Sheedy, Patrick F.

P10 Coronary artery calcification (CAC), quantified by electron beam computed tomography, provides a measure of extent of coronary atherosclerosis in asymptomatic and symptomatic individuals. It is well recognized that coronary artery disease and CAC are complex processes that are influenced by many genetic and environmental factors. Several aspects of CAC quantity make genetic studies of it particularly challenging. These include the non-normality of CAC frequency distributions and the strong age- and sex-dependence of CAC levels. To search for regions that may contain genes influencing CAC quantity, a genome-wide scan was conducted on a sample enriched for hypertension from the Epidemiology of Coronary Artery Calcification Study. The genome-wide linkage scan was based on 370 anonymous markers spanning the 22 autosomal chromosomes in 29 families. The analysis sample consisted of 20 affected sib-pairs, 8 affected sib-trios and 1 family with 6 affected siblings. Here, affection status was defined as being above the 70th sex- and age-specific percentile based on a reference population. Mode-of-inheritance-free qualitative linkage analysis was used to analyze sib-pair data. Maximum multipoint lod scores were calculated using the computer software Genehunter-2. Weighted analyses were conducted using Holmans “possible triangle” constraint. The overall maximum lod scores were observed on chromosomes 6 (lod=2.22) and 10 (lod=3.24). Additional lod scores greater than 1.0 were observed on chromosomes 2, 14, 15 and 17. These results identify regions that may harbor genes involved in high sex- and age-specific levels of CAC (supported by HL46292).

To examine whether changes in renal perfusion pressure (RPP) within the range of autoregulation induce detectable changes in tubular dynamics in an entire nephron population of the intact kidney, we measured, using electron beam computed tomography (EBCT), transit times (TT, s) and intratubular concentration (%) of filterable contrast media in various nephron segments simultaneously with renal regional perfusion. In seven dogs ( group A) this was performed at the upper and lower limits of autoregulation (RPP = 130 and 95 mmHg, respectively) while group B( n = 5) served as control. In group A alone, a decrease in RPP led to an increase in TT by 40%, 68%, and 32% in the proximal tubules, ascending limb of Henle’s loop, and distal tubules, respectively, in association with an increase in intratubular concentration (+50%, 80%, and 42%, respectively). Papillary perfusion decreased, whereas perfusion of the adjacent, outlying inner medulla increased. The decrease in papillary perfusion correlated positively with the concurrent change in sodium excretion ( R = 0.81). This study demonstrates that changes in RPP within the autoregulatory range elicit changes of tubular sodium reabsorption mainly in proximal, distal, and ascending tubules, in which most of the nephrons participate. These tubular changes are associated with an alteration of perfusion circumscribed to two areas of the inner renal medulla.

Dual-energy X-ray absorptiometry (DEXA) is reported to be inferior to computed tomography (CT) to measure changes in appendicular soft tissue composition. We compared CT- and DEXA-measured thigh muscle and fat mass to evaluate the random and systematic discrepancies between these two methods. Thigh skeletal muscle area (single-slice CT) was suboptimally ( r2= 0.74, P < 0.0001) related to DEXA-measured thigh fat-free mass (FFM). In contrast, thigh muscle and adipose tissue volumes (multislice CT) were highly related to DEXA-measured thigh FFM and fat (both r2= 0.96, P < 0.0001). DEXA-measured leg fat was significantly less than multislice-CT-measured leg adipose tissue volume, whereas multislice-CT-measured leg muscle mass was less ( P < 0.0001) than DEXA-measured leg FFM. The systematic discrepancies between the two approaches were consistent with the 10–15% nonfat components of adipose tissue. In conclusion, CT and DEXA measures of appendicular soft tissue are highly related. Systematic differences between DEXA and CT likely relate to the underlying principles of the techniques.

