Contribution of Genetic Background, Traditional Risk Factors, and HIV-Related Factors to Coronary Artery Disease Events in HIV-Positive Persons

Background Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection. Methods In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort. Results A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9×10−4). In the final multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval [CI], 1.05–2.04). This effect was similar to hypertension (OR = 1.36; 95% CI, 1.06–1.73), hypercholesterolemia (OR = 1.51; 95% CI, 1.16–1.96), diabetes (OR = 1.66; 95% CI, 1.10–2.49), ≥1 year lopinavir exposure (OR = 1.36; 95% CI, 1.06–1.73), and current abacavir treatment (OR = 1.56; 95% CI, 1.17–2.07). The effect of the genetic risk score was additive to the effect of nongenetic CAD risk factors, and did not change after adjustment for family history of CAD. Conclusions In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD.

Quantification of coronary artery stenosis with high-resolution CT in comparison with histopathology in an ex vivo study

PURPOSE To investigate the ex vivo performance of high-resolution computed tomography (CT) for quantitative assessment of percentage diameter stenosis in coronary arteries compared to histopathology. MATERIALS AND METHODS High-resolution CT was performed in 26 human heart specimens after the injection of iodinated contrast media into the coronary arteries. Coronary artery plaques were visually identified on CT images and the grade of stenosis for each plaque was measured with electronic calipers. All coronary plaques were characterized by histopathology according to the Stary classification, and the percentage of stenosis was measured. RESULTS CT depicted 84% (274/326) of all coronary plaques identified by histology. Missed plaques by CT were of Stary type I (n=31), type II (n=16), and type III (n=5). The stenosis degree significantly correlated between CT and histology (r=0.81, p<0.001). CT systematically overestimated the stenosis of calcified plaques (mean difference - 11.0 ± 9.5%, p<0.01) and systematically underestimated the stenosis of non-calcified plaques (mean difference -6.8 ± 10.4%, p<0.05), while there was no significant difference for mixed-type plaques (mean difference -0.4 ± 11.7%, p=0.85). There was a significant underestimation of stenosis degree as measured by CT for Stary II plaques (mean difference -14 ± 9%, p<0.01) and a significant overestimation for Stary VII plaques (mean difference 9 ± 10%, p<0.05), but there was no significant difference in stenosis degree between both modalities for other plaque types. CONCLUSIONS High-resolution CT reliably depicts advanced stage coronary plaques with an overall good correlation of stenosis degree compared to histology, however, the degree of stenosis is systematically overestimated in calcified and underestimated in non-calcified plaques.

Differential healing response attributed to culprit lesions of patients with acute coronary syndromes and stable coronary artery after implantation of drug-eluting stents: An optical coherence tomography study

BACKGROUND Pathology studies have shown delayed arterial healing in culprit lesions of patients with acute coronary syndrome (ACS) compared with stable coronary artery disease (CAD) after placement of drug-eluting stents (DES). It is unknown whether similar differences exist in-vivo during long-term follow-up. Using optical coherence tomography (OCT), we assessed differences in arterial healing between patients with ACS and stable CAD five years after DES implantation. METHODS AND RESULTS A total of 88 patients comprised of 53 ACS lesions with 7864 struts and 35 stable lesions with 5298 struts were suitable for final OCT analysis five years after DES implantation. The analytical approach was based on a hierarchical Bayesian random-effects model. OCT endpoints were strut coverage, malapposition, protrusion, evaginations and cluster formation. Uncovered (1.7% vs. 0.7%, adjusted p=0.041) or protruding struts (0.50% vs. 0.13%, adjusted p=0.038) were more frequent among ACS compared with stable CAD lesions. A similar trend was observed for malapposed struts (1.33% vs. 0.45%, adj. p=0.072). Clusters of uncovered or malapposed/protruding struts were present in 34.0% of ACS and 14.1% of stable patients (adj. p=0.041). Coronary evaginations were more frequent in patients with ST-elevation myocardial infarction compared with stable CAD patients (0.16 vs. 0.13 per cross section, p=0.027). CONCLUSION Uncovered, malapposed, and protruding stent struts as well as clusters of delayed healing may be more frequent in culprit lesions of ACS compared with stable CAD patients late after DES implantation. Our observational findings suggest a differential healing response attributable to lesion characteristics of patients with ACS compared with stable CAD in-vivo.

