Coronary artery disease (CAD) is often polygenic due to multiple mutations that contribute small effects to susceptibility. Since most prior studies only evaluated the contribution of single ...candidate genes, we therefore looked at a combination of genes in predicting early-onset CAD apolipoprotein E (
APOE) ε4, butyrylcholinesterase (
BChE) K, peroxisome proliferator-activated receptor γ2 (PPARγ2) Pro12Ala and endothelial nitric oxide synthase (
ENOS) T-786C.
We examined the frequencies, individually and in combination, of all four alleles among patients with early-onset CAD (
n = 150; <50 years), late-onset CAD (
n = 150; >65 years) and healthy controls (
n = 150, age range 47–93 years). Differences in the proportion of subjects in each group with the given gene combination were assessed and likelihood ratios (LR) were calculated using logistic regression to combine the results of multiple genes.
Early-onset CAD patients had increased, but non-significant, frequencies of PPARγ2 Pro12/Pro12 (
P = 0.39) and
ENOS T-786C (
P = 0.72), while
BChE-K was only significantly higher in early-onset CAD patients compared to controls (
P = 0.03). There were significantly more
APOE ε4 alleles alone (
P = 0.02) or in combination with
BChE-K (
P = 0.02) among early-onset CAD patients compared to late-onset CAD ones or controls. When combined, there was a higher prevalence of all four alleles in early-onset CAD (early-onset CAD patients: 10.7%, late-onset CAD patients: 3.3% and controls: 2.7%,
P = 0.01). LR for early-onset CAD for a single allele was relatively small (1.08 for
PPARγ2 to 1.70 for
APOE ε4). This increased to 2.78 (1.44–5.37) when combining all four alleles, therefore increasing the pre-test probability of CAD from 5% to a post-test probability of 12.7%.
While any single mutation causes only a mildly increased LR (none > 1.7), in combination, the likelihood of early-onset CAD increased to 2.78 with four mutations. The genetics of early-onset CAD appear to be multifactorial, requiring polygenic models to elucidate risk.
This study identifies the most sensitive electrocardiographic leads for monitoring ST-segment changes caused by acute coronary ischemia. The data set consisted of 120-lead electrocardiograms (ECGs) ...digitally recorded during balloon-inflation angioplasty in 3 groups of patients with single-vessel disease (left anterior descending LAD, 32; right coronary artery RCA, 36; left circumflex LCx, 23). The ST deviation was measured in all recorded leads during baseline and ischemic states, and its difference between these 2 states (Delta ST) was calculated at 352 sites and plotted as Delta ST maps. The patients in each group were divided, by means of Delta ST criteria, into subgroups of ldquo respondersrdquo and ldquo nonresponders.rdquo Mean Delta STs for each group/subgroup were calculated and standardized by the corresponding standard deviation (SD); these values were plotted as mean Delta ST and t maps. Sites where extrema of Delta ST occurred most frequently were sought in bootstrap trials, performed in each group/subgroup. The results suggest that the optimal sites for the ischemia-sensitive leads are: V3 (+) and just below V8 (minus ) for LAD-related ischemia; the left iliac crest (+) and above V3 at the third intercostal space (minus ) for RCA-related ischemia; and just below V8 (+) and above V2 at the third intercostal space (minus ) for LCx-related ischemia. Three ldquo optimalrdquo bipolar leads using these sites registered, in the responders from the LAD, RCA, and LCx groups, mean Delta ST (plusmnSD) of 232 plusmn 59, 245 plusmn 96 and 158 plusmn 91 mu V, respectively; the corresponding t values were 15.14, 9.90, and 6.75. In the 12-lead ECG, only lead V3 approached optimal Delta ST and t values for the LAD responders (187 plusmn 61 mu V; t = 11.75) and lead III for the RCA responders (191 plusmn 76 mu V; t = 9.73), but even these values were significantly suboptimal (P = 0.0011 and P = 0.0120, respectively). We found that the ldquo optimalrdquo bipolar leads can be derived, to an excellent approximation, from the 12 standard leads or from 3 EASI leads (with 3 electrodes at Frank's transverse level and 1 on the manubrium), by using precalculated regression coefficients. By means of bootstrap trials, we estimated the mean sensitivity (SE) and the mean positive predictive value (PPV) with which 3 ldquo optimalrdquo vessel-specific leads could identify ischemia related to the LAD, RCA, and LCx arteries, in the test set, as (SE/PPV) 94.7/92.8%, 78.7/80.9%, and 81.5/80.9%. A similar diagnostic performance can be achieved by vessel-specific leads derived from the 12-lead ECG (93.0/93.4%, 76.6/82.0%, and 82.7/77.1%) and, interestingly, from the EASI lead system (97.8/88.4%, 78.0/80.2%, and 76.8/83.2%). Thus, although the ldquo optimalrdquo bipolar leads for detecting ischemia related to each of the 3 coronary arteries were found to require sampling outside the 12-lead ECG, these leads can be derived from the full set of 12 standard leads ormdash for clinical monitoring applicationsmdash from the EASI lead system by using fewer electrodes at convenient locations.
