Angiographic Coronary Artery Disease Burden Research Articles

Abstract 3119: Angiographic Burden Of Coronary Atherosclerosis Contributes To Adverse ASCVD Outcomes Independent Of Traditional Risk Factors

Background: Coronary artery disease (CAD) is a major contributor to cardiovascular morbidity (including myocardial infarction [MI] and heart failure [HF]), and mortality. Although burden of CAD (number and degree of coronary artery stenosis) has been observationally linked to these outcomes, the causal contribution (and independence from traditional cardiovascular risk factors) has been poorly defined. Methods: The primary exposure for this experiment was a genetic instrument for burden of CAD that was constructed from a GWAS of semi-quantitative CAD burden among VA Million Veteran Program participants undergoing coronary angiography. Two-sample Mendelian randomization (MR) was performed to test 1) bidirectional associations between traditional ASCVD risk factors (including blood lipids, blood pressure, diabetes, obesity, and smoking) and CAD burden and 2) between CAD burden and adverse cardiovascular outcomes (MI, HF, and parental longevity as a proxy of lifespan). Multivariable MR (MVMR) for mediation was then performed to determine whether traditional risk factors mediate the association between CAD burden and adverse outcomes. Results: As expected, traditional cardiovascular risk factors including lipid levels, diabetes and obesity were associated with increased burden of CAD, MI, HF, and lifespan. Angiographic CAD burden was associated with increased risk of MI, HF, and lifespan. MVMR demonstrated experiment wide independent contributions of CAD burden to HF (OR 1.13 [95% CI 1.08-1.19], p = 2.3E-6), lifespan (b = -0.06, se = 0.01, p = 9.7E-05) and MI (OR 1.74 [95% CI 1.55-1.95], p = 3.4E-21), after accounting for traditional ASCVD risk factors. The effects of lipids on HF and lifespan were partially mediated by angiographic burden of CAD. Conclusion: This study suggests that increased angiographic burden of coronary artery disease is associated with adverse cardiovascular outcomes, with an independent contribution beyond traditional cardiovascular risk factors. More aggressive primary prevention of traditional cardiovascular risk factors may be indicated to prevent development and progression/growth of coronary plaques and mitigate subsequent adverse cardiovascular outcomes.

Perivascular Adipose Tissue Inflammation in Ischemic Heart Disease.

There is growing recognition that adipose tissue-derived proatherogenic mediators contribute to obesity-related cardiovascular disease. We sought to characterize regional differences in perivascular adipose tissue (PVAT) phenotype in relation to atherosclerosis susceptibility. Approach and Results: We examined thoracic PVAT samples in 34 subjects (body mass index 32±6 kg/m2, age 59±11 years) undergoing valvular, aortic, or coronary artery bypass graft surgeries and performed transcriptomic characterization using whole-genome expression profiling and quantitative polymerase chain reaction analyses. We identified a highly inflamed region of PVAT surrounding the human aortic root in close proximity to coronary takeoff and adjoining epicardial fat. In subjects undergoing coronary artery bypass graft, we found 300 genes significantly upregulated (false discovery rate Q<0.1) in paired samples of PVAT surrounding the aortic root compared with nonatherosclerotic left internal mammary artery. Genes encoding proteins mechanistically implicated in atherogenesis were enriched in aortic PVAT consisting of signaling pathways linked to inflammation, WNT (wingless-related integration site) signaling, matrix remodeling, coagulation, and angiogenesis. Overexpression of several proatherogenic transcripts, including IL1β, CCL2 (MCP-1), and IL6, were confirmed by quantitative polymerase chain reaction and significantly bolstered in coronary artery disease subjects. Angiographic coronary artery disease burden quantified by the Gensini score positively correlated with the expression of inflammatory genes in PVAT. Moreover, periaortic adipose inflammation was markedly higher in obese subjects with striking upregulation (≈8-fold) of IL1β expression compared to nonobese individuals. Proatherogenic mediators that originate from dysfunctional PVAT may contribute to vascular disease mechanisms in human vessels. Moreover, PVAT may adopt detrimental properties under obese conditions that play a key role in the pathophysiology of ischemic heart disease. Graphic Abstract: A graphic abstract is available for this article.