Background Bone-marrow derived progenitor cells (PCs) may play a role in maintaining vascular health by actively repairing damaged endothelium. The purpose of this study in asymptomatic Old Order Amish men (n = 90) without hypertension or diabetes was to determine if PC count, as determined by CD34+ cell count in peripheral blood, was associated with 10-year risk of cardiovascular disease (CVD) and measures of subclinical atherosclerosis. Methods and Results CD34+ cell count by fluorescence-activated cell sorting, coronary artery calcification (CAC) by electron beam computed tomography, and CVD risk factors were obtained. Carotid intimal-medial thickness (CIMT) also was obtained in a subset of 57 men. After adjusting for 10-year CVD risk, CD34+ cell count was significantly associated with CAC quantity ( p =0.03) and CIMT ( p < 0.0001). A 1-unit increase in natural-log transformed CD34+ cell count was associated with an estimated 55.2% decrease (95% CI: −77.8% to −9.3%) in CAC quantity and an estimated 14.3% decrease (95% CI: −20.1% to −8.1%) in CIMT. Conclusions Increased CD34+ cell count was associated with a decrease in extent of subclinical atherosclerosis in multiple arterial beds, independent of 10-year CVD risk. Further investigations of associations of CD34+ cell count with subclinical atherosclerosis in asymptomatic individuals could provide mechanistic insights into the atherosclerotic process.

Abstract Intraluminal airway pressure and pharyngeal muscle activity are widely recognized as major determinants of the size and collapsibility of the upper airway. In addition, changes in the volume or pressure of tissue surrounding the pharyngeal airway may significantly influence its size. The present study used fast computed tomography (CT) to determine the effects of changes in central venous pressure (CVP) on upper airway size. Ten awake male patients with obstructive sleep apnea (OSA) were studied. Scans were performed at functional residual capacity (FRC) and at the end of a tidal inspiration (VTei) under three conditions of CVP: (1) at baseline (CVP nl) with patients lying supine; (2) at decreased CVP (CVP-) by inflating blood pressure cuffs to 40 mm Hg on both legs; and (3) at increased CVP (CVP+) by elevating both legs to 33 degrees. At FRC, changes in CVP had no significant effect on either mean or minimum cross-sectional area (CSA) of the upper airway. In contrast, an analysis of variance (ANOVA) indicated that alterations in CVP were associated with changes in mean CSA (p = 0.03) and to a lesser extent in minimum CSA (p = 0.07) at VTei. With the legs elevated (CVP+), neither mean nor minimum CSA showed any significant change with tidal breathing. However, after leg-cuff inflation (CVP-), highly significant increases in both mean (163 +/- 22 to 218 +/- 19 mm2, p = 0.001) and minimum (48 +/- 8 to 85 +/- 12 mm2, p = 0.02) CSA were detected. Changes in mean and minimum CSA with tidal breathing at baseline (CVP nl) were intermediate. These results indicate that changes in CVP significantly alter the response of the upper airway to tidal breathing. They further suggest that increases in upper airway size with tidal breathing may be related to reduction in venous blood volume in pharyngeal and neck tissues as the generation of negative intrathoracic pressure during inspiration increases venous return to the chest.

Abstract Fast-CT scanning was used to study the effects of changes in body position on upper airway (UA) size and shape in 11 awake subjects with obstructive sleep apnea (OSA). Six patients with position (P)-dependent OSA were compared with five patients with nonposition (NP)-dependent OSA. Scans were repeated in the prone (PRN), right side (RS), and supine (SUP) body positions at both functional residual capacity and end-inspiratory tidal volume. Significant group, group by position, and borderline group by respiration effects were detected for minimum but not mean UA dimension data. Significant differences between groups were noted in minimum cross-sectional area and minimum lateral distance but not in minimum anteroposterior distance in the RS and SUP positions. Turning from the PRN to the RS or SUP position tended to decrease UA size in the NP group by decreasing the lateral distance, while the opposite effect was found in the P group. The results indicate that changes in body position during wakefulness affect the lateral but not the anteroposterior dimensions of the UA, and the UA behaves differently in patients with NP and P OSA in response to changes in body position.

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. Conclusion— 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.