Background The number of patients with coronary artery disease and type 2 diabetes will increase dramatically over the next decade. Diabetes has been related to accelerated atherosclerosis and many ...patients with diabetes will require coronary artery bypass graft (CABG) surgery utilizing saphenous vein grafts. After CABG, accelerated atherosclerosis in saphenous vein grafts leads to graft failure in approximately 50% of cases over a 10-year period. Rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, has been shown to improve multiple metabolic parameters in patients with type 2 diabetes. However, its role in the prevention of atherosclerosis progression is uncertain. Study design VeIn-Coronary aTherOsclerosis and Rosiglitazone after bypass surgerY (VICTORY) is a cardiometabolic trial in which patients with type 2 diabetes, one to 10 years after CABG, will be randomly assigned to receive rosiglitazone (up to 8 mg/day) or a placebo after qualifying angiography and intravascular ultrasound of a segment of one vein graft with or without a native anastomosed coronary artery. A comprehensive set of athero-thrombo-inflammatory markers will be serially assessed during the 12-month follow-up period. Body fat distribution and body composition will be assessed by computed tomography and dual energy x-ray absorptiometry, respectively, at baseline, six months and 12 months follow-up. For atherosclerosis progression evaluation, repeat angiography and intravascular ultrasound will be performed after 12 months follow-up. The primary end point of the study will be the change in atherosclerotic plaque volume in a 40 mm or longer segment of one vein graft. Conclusions The VICTORY trial is the first cardiometabolic study to evaluate the antiatherosclerotic and metabolic effects of rosiglitazone in post-CABG patients with type 2 diabetes.
Coronary artery disease (CAD) is often polygenic due to multiple mutations that contribute small effects to susceptibility. Since most prior studies only evaluated the contribution of single ...candidate genes, we therefore looked at a combination of genes in predicting early-onset CAD apolipoprotein E (APOE) epsilon4, butyrylcholinesterase (BChE) K, peroxisome proliferator-activated receptor gamma2 (PPARgamma2) Pro12Ala and endothelial nitric oxide synthase (ENOS) T-786C.
We examined the frequencies, individually and in combination, of all four alleles among patients with early-onset CAD (n = 150; <50 years), late-onset CAD (n = 150; >65 years) and healthy controls (n = 150, age range 47-93 years). Differences in the proportion of subjects in each group with the given gene combination were assessed and likelihood ratios (LR) were calculated using logistic regression to combine the results of multiple genes.
Early-onset CAD patients had increased, but non-significant, frequencies of PPARgamma2 Pro12/Pro12 (P = 0.39) and ENOS T-786C (P = 0.72), while BChE-K was only significantly higher in early-onset CAD patients compared to controls (P = 0.03). There were significantly more APOE epsilon4 alleles alone (P = 0.02) or in combination with BChE-K (P = 0.02) among early-onset CAD patients compared to late-onset CAD ones or controls. When combined, there was a higher prevalence of all four alleles in early-onset CAD (early-onset CAD patients: 10.7%, late-onset CAD patients: 3.3% and controls: 2.7%, P = 0.01). LR for early-onset CAD for a single allele was relatively small (1.08 for PPARgamma2 to 1.70 for APOE epsilon4). This increased to 2.78 (1.44-5.37) when combining all four alleles, therefore increasing the pre-test probability of CAD from 5% to a post-test probability of 12.7%.