Coronary Angiography for Follow-up of Heart Transplant Recipients: Usefulness of the Gensini Score.

Posttransplant cardiac allograft vasculo-pathy affects long-term survival after heart transplant. Because cardiac transplant recipients do not feel angina pectoris as a result of denervation of the transplanted heart graft, early diagnosis is difficult. The Gensini score, a widely used and simple scoring system, can determine the severity of coronary artery disease by angiography. Although this system has been widely used to evaluate natural coronary atherosclerosis, its use in heart transplant recipients has not been studied. Here, we evaluated cardiac allograft vasculo-pathy using the Gensini score. We retrospectively analyzed 105 heart transplant patients seen between February 2004 and April 2018, including their immunosuppressive therapies. The Gensini score was calculated to determine severity score for each coronary stenosis according to degree of luminal narrowing and location. Of 105 heart transplant patients, 21 were diagnosed with cardiac allograft vasculopathy. Most patients received tacrolimus, prednisolone, and mycophenolate mofetil as standard therapy. Of 63 included patients, 21 (33.3%) showed cardiac allograft vasculopathy on coronary angiography. In accordance with the International Society of Heart and Lung Transplantation rating system, 42 of 63 patients (66.6%) were rated as 0 (no detectable angiographic lesions). Mean Gensini score was 34.8 ± 26. In the 21 patients with cardiac allograft vasculopathy, Gensini score showed mild cardiac allograft vas-culopathy (score ≤ 10) in 8 patients (38%), moderate (score > 10 and ≤ 40) in 6 patients (28.5%), and severe (score > 40) in 7 patients (33.3%). Angiographic coronary artery disease burden using Gensini was strongly correlated with cardiac allograft vasculopathy severity. The Gensini score could provide valid assessment of cardiac allograft vasculopathy burden for use in clinical practice. However, more research is needed to identify and treat cardiac allograft vasculopathy for successful long-term survival of heart transplant patients.

Effects of coronary revascularization on global coronary flow reserve in stable coronary artery disease.

AimsCoronary flow reserve (CFR) is an integrated measure of the entire coronary vasculature, and is a powerful prognostic marker in coronary artery disease (CAD). The extent to which coronary revascularization can improve CFR is unclear. This study aimed to evaluate the impact of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) on CFR in patients with stable CAD.Methods and resultsIn a prospective, multicentre observational study, CFR was measured by 15O-water positron emission tomography as the ratio of stress to rest myocardial blood flow at baseline and 6 months after optimal medical therapy (OMT) alone, PCI, or CABG. Changes in the SYNTAX and Leaman scores were angiographically evaluated as indicators of completeness of revascularization. Follow-up was completed by 75 (25 OMT alone, 28 PCI, and 22 CABG) out of 82 patients. The median SYNTAX and Leaman scores, and baseline CFR were 14.5 [interquartile range (IQR): 8–24.5], 5.5 (IQR: 2.5–12.5), and 1.94 (IQR: 1.67–2.66), respectively. Baseline CFR was negatively correlated with the SYNTAX (ρ = −0.40, P < 0.001) and Leaman scores (ρ = −0.33, P = 0.004). Overall, only CABG was associated with a significant increase in CFR [1.67 (IQR: 1.14–1.96) vs. 1.98 (IQR: 1.60–2.39), P < 0.001]. Among patients with CFR <2.0 (n = 41), CFR significantly increased in the PCI [1.70 (IQR: 1.42–1.79) vs. 2.21 (IQR: 1.78–2.49), P = 0.002, P < 0.001 for interaction between time and CFR] and CABG groups [1.28 (IQR: 1.13–1.80) vs. 1.86 (IQR: 1.57–2.22), P < 0.001]. The reduction in SYNTAX or Leaman scores after PCI or CABG was independently associated with the percent increase in CFR after adjusting for baseline characteristics (P = 0.012 and P = 0.011, respectively).ConclusionCoronary revascularization ameliorated reduced CFR in patients with obstructive CAD. The degree of improvement in angiographic CAD burden by revascularization was correlated with magnitude of improvement in CFR.