Coronary artery stents: influence of adaptive statistical iterative reconstruction on image quality using 64-HDCT

OBJECTIVE: The assessment of coronary stents with present-generation 64-detector row computed tomography (HDCT) scanners is limited by image noise and blooming artefacts. We evaluated the performance of adaptive statistical iterative reconstruction (ASIR) for noise reduction in coronary stent imaging with HDCT. METHODS AND RESULTS: In 50 stents of 28 patients (mean age 64 ± 10 years) undergoing coronary CT angiography (CCTA) on an HDCT scanner the mean in-stent luminal diameter, stent length, image quality, in-stent contrast attenuation, and image noise were assessed. Studies were reconstructed using filtered back projection (FBP) and ASIR-FBP composites. ASIR resulted in reduced image noise vs. FBP (P < 0.0001). Two readers graded the CCTA stent image quality on a 4-point Likert scale and determined the proportion of interpretable stent segments. The best image quality for all clinical images was obtained with 40 and 60% ASIR with significantly larger luminal area visualization compared with FBP (+42.1 ± 5.4% with 100% ASIR vs. FBP alone; P < 0.0001) while the stent length was decreased (-4.7 ± 0.9%,

Association of biomarkers of lipid modification with functional and morphological indices of coronary stenosis severity in stable coronary artery disease

Biomarkers of blood lipid modification and oxidative stress have been associated with increased cardiovascular morbidity. We sought to determine whether these biomarkers were related to functional indices of stenosis severity among patients with stable coronary artery disease. We studied 197 consecutive patients with stable coronary artery disease due to single vessel disease. Fractional flow reserve (FFR) ≤ 0.80 was assessed as index of a functionally significant lesion. Serum levels of secretory phospholipase A2 (sPLA2) activity, secretory phospholipase A2 type IIA (sPLA2-IIA), myeloperoxydase (MPO), lipoprotein-associated phospholipase A2 (Lp-PLA2), and oxidized low-density lipoprotein (OxLDL) were assessed using commercially available assays. Patients with FFR > 0.8 had higher sPLA2 activity, sPLA2 IIA, and OxLDL levels than patients with FFR ≤ 0.8 (21.25 [16.03-27.28] vs 25.85 [20.58-34.63] U/mL, p < 0.001, 2.0 [1.5-3.4] vs 2.6 [2.0-3.4] ng/mL, p < 0.01; and 53.0 [36.0-71.0] vs 64.5 [50-89.25], p < 0.001 respectively). Patients with FFR > 0.80 had similar Lp-PLA2 and MPO levels versus those with FFR ≤ 0.8. sPLA2 activity, sPLA2 IIA significantly increased area under the curve over baseline characteristics to predict FFR ≤ 0.8 (0.67 to 0.77 (95 % confidence interval [CI]: 0.69-0.85) p < 0.01 and 0.67 to 0.77 (95 % CI: 0.69-0.84) p < 0.01, respectively). Serum sPLA2 activity as well as sPLA2-IIA level is related to functional characteristics of coronary stenoses in patients with stable coronary artery disease.

Coronary artery disease severity and aortic stenosis: clinical outcomes according to SYNTAX score in patients undergoing transcatheter aortic valve implantation.