Background —Electron beam CT (EBCT) is an accurate, noninvasive method to detect and quantify coronary artery calcification, a marker of coronary artery disease (CAD). This investigation examined the accuracy of EBCT to detect obstructive CAD (≥50% stenosis) and determined the optimal strata for quantity of coronary artery calcification to facilitate clinical decision-making. Methods and Results —Clinical research patients (n=213) were examined with coronary angiography and EBCT (angiography group), and 765 research participants were examined with only EBCT (nonangiography group). Of the angiography group, 53% had obstructive CAD. After adjustment for verification bias, the estimated sensitivity and specificity for calcium score ≥1 were 97.0% and 72.4%, respectively. Likelihood ratios for strata of calcium score associated with obstructive CAD were calculated in each sex and 2 age groups. Among those ≥50 years old, the same 4 strata of EBCT calcium scores were identified in each sex; likelihood ratios ranged from 0.03 (calcium score 0) to 12.85 (calcium score ≥200). The same 3 strata of EBCT calcium scores were identified in each sex among those <50 years old; likelihood ratios ranged from 0.13 (calcium score 0) to 190 (calcium score ≥100). Conclusions —A calcium score ≥200 among those ≥50 years old and calcium score ≥100 among those <50 years old provided strong evidence that patients of either sex had obstructive CAD. A calcium score of 0 provided strong evidence that patients ≥50 years old did not have obstructive CAD.

Background —We previously demonstrated that in vivo electron-beam computed tomography (EBCT)–based indicator-dilution methods provide an estimate of intramyocardial blood volume (BV) and perfusion (F), which relate as BV=aF+b√F, where a characterizes the recruitable (exchange) and b the nonrecruitable (conduit) component of the myocardial microcirculation. In the present study, we compared BV and F with intracoronary Doppler ultrasound–based coronary blood flow (CBF) as a method for detecting and quantifying differential responses of these microvascular components to vasoactive drugs in normal (control) and hypercholesterolemic (HC) pigs. Methods and Results —BV and F values were obtained from contrast-enhanced EBCT studies in 14 HC and 14 control pigs. BV, F, and CBF values were obtained at baseline (intracoronary infusion of saline) and after 5 minutes each of intracoronary infusion of adenosine (100 μg · kg − 1 · min − 1 ) and nitroglycerin (40 μg/min). BV and CBF reserves in response to adenosine were attenuated in HC pigs compared with controls (90±36% versus 127±42%, P <0.03, and 485±182% versus 688±160%, P <0.01, respectively). The relationship between BV and F showed consistently lower recruitable BV in HC versus control pigs. Nonrecruitable BV reserve in response to adenosine was attenuated in HC compared with controls (77±20% versus 135±28%, P <0.001). Our findings are consistent with HC-induced impairment of intramyocardial resistance vessel function. Conclusions —EBCT technology allows minimally invasive evaluation of intramyocardial microcirculatory function and permits assessment of microvascular BV distribution in different functional components. This method may be of value in evaluating the coronary microcirculation in pathophysiological states such as hypercholesterolemia.

Background Coronary artery calcium identified by electron beam computed tomography (EBCT) has potential for noninvasive localization of coronary atherosclerotic disease. However, the effect of a patient’s sex on its diagnostic capability has not been examined in a clinical population. Methods and Results Fifty women and 89 men had EBCT scans done an average of 1 day after coronary arteriography. Maximum arteriographic percent luminal diameter stenosis of any artery was paired with the total EBCT coronary calcium score for each subject. The women (age, 56±11 years [mean±SD]) were older than the men (age, 47±7 years), but the subjects were matched for indications for arteriography and extent of disease as assessed by arteriography. Sensitivity, specificity, and positive and negative predictive values for coronary calcium were nearly identical for men and women, regardless of the degree of arteriographic disease. EBCT was highly sensitive to the presence of arteriographic disease (range, 94% to 100%), but had only moderate specificity (57% to 66%) for significant disease (≥50% stenosis) and low specificity (35% to 38%) for any arteriographic disease (>0% stenosis). Negative predictive values in men and women ranged from 79% to 91% for any arteriographic disease and from 95% to 100% for significant disease, respectively. Numerical calcium scores were significantly different between subjects with normal arteriograms and those with significant disease; however, calcium score had limited power to separate trivial, moderate, and significant disease. Receiver operating characteristic curve areas, determined as an extension of the analyses of sensitivity and specificity, were high for EBCT-defined calcium scores for both any arteriographic disease and significant arteriographic disease, and were not different between the sexes. Conclusions In a middle-aged population, noninvasive definition of coronary calcium by EBCT has similar predictive value for arteriographic coronary artery disease in men and women.