Excess Cardiovascular Risk in Women Relative to Men Referred for Coronary Angiography Is Associated With Severely Impaired Coronary Flow Reserve, Not Obstructive Disease.

Cardiovascular disease (CVD) fatality rates are higher for women than for men, yet obstructive coronary artery disease (CAD) is less prevalent in women. Coronary flow reserve (CFR), an integrated measure of large- and small-vessel CAD and myocardial ischemia, identifies patients at risk for CVD death, but is not routinely measured in clinical practice. We sought to investigate the impact of sex, CFR, and angiographic CAD severity on adverse cardiovascular events. Consecutive patients (n=329, 43% women) referred for invasive coronary angiography after stress testing with myocardial perfusion positron emission tomography and with left ventricular ejection fraction >40% were followed (median, 3.0 years) for a composite end point of major adverse cardiovascular events, including cardiovascular death and hospitalization for nonfatal myocardial infarction or heart failure. The extent and severity of angiographic CAD were estimated by using the CAD prognostic index, and CFR was quantified by using positron emission tomography. Although women in comparison with men had lower pretest clinical scores, rates of prior myocardial infarction, and burden of angiographic CAD (P<0.001), they demonstrated greater risk of CVD events, even after adjustment for traditional risk factors, imaging findings, and early revascularization (adjusted hazard ratio, 2.05; 95% confidence interval, 1.05-4.02; P=0.03). Impaired CFR was similarly present among women and men, but in patients with low CFR (<1.6, n=163), women showed a higher frequency of nonobstructive CAD, whereas men showed a higher frequency of severely obstructive CAD (P=0.002). After also adjusting for CFR, the effect of sex on outcomes was no longer significant. When stratified by sex and CFR, only women with severely impaired CFR demonstrated significantly increased adjusted risk of CVD events (P<0.0001, P for interaction=0.04). Women referred for coronary angiography had a significantly lower burden of obstructive CAD in comparison with men but were not protected from CVD events. Excess cardiovascular risk in women was independently associated with impaired CFR, representing a hidden biological risk, and a phenotype less amenable to revascularization. Impaired CFR, particularly absent severely obstructive CAD, may represent a novel target for CVD risk reduction.

Abstract 13679: Excess Cardiovascular Risk in Women Relative to Men Referred for Coronary Angiography is Associated With Impaired Coronary Flow Reserve From Diffuse versus Obstructive Coronary Artery Disease

Introduction: Case fatality rates for cardiovascular disease (CVD) are higher for women of all ages as compared with men, yet obstructive coronary artery disease (CAD) is less prevalent in women. Coronary flow reserve (CFR) is an integrated measure of large and small vessel CAD and myocardial ischemia, and identifies patients at risk for CVD death, independently of angiographic disease severity. Methods: Consecutive patients (N=329, 43% women) referred for invasive coronary angiography after stress testing with myocardial perfusion PET and with LV ejection fraction &gt;40% were followed (median 3.0 years) for CVD death, nonfatal MI, or heart failure admission. The extent/severity of angiographic CAD was estimated using the CAD prognostic index (CADPI), and CFR quantified using PET. Results: Although women relative to men had lower pretest clinical scores, rates of prior MI, and burden of angiographic CAD (p&lt;0.001), they demonstrated greater risk of CVD events (adjusted HR 2.05, 95%CI 1.05-4.02, p=0.03), even after adjustment for clinical risk factors, LV ejection fraction and ischemia, angiographic disease and time-dependent early revascularization. Impaired CFR was similarly present among women and men, but in patients with low CFR (&lt;1.6, n=163), women showed higher frequency of nonobstructive CAD, while men showed higher frequency of severely obstructive CAD (p=0.002). After also adjusting for CFR (adjusted HR for unit decrease in CFR, 1.69; 95%CI 1.04-2.76, p=0.03), the effect of sex on outcomes was no longer significant (p=0.10). When stratified by sex and CFR (Figure), only women with impaired CFR demonstrated significantly increased adjusted risk of CVD events (p&lt;0.0001, model p for interaction=0.04). Conclusions: Although women referred for coronary angiography had significantly lower burden of obstructive epicardial CAD relative to men, they were not protected from CVD events. Impaired CFR from diffuse CAD may represent a target for CVD risk reduction.