AIM The aim of this study was to evaluate whether coronary artery disease (CAD) severity exerts a gradient of risk in patients with aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS A total of 445 patients with severe AS undergoing TAVI were included into a prospective registry between 2007 and 2012. The preoperative SYNTAX score (SS) was determined from baseline coronary angiograms. In case of revascularization prior to TAVI, residual SS (rSS) was also determined. Clinical outcomes were compared between patients without CAD (n = 158), patients with low SS (0-22, n = 207), and patients with high SS (SS >22, n = 80). The pre-specified primary endpoint was the composite of cardiovascular death, stroke, or myocardial infarction (MI). At 1 year, CAD severity was associated with higher rates of the primary endpoint (no CAD: 12.5%, low SS: 16.1%, high SS: 29.6%; P = 0.016). This was driven by differences in cardiovascular mortality (no CAD: 8.6%, low SS: 13.6%, high SS: 20.4%; P = 0.029), whereas the risk of stroke (no CAD: 5.1%, low SS: 3.3%, high SS: 6.7%; P = 0.79) and MI (no CAD: 1.5%, low SS: 1.1%, high SS: 4.0%; P = 0.54) was similar across the three groups. Patients with high SS received less complete revascularization as indicated by a higher rSS (21.2 ± 12.0 vs. 4.0 ± 4.4, P < 0.001) compared with patients with low SS. High rSS tertile (>14) was associated with higher rates of the primary endpoint at 1 year (no CAD: 12.5%, low rSS: 16.5%, high rSS: 26.3%, P = 0.043). CONCLUSIONS Severity of CAD appears to be associated with impaired clinical outcomes at 1 year after TAVI. Patients with SS >22 receive less complete revascularization and have a higher risk of cardiovascular death, stroke, or MI than patients without CAD or low SS.

High-density lipoprotein cholesterol, coronary artery disease, and cardiovascular mortality.

AIMS High-density lipoprotein (HDL) cholesterol is a strong predictor of cardiovascular mortality. This work aimed to investigate whether the presence of coronary artery disease (CAD) impacts on its predictive value. METHODS AND RESULTS We studied 3141 participants (2191 males, 950 females) of the LUdwigshafen RIsk and Cardiovascular health (LURIC) study. They had a mean ± standard deviation age of 62.6 ± 10.6 years, body mass index of 27.5 ± 4.1 kg/m², and HDL cholesterol of 38.9 ± 10.8 mg/dL. The cohort consisted of 699 people without CAD, 1515 patients with stable CAD, and 927 patients with unstable CAD. The participants were prospectively followed for cardiovascular mortality over a median (inter-quartile range) period of 9.9 (8.7-10.7) years. A total of 590 participants died from cardiovascular diseases. High-density lipoprotein cholesterol by tertiles was inversely related to cardiovascular mortality in the entire cohort (P = 0.009). There was significant interaction between HDL cholesterol and CAD in predicting the outcome (P = 0.007). In stratified analyses, HDL cholesterol was strongly associated with cardiovascular mortality in people without CAD [3rd vs. 1st tertile: HR (95% CI) = 0.37 (0.18-0.74), P = 0.005], but not in patients with stable [3rd vs. 1st tertile: HR (95% CI) = 0.81 (0.61-1.09), P = 0.159] and unstable [3rd vs. 1st tertile: HR (95% CI) = 0.91 (0.59-1.41), P = 0.675] CAD. These results were replicated by analyses in 3413 participants of the AtheroGene cohort and 5738 participants of the ESTHER cohort, and by a meta-analysis comprising all three cohorts. CONCLUSION The inverse relationship of HDL cholesterol with cardiovascular mortality is weakened in patients with CAD. The usefulness of considering HDL cholesterol for cardiovascular risk stratification seems limited in such patients.

Quantitative Myocardial Contrast Echocardiography during Pharmacological Stress for Diagnosis of Coronary Artery Disease: A Systematic Review and Meta-analysis of Diagnostic Accuracy Studies

AIMS: We conducted a meta-analysis to evaluate the accuracy of quantitative stress myocardial contrast echocardiography (MCE) in coronary artery disease (CAD). METHODS AND RESULTS: Database search was performed through January 2008. We included studies evaluating accuracy of quantitative stress MCE for detection of CAD compared with coronary angiography or single-photon emission computed tomography (SPECT) and measuring reserve parameters of A, beta, and Abeta. Data from studies were verified and supplemented by the authors of each study. Using random effects meta-analysis, we estimated weighted mean difference (WMD), likelihood ratios (LRs), diagnostic odds ratios (DORs), and summary area under curve (AUC), all with 95% confidence interval (CI). Of 1443 studies, 13 including 627 patients (age range, 38-75 years) and comparing MCE with angiography (n = 10), SPECT (n = 1), or both (n = 2) were eligible. WMD (95% CI) were significantly less in CAD group than no-CAD group: 0.12 (0.06-0.18) (P < 0.001), 1.38 (1.28-1.52) (P < 0.001), and 1.47 (1.18-1.76) (P < 0.001) for A, beta, and Abeta reserves, respectively. Pooled LRs for positive test were 1.33 (1.13-1.57), 3.76 (2.43-5.80), and 3.64 (2.87-4.78) and LRs for negative test were 0.68 (0.55-0.83), 0.30 (0.24-0.38), and 0.27 (0.22-0.34) for A, beta, and Abeta reserves, respectively. Pooled DORs were 2.09 (1.42-3.07), 15.11 (7.90-28.91), and 14.73 (9.61-22.57) and AUCs were 0.637 (0.594-0.677), 0.851 (0.828-0.872), and 0.859 (0.842-0.750) for A, beta, and Abeta reserves, respectively. CONCLUSION: Evidence supports the use of quantitative MCE as a non-invasive test for detection of CAD. Standardizing MCE quantification analysis and adherence to reporting standards for diagnostic tests could enhance the quality of evidence in this field.

