerosis has not been demonstrated in PCOS women. Electron beam computed tomography (EBCT) noninvasively measures coronary artery calcium (CAC), a marker for coronary atherosclerosis. We measured CAC by EBCT in 30- to 45-yr-old premenopausal PCOS women and compared the results to CAC in 1) recruited normal ovulatory volunteers matched for age and weight to the PCOS cohort, and 2) community-dwelling women of similar age in an extant coronary calcium database. Healthy, community-dwelling, ovulatory controls (n = 71) were matched by age and body mass index (BMI) to PCOS women (n = 36). Women with diabetes or known CHD were excluded. Subjects underwent EBCT scanning, oral glucose tolerance testing, and CHD risk factor assessment. PCOS women had significantly higher levels of serum total and low density lipoprotein cholesterol and testosterone levels than matched controls. PCOS and control women were obese and had a greater mean BMI than community-dwelling women (33 kg/m(2) for PCOS vs. 31 kg/m(2) for control; P < 0.001). CAC was more prevalent in PCOS women (39%) than in matched controls (21%; odds ratio, 2.4; P = 0.05) or community-dwelling women (9.9%; odds ratio, 5.9; P < 0.001). BMI, waist circumference, and total and low density lipoprotein cholesterol levels predicted CAC prevalence after adjustment for BMI. CAC is more prevalent in PCOS women than in obese or nonobese women of similar age. PCOS women are at increased risk for atherosclerosis and should be targeted for primary prevention of CHD.