Different Stages Of Coronary Artery Disease Research Articles

Risk stratification of coronary artery disease using the artificial intelligence-enabled electrocardiogram

Abstract Background Atherosclerotic cardiovascular disease (ASCVD), of which coronary artery disease (CAD) is the primary manifestation, is the leading cause of death worldwide. The AHA/ACC Pooled Cohort Equation (PCE) facilitates risk stratification and initiation of primary prevention of ASCVD, however their performance is suboptimal. Purpose We develop an artificial intelligence-based electrocardiogram (ECG) analysis (AI-ECG) algorithm to detect different stages of CAD and assessed the value of AI-ECG over PCE to predict incident myocardial infarction (MI) and survival over 3-years. Methods Using electronic health record data from approximately 7 million patients seen at over 70 hospitals and clinics across 5 states in the USA, we created independent AI-ECG models to identify elevated coronary artery calcium (CAC) by computer tomography, the presence of obstructive CAD by stress test or angiography, and left ventricular regional akinesis by echocardiogram, presumed to represent prior MI. Deep structured data, AI-enabled natural language processing of unstructured data were used to ensure cohort, and physician review of labeling were used to ensure cohort accuracy. These models were ensembled into a single model that was used to assess the utility of AI-ECG for predicting new occurrence MI in PCE- and age-stratified cohorts of patient with no prior history of ASCVD, over a 3-year timeframe using Cox’s proportional hazards analysis. Results A total of 6,080 patients (15,192 ECGs) were labeled positive for CAC ≥ 300, 12,561 patients (18,915 ECGs) positive for obstructive CAD, and 10,767 patients (23,870 ECGs) positive for regional akinesis. AI-ECG for identifying elevated CACS, obstructive CAD, and regional akinesis achieved AUROCs of 0.86, 0.80, and 0.93, respectively. All AI-ECG models identified increased 3-year risk for MI and death in AI-ECG positive versus AI-ECG negative patients and subgroups with 2 or 3 positive results had stepwise increased risk (Figure A). In a 3-year survival analysis of all-comer patients, the hazard ratio for those that tested positive on 1, 2, or 3 versus 0 positive disease-specific models were 1.61 (1.53-1.69). 2.40 (2.27-2.55), 3.42 (3.21-3.65), respectively. Risk stratification was also observed in cohorts without prior ASCVD stratified by low and high PCE-derived 10-year ASCVD risk (Figure B) and in cohorts stratified by age, including under the age of 40. Conclusions AI-ECG has potential to address unmet need for accessible risk stratification in patients in whom PCE under, over, or insufficiently estimate ASCVD risk, and in whom risk assessment over periods of time shorter than 10 years is desired.

Pericoronary adipose tissue computed tomography attenuation distinguishes different stages of coronary artery disease: a cross-sectional study.

Vascular inflammation inhibits local adipogenesis in pericoronary adipose tissue (PCAT) and this can be detected on coronary computed tomography angiography (CCTA) as an increase in CT attenuation of PCAT surrounding the proximal right coronary artery (RCA). In this cross-sectional study, we assessed the utility of PCAT CT attenuation as an imaging biomarker of coronary inflammation in distinguishing different stages of coronary artery disease (CAD). Sixty patients with acute myocardial infarction (MI) were prospectively recruited to undergo CCTA within 48 h of admission, prior to invasive angiography. These participants were matched to patients with stable CAD (n = 60) and controls with no CAD (n = 60) by age, gender, BMI, risk factors, medications, and CT tube voltage. PCAT attenuation around the proximal RCA was quantified per-patient using semi-automated software. Patients with MI had a higher PCAT attenuation (-82.3 ± 5.5 HU) compared with patients with stable CAD (-90.6 ± 5.7 HU, P < 0.001) and controls (-95.8 ± 6.2 HU, P < 0.001). PCAT attenuation was significantly increased in stable CAD patients over controls (P = 0.01). The association of PCAT attenuation with stage of CAD was independent of age, gender, cardiovascular risk factors, epicardial adipose tissue volume, and CCTA-derived quantitative plaque burden. No interaction was observed for clinical presentation (MI vs. stable CAD) and plaque burden on PCAT attenuation. PCAT CT attenuation as a quantitative measure of global coronary inflammation independently distinguishes patients with MI vs. stable CAD vs. no CAD. Future studies should assess whether this imaging biomarker can track patient responses to therapies in different stages of CAD.

Reduced Plasma Kallistatin Is Associated With the Severity of Coronary Artery Disease, and Kallistatin Treatment Attenuates Atherosclerotic Plaque Formation in Mice.