Subgingival Aggregatibacter actinomycetemcomitans associates with the risk of coronary artery disease

AIM We investigated the association between angiographically verified coronary artery disease (CAD) and subgingival Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola. MATERIALS AND METHODS The cross-sectional study population (n = 445) comprised 171 (38.4%) patients with Stable CAD, 158 (35.5%) with acute coronary syndrome (ACS) and 116 (26.1%) with no significant CAD (No CAD). All patients participated in clinical and radiological oral health examinations. Pooled subgingival bacterial samples were analysed by checkerboard DNA-DNA hybridization assays. RESULTS In all study groups, the presence of P. gingivalis, T. forsythia and T. denticola indicated a significant (p ≤ 0.001) linear association with the extent of alveolar bone loss (ABL), but A. actinomycetemcomitans did not (p = 0.074). With a threshold level of bacterial cells 1 × 10(5) A. actinomycetemcomitans was significantly more prevalent in the Stable CAD group (42.1%) compared to the No CAD group (30.2%) (p = 0.040). In a multi-adjusted logistic regression analysis using this threshold, A. actinomycetemcomitans positivity associated with Stable CAD (OR 1.83, 95% CI 1.00-3.35, p = 0.049), but its level or levels of other bacteria did not. CONCLUSIONS The presence of subgingival A. actinomycetemcomitans associates with an almost twofold risk of Stable CAD independently of alveolar bone loss.

High-speed rotational atherectomy before paclitaxel-eluting stent implantation in complex calcified coronary lesions: the randomized ROTAXUS (Rotational Atherectomy Prior to Taxus Stent Treatment for Complex Native Coronary Artery Disease) trial

OBJECTIVES This study sought to determine the effect of rotational atherectomy (RA) on drug-eluting stent (DES) effectiveness. BACKGROUND DES are frequently used in complex lesions, including calcified stenoses, which may challenge DES delivery, expansion, and effectiveness. RA can adequately modify calcified plaques and facilitate stent delivery and expansion. Its impact on DES effectiveness is widely unknown. METHODS The ROTAXUS (Rotational Atherectomy Prior to TAXUS Stent Treatment for Complex Native Coronary Artery Disease) study randomly assigned 240 patients with complex calcified native coronary lesions to RA followed by stenting (n = 120) or stenting without RA (n = 120, standard therapy group). Stenting was performed using a polymer-based slow-release paclitaxel-eluting stent. The primary endpoint was in-stent late lumen loss at 9 months. Secondary endpoints included angiographic and strategy success, binary restenosis, definite stent thrombosis, and major adverse cardiac events at 9 months. RESULTS Despite similar baseline characteristics, significantly more patients in the standard therapy group were crossed over (12.5% vs. 4.2%, p = 0.02), resulting in higher strategy success in the rotablation group (92.5% vs. 83.3%, p = 0.03). At 9 months, in-stent late lumen loss was higher in the rotablation group (0.44 ± 0.58 vs. 0.31 ± 0.52, p = 0.04), despite an initially higher acute lumen gain (1.56 ± 0.43 vs. 1.44 ± 0.49 mm, p = 0.01). In-stent binary restenosis (11.4% vs. 10.6%, p = 0.71), target lesion revascularization (11.7% vs. 12.5%, p = 0.84), definite stent thrombosis (0.8% vs. 0%, p = 1.0), and major adverse cardiac events (24.2% vs. 28.3%, p = 0.46) were similar in both groups. CONCLUSIONS Routine lesion preparation using RA did not reduce late lumen loss of DES at 9 months. Balloon dilation with only provisional rotablation remains the default strategy for complex calcified lesions before DES implantation.