While any single mutation causes only a mildly increased LR (none > 1.7), in combination, the likelihood of early-onset CAD increased to 2.78 with four mutations. The genetics of early-onset CAD appear to be multifactorial, requiring polygenic models to elucidate risk.
The common K variant of butyrylcholinesterase (BChE-K), an enzyme which metabolizes acetylcholine and organophosphates, has been associated with Alzheimer's disease, especially in the presence of the ...apolipoprotein E epsilon 4 allele (APOE-epsilon 4). Although APOE-epsilon 4 has been associated with the development of coronary artery disease (CAD), an association between the BChE-K variant and CAD has not been explored. Paraoxonase 1 (PON1), located within HDL, is an enzyme which also metabolizes organophosphates and may be antiatherogenic. The R192 variant of PON1 (PON1-R) has been associated with CAD.
To determine whether BChE-K is also associated with premature CAD, we examined the frequency of BChE-K among patients with early-onset CAD (n = 150; < 50 yr) vs. late-onset CAD (n = 150; > 65 yr) by molecular analysis. We also examined the frequency of the PON1-R allele in both groups, and explored whether there was synergism between BChE-K and APOE-epsilon 4, BChE-K and PON1-R or PON1-R and APOE-epsilon 4.
The frequency of the BChE-K allele tended to be greater among early-onset CAD patients compared to late-onset CAD patients (41.3% vs. 31.3%; p = 0.07), but without any significant difference between males and females. There was no difference in the prevalence of the PON1-R allele between those with early- or late-onset CAD (46.0% vs. 52.7%; p = 0.25). Twenty-two patients with early-onset CAD had both the BChE-K plus APOE-epsilon 4 alleles (14.7%) compared to 11 late-onset CAD patients (7.3%) (p = 0.04). There was no such association between BChE-K and PON1-R, nor PON1-R and APOE-epsilon 4.
Our study suggests that there is a minor association between BChE-K and early-onset CAD, especially in the presence of the APOE-epsilon 4 allele.
To determine the impact of mutations in the HFE gene (human leukocyte antigen H) on predisposition to coronary artery disease (CAD) in patients not diagnosed with hereditary hemochromatosis.
Elevated ...iron stores can predispose to acute myocardial infarction. Two mutations (C282Y and H63D) in the novel major histocompatibility complex (MHC) class 1 gene HFE were found in most patients with hereditary hemochromatosis causing high iron stores. The effect of these mutations on predisposition to CAD has not been investigated previously.
Three hundred patients with a history of myocardial infarction or angina pectoris and angiographically documented CAD were studied. Patients were divided into two groups: group 1 (150 patients), manifesting early onset CAD and presenting with these findings under age 50 years; and group 2 (150 patients), presenting for the first time over age 65 years. Prevalence of the C282Y and H63D mutations was assessed by molecular analysis, and plasma ferritin was measured immunochemically.
There was no difference in the prevalence of homozygous, heterozygous or compound heterozygous (C282Y/H63D) states between the groups. Males in group 1 had higher plasma ferritin than those in group 2 (234 +/- 174 micrograms/L versus 136 +/- 103 micrograms/L, P < 0.0001), but this was not significantly different in females (75 +/- 54 micrograms/L versus 92 +/- 73 micrograms/L, P = 0.26). Ferritin remained higher in group 1 than in group 2 males after exclusion of mutation carriers (195 +/- 121 micrograms/L versus 109 +/- 76 micrograms/L, respectively, P < 0.0001), but did not change in females.
Higher iron stores were found in males with early onset CAD. This association was not related to the C282Y or H63D mutation in HFE. It is suggested that association of the MHC locus with delayed onset CAD is probably unrelated to HFE in these patients, and that HFE mutations are not a major risk factor in the development of high iron stores in early onset CAD.
This collection weitten by leading figures in cognitive science includes their lively debates with Dartnall about his call for a new epistemology, an alternative to the standard representational ...story in cognitive science. Dartnall aims to show that new epistemology is already with us in some leading-edge models of human creativity. Such an epistemology steers a middle road between the representationism of classical cognitive science and a radical anti-representationism that denies the existence or importance of representations.Dartnall, who debates contributors at each chapter's end, believes that creativity inheres-not only in big ticket items such as plays, poems, or sonatas-but in our ability to produce cognitive content at all, so that representations are the creative products of our knowledge, rather than its passive carriers.
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