BackgroundKallistatin exerts beneficial effects on organ injury by inhibiting oxidative stress and inflammation. However, the role of kallistatin in atherosclerosis is largely unknown. Here, we investigated the role and mechanisms of kallistatin in patients with coronary artery disease (CAD), atherosclerotic plaques of apoE−/− mice, and endothelial activation.Methods and ResultsPlasma kallistatin levels were analyzed in 453 patients at different stages of CAD. Kallistatin levels were significantly lower in patients with CAD and negatively associated with CAD severity and oxidative stress. Human kallistatin cDNA in an adenoviral vector was injected intravenously into apoE−/− mice after partial carotid ligation, with or without nitric oxide synthase inhibitor (Nω‐nitro‐L‐arginine methyl ester) or sirtuin 1 inhibitor (nicotinamide). Kallistatin gene delivery significantly reduced macrophage deposition, oxidative stress, and plaque volume in the carotid artery, compared with control adenoviral injection. Kallistatin administration increased endothelial nitrous oxide synthase, sirtuin 1, interleukin‐10, superoxide dismutase 2, and catalase expression in carotid plaques. The beneficial effects of kallistatin in mice were mitigated by Nω‐nitro‐L‐arginine methyl ester or nicotinamide. Furthermore, human kallistatin protein suppressed tumor necrosis factor‐α–induced NADPH oxidase activity and increased endothelial nitrous oxide synthase and sirtuin 1 expression in cultured human endothelial cells. These effects were also abolished by Nω‐nitro‐L‐arginine methyl ester or nicotinamide.ConclusionsThis was the first study to demonstrate that reduced plasma kallistatin levels in patients are associated with CAD severity and oxidative stress. Kallistatin treatment prevents carotid atherosclerotic plaque formation in mice by stimulating the sirtuin 1/endothelial nitrous oxide synthase pathway. These findings indicate the potential protective effects of kallistatin on atherosclerosis in human subjects and mouse models.

Myeloperoxidase Is Not Useful for Detecting Stress Inducible Myocardial Ischemia but May Be Indicative of the Severity of Coronary Artery Disease

Background and ObjectivesElevated levels of myeloperoxidase (MPO) have been found in patients in different stages of coronary artery disease (CAD). The aim of this study was to assess whether the MPO liberation is increased by stress inducible myocardial ischemia and could be used to improve the diagnostic accuracy of non-invasive evaluation for myocardial ischemia.Subjects and MethodsSeventy-six patients with suspected myocardial ischemia who underwent stress myocardial perfusion scintigraphy (MPS) were enrolled. 59 patients with an acute coronary syndrome (ACS) who received a percutaneous coronary intervention along with 12 healthy volunteers were also included in the study. In every subject the MPO plasma levels were assessed by enzyme linked immunosorbent assay. In patients undergoing MPS, the MPO levels were measured serially before and after the stress testing.ResultsOf the 76 patients undergoing MPS, 38 were diagnosed with a stress inducible myocardial ischemia. The patients with a stress induced ischemia had significantly higher basal MPO levels than those without it (32±3 ng/mL vs. 24±4 ng/mL, p=0.03). However, there was no relevant change in the MPO levels after the stress test compared to the baseline. The patients with ACS showed significantly higher MPO levels than the patients undergoing MPS (131±14 ng/mL vs. 28±2 ng/mL, p<0.01) and the healthy subjects (131±14 ng/mL vs. 26±2 ng/mL, p<0.01).ConclusionSince the MPO plasma levels did not increase after the stress MPS, MPO appears not to be a useful biomarker for detecting a stress inducible myocardial ischemia. Yet, the MPO levels correlate with the different stages of CAD and may hold significance as an indicator for its clinical severity.

Plasma Biomarkers for Prediction of Sudden Cardiac Death

Sudden cardiac death (SCD) accounts for most cardiovascular deaths in the United States, claiming an estimated 300 000 lives per year.1 Despite intense efforts to develop resuscitation techniques, survival rates are still low, at ≈5%.2 This has led to a renewed focus in this field directed toward optimizing risk prediction to identify the candidate that would qualify for prophylactic or preventive interventions.3 At present, the clinical risk stratification is largely limited to the use of left ventricular ejection fraction (LVEF) for identifying primary prophylaxis candidates, but specificity of this predictor is modest.4 Moreover, the absolute numbers of these high-risk patients in the general population are low. Instead, the highest prevalence of SCD is likely observed among previously asymptomatic individuals, even though it is well-known that coronary artery disease (CAD) is present in most SCD cases.5 This underscores the need for the development of risk stratification models that can be applied to the general population where the largest health benefit is likely to be realized. The underpinnings of SCD are complex, and it is reasonable to believe that the risk stratification instrument of the future is likely to involve other components beyond clinical risk markers. Novel genomic variants show promise but are still in early phases of development as risk stratification targets. However, the “unbiased” approaches made possible through genomewide association studies have led to the recent identification of specific genetic variants that could predict SCD.6,7 This has reignited the interest in plasma biomarkers as a means for risk stratification. This article will review the emerging evidence and role of plasma biomarkers in predicting SCD in the general population and suggest a blueprint for future studies of potential utility. ### Uniform Definition of SCD Given the complexity and dynamic nature of the condition, there has been some variability …