Function of Natural Internal Mammary-to-Coronary Artery Bypasses and Its Effect on Myocardial Ischemia.

BACKGROUND The function of naturally existing internal mammary (IMA)-to-coronary artery bypasses and their quantitative effect on myocardial ischemia are unknown. METHODS AND RESULTS The primary end point of this study was collateral flow index (CFI) obtained during two 1-minute coronary artery balloon occlusions, the first with and the second without simultaneous distal IMA occlusion. The secondary study end point was the quantitatively determined intracoronary ECG ST-segment elevation. CFI is the ratio of simultaneously recorded mean coronary occlusive pressure divided by mean aortic pressure both subtracted by mean central venous pressure. A total of 180 pairs of CFI measurements were performed among 120 patients. With and without IMA occlusion, CFI was 0.110±0.074 and 0.096±0.072, respectively (P<0.0001). The difference of CFI obtained in the presence minus CFI obtained in the absence of IMA occlusion was highest and most consistently positive during left IMA with left anterior descending artery occlusion and during right IMA with right coronary artery occlusion (ipsilateral occlusions): 0.033±0.044 and 0.025±0.027, respectively. This CFI difference was absent during right IMA with left anterior descending artery occlusion and during left IMA with right coronary artery occlusion (contralateral occlusions): -0.007±0.034 and 0.001±0.023, respectively (P=0.0002 versus ipsilateral occlusions). The respective CFI differences during either IMA with left circumflex artery occlusion were inconsistently positive. Intracoronary ECG ST-segment elevations were significantly reduced during ipsilateral IMA occlusions but not during contralateral or left circumflex artery occlusions. CONCLUSION There is a functional, ischemia-reducing extracardiac coronary artery supply via ipsilateral but not via contralateral natural IMA bypasses. CLINICAL TRIAL REGISTRATION URL http://www.clinicaltrials.gov. Unique identifier: NCTO1676207.

Fractional Flow Reserve–Guided PCI for Stable Coronary Artery Disease

Background We hypothesized that in patients with stable coronary artery disease and stenosis, percutaneous coronary intervention (PCI) performed on the basis of the fractional flow reserve (FFR) would be superior to medical therapy. Methods In 1220 patients with stable coronary artery disease, we assessed the FFR in all stenoses that were visible on angiography. Patients who had at least one stenosis with an FFR of 0.80 or less were randomly assigned to undergo FFR-guided PCI plus medical therapy or to receive medical therapy alone. Patients in whom all stenoses had an FFR of more than 0.80 received medical therapy alone and were included in a registry. The primary end point was a composite of death from any cause, nonfatal myocardial infarction, or urgent revascularization within 2 years. Results The rate of the primary end point was significantly lower in the PCI group than in the medical-therapy group (8.1% vs. 19.5%; hazard ratio, 0.39; 95% confidence interval [CI], 0.26 to 0.57; P<0.001). This reduction was driven by a lower rate of urgent revascularization in the PCI group (4.0% vs. 16.3%; hazard ratio, 0.23; 95% CI, 0.14 to 0.38; P<0.001), with no significant between-group differences in the rates of death and myocardial infarction. Urgent revascularizations that were triggered by myocardial infarction or ischemic changes on electrocardiography were less frequent in the PCI group (3.4% vs. 7.0%, P=0.01). In a landmark analysis, the rate of death or myocardial infection from 8 days to 2 years was lower in the PCI group than in the medical-therapy group (4.6% vs. 8.0%, P=0.04). Among registry patients, the rate of the primary end point was 9.0% at 2 years. Conclusions In patients with stable coronary artery disease, FFR-guided PCI, as compared with medical therapy alone, improved the outcome. Patients without ischemia had a favorable outcome with medical therapy alone. (Funded by St. Jude Medical; FAME 2 ClinicalTrials.gov number, NCT01132495 .).