Abstract 10383: Comparative Assessment of Medical Therapy, PCI, or CABG on Clinical Outcomes in Diabetic Patients With Stable CAD According to Coronary Angiography and Left Ventricular Function: Patient-level Meta-analysis of the BARI-2D, COURAGE, and FREEDOM Trials

Introduction: The benefits of optimal medical therapy (OMT) with or without percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery have been evaluated in patients with Type 2 Diabetes Mellitus (T2DM) and stable coronary artery disease (CAD) but analyses have not been stratified by detailed angiographic CAD burden or left ventricular ejection fraction (LVEF). Methods: A patient-level meta-analysis was undertaken among T2DM patients enrolled in COURAGE, BARI 2D and FREEDOM to assess the impact of randomization to OMT, PCI + OMT, or CABG + OMT on a composite end-point of Death/MI/Stroke and stratified by LVEF (≥ 50%, &lt; 50%), 1, 2 or 3 vessel disease (VD) (% diameter stenosis ≥ 50%) and presence or absence of proximal left anterior descending (pLAD) disease. Hazard ratios (HR) for treatment groups were calculated from Cox regression models including all patients adjusting for trial and revascularization stratum in BARI 2D. Multivariable adjustment for risk factors was performed as a sensitivity analysis. Results: There were 5,034 patients included in the analysis (BARI 2D: n=2,368, COURAGE: n=766, FREEDOM: n=1,900) of whom 17% had LVEF &lt; 50%, 29% had pLAD, and 77% had 2 or 3 VD. A total of 1,591 patients were randomized to OMT alone, 2,118 to PCI + OMT, and 1,325 to CABG + OMT. There were 1,116 events during a median 4.5 year follow-up. There was no significant effect on outcomes with OMT vs PCI + OMT irrespective of LVEF, presence/absence of pLAD and number of VD. By contrast, CABG + OMT significantly reduced the risk of Death/MI/Stroke in patients with 2 or 3 VD, irrespective of LVEF and presence/absence of pLAD (see Table). Results were similar with multivariable adjustment. Conclusions: In patients with T2DM and stable CAD, OMT alone appears to be as effective as PCI + OMT while CABG + OMT significantly reduces cardiovascular events in those with multivessel CAD, irrespective of LVEF or presence of pLAD.

189 Genetic Variation in ADAMTS7 is Associated with Severity of Coronary Artery Disease

Purpose Genome-wide association studies have identified ADAMTS7 as a risk locus for coronary artery disease (CAD) and myocardial infarction (MI). Functional studies suggest ADAMTS7 may promote cellular processes in atherosclerosis. We studied if risk variant carriers exhibit a greater burden of angiographic CAD. Methods We genotyped ADAMTS7 in the Southampton Atherosclerosis Study (SAS, n = 1359), and replicated in the Emory Genebank (Emory GB, n = 2684). Angiographic CAD was phenotyped as presence of >50% stenosis in epicardial vessel and semi-quantitative scores including the Gensini Score (GS), Sullivan Extent Score (SES) and the Duke Severity Index (DSI); and ex-vivo immunohistochemical analysis of human coronary plaques (n = 48). Results We confirmed an association between ADAMTS7 genotype and presence of CAD under an additive genotype model in SAS (p = 0.05) and Emory GB (p = 0.017), but found no associations with MI in the presence of CAD. ADAMTS genotypes were associated with all of the angiographic severity scores in SAS (GS p = 0.017, SES p = 0.045, DSI p = 0.029), and independently replicated in Emory GB (GS p Conclusions The ADAMTS7 risk variant is associated with multiple angiographic measures of CAD burden and plaque remodelling, further supporting the role of this protease in promoting atherosclerosis.

126 CHROMOSOME 9P21 LOCUS AND ANGIOGRAPHIC CORONARY ARTERY DISEASE BURDEN: A COLLABORATIVE META-ANALYSIS

<h3>Background</h3> Chromosome 9p21 variants have been strongly associated with coronary heart disease in genome-wide association studies, but questions remain on the mechanism of risk, specifically whether the locus contributes to coronary atheroma burden or plaque instability. We investigated the relationship of 9p21 locus with (1) angiographic coronary artery disease (CAD) burden and (2) myocardial infarction (MI) in individuals with underlying CAD. Methods:We established a collaboration of 21 studies consisting of 33,673 subjects with information on both CAD (clinical or angiographic) and MI status along with 9p21 genotype. Tabular data were provided for each cohort on the presence and burden of angiographic CAD; MI cases with underlying CAD; and the diabetic status of all subjects. <h3>Results</h3> We first confirmed an association between 9p21 and CAD using angiographically defined cases and controls (pooled OR=1.31 (95% CI 1.20 to 1.43)). Among subjects with angiographic CAD (n=20,987), random-effects model identified an association with multi-vessel CAD, compared to those with single-vessel disease (OR=1.10 (95% CI 1.04 to 1.17) per copy of risk allele). Genotypic models showed an OR of 1.15 (95% CI 1.04 to 1.26) for heterozygous carrier and 1.23 (95% CI 1.08 to 1.39) for homozygous carrier. Finally, there was no significant association between 9p21 and prevalent MI when both cases (n=17 791) and controls (n=15 882) had underlying CAD (OR=0.99 (95% CI 0.95 to 1.03) per risk allele). <h3>Conclusions</h3> The 9p21 locus shows convincing association with greater burden of CAD, but not with MI in the presence of underlying CAD. This adds further weight to the hypothesis that 9p21 locus primarily mediates an atherosclerotic phenotype.

Association between the chromosome 9p21 locus and angiographic coronary artery disease burden: a collaborative meta-analysis.

This study sought to ascertain the relationship of 9p21 locus with: 1) angiographic coronary artery disease (CAD) burden; and 2) myocardial infarction (MI) in individuals with underlying CAD. Chromosome 9p21 variants have been robustly associated with coronary heart disease, but questions remain on the mechanism of risk, specifically whether the locus contributes to coronary atheroma burden or plaque instability. We established a collaboration of 21 studies consisting of 33,673 subjects with information on both CAD (clinical or angiographic) and MI status along with 9p21 genotype. Tabular data are provided for each cohort on the presence and burden of angiographic CAD, MI cases with underlying CAD, and the diabetic status of all subjects. We first confirmed an association between 9p21 and CAD with angiographically defined cases and control subjects (pooled odds ratio [OR]: 1.31, 95% confidence interval [CI]: 1.20 to 1.43). Among subjects with angiographic CAD (n = 20,987), random-effects model identified an association with multivessel CAD, compared with those with single-vessel disease (OR: 1.10, 95% CI: 1.04 to 1.17)/copy of risk allele). Genotypic models showed an OR of 1.15, 95% CI: 1.04 to 1.26 for heterozygous carrier and OR: 1.23, 95% CI: 1.08 to 1.39 for homozygous carrier. Finally, there was no significant association between 9p21 and prevalent MI when both cases (n = 17,791) and control subjects (n = 15,882) had underlying CAD (OR: 0.99, 95% CI: 0.95 to 1.03)/risk allele. The 9p21 locus shows convincing association with greater burden of CAD but not with MI in the presence of underlying CAD. This adds further weight to the hypothesis that 9p21 locus primarily mediates an atherosclerotic phenotype.