Impact of Functional, Morphological and Clinical Parameters on Epicardial Adipose Tissue in Patients With Coronary Artery Disease

Because a close relationship between epicardial adipose tissue (EAT) and coronary artery disease (CAD) has been shown, the impact of functional, morphological and clinical parameters to identify potential determinants of EAT was investigated. Clinical and cardiac magnetic resonance parameters were determined and correlated to the amount of EAT in 158 patients with CAD and 40 healthy subjects. Patients with CAD and left ventricular function (LVEF) ≥50% revealed significantly elevated EAT (36±11g/m²) compared to healthy controls (31±8g/m²) and to patients with LVEF <50% (26±8.0g/m²). In the whole study population, only LVEF (P=0.003), body mass index (BMI) (P=0.004) and left ventricular end diastolic diameter (LV-EDD) (P=0.004) remained significantly associated with EAT after multivariate analysis. Subgroup analysis in patients with CAD and LVEF ≥50% showed that BMI (P=0.03) was the only correlate of EAT. However, in patients with CAD and LVEF <50%, indexed LV end diastolic mass (LV-EDMI) (P=0.003) and the extent of late gadolinium enhancement (LGE %) (P=0.03) remained significantly correlated with EAT in multivariate analysis. The amount and the determinants of EAT differ according to the LVEF in patients with CAD. Thus, different amounts of EAT reflect different stages of CAD underlining the complex interaction of EAT in the pathogenesis and progression of ischemic cardiomyopathy.

Expression of Ubiquitin in Peripheral Inflammatory Cells from Patients with Coronary Artery Disease

In addition to its role in the removal of damaged and unneeded proteins, the ubiquitin-proteasome system (UPS) may play a key role in coronary artery disease (CAD). To investigate the expression of ubiquitin in monocytes and lymphocytes isolated from patients at different stages of CAD, 120 patients with CAD (40 with acute myocardial infarction [AMI], 40 with unstable angina pectoris [UAP] and 40 with stable angina pectoris [SAP]) were selected; 40 patients with normal coronary arteries served as controls. At both the mRNA and protein levels, ubiquitin expression was higher in patients with CAD than in controls, and patients with AMI had a much higher expression of ubiquitin (at both the mRNA and protein levels) than those with SAP and UAP. These data indicate that ubiquitin expression increased with increasing severity of CAD, suggesting that ubiquitin may play a critical role in the development and progression of CAD.

Plasma resistin is increased in patients with unstable angina

Resistin, a novel adipokine linked to insulin resistance and obesity in rodents, which is derived mainly from macrophages and identified in atheromas in human, has been shown to play a potential role in atherosclerosis. Resistin levels were reported to increase in coronary artery disease (CAD), while data concerning resistin in different stages of CAD in Chinese people are lacking. The aim of this study was to assess whether plasma concentrations of resistin differed between patients with unstable and stable angina pectoris. Plasma resistin levels were determined by means of enzyme-linked immunosorbent assay (ELISA) in 46 patients with unstable angina (UAP), 37 with stable angina (SAP) and 31 control subjects. Plasma concentrations of resistin were significantly increased in UAP group (geometric mean (interquartile range) 12.09 ng/ml (8.40, 18.08)) in comparison with SAP (9.04 ng/ml (7.09, 11.44)) and control groups (8.71 ng/ml (6.58, 11.56)). No differences in resistin levels were found between patients with SAP and controls. We also found that plasma resistin positively correlated with leukocyte counts (r = 0.21, P = 0.027), high sensitive C-reactive protein (hs-CRP) (r = 0.25, P = 0.008), and endothelin-1 (r = 0.21, P = 0.025) after adjustment for age, sex and BMI. Resistin may be involved in the development of CAD by influencing systemic inflammation and endothelial activation.

Adiponectin serum concentrations in men with coronary artery disease: The LUdwigshafen RIsk and Cardiovascular Health (LURIC) study

Background Adiponectin, the most abundant adipocytokine of adipose tissue cells, has recently been found to be decreased in coronary artery disease (CAD). Data concerning adiponectin in different stages of CAD are rare, and it was not investigated if adiponectin levels are influenced by the severity of angina pectoris. Methods Thus, we measured adiponectin serum levels by means of ELISA in 1626 male probands, including 273 control subjects, 367 subjects with silent CAD, 608 patients with stable, and 378 patients with unstable angina. Results As compared to controls (8.56; 5.85 to 12.85 μg/ml) and subjects with silent CAD (8.60; 5.99 to 12.64 μg/ml), adiponectin was significantly decreased in patients with stable (7.22; 5.06 to 10.41 μg/ml; p < 0.001 for both) and unstable angina (6.72; 4.08 to 10.08 μg/ml; p < 0.001 for both). By a logistic regression analysis, low adiponectin levels were identified as a significant independent predictor for stable and unstable angina ( p < 0.001 for both). No significant differences of adiponectin were observed, neither between the stable and unstable angina group, nor between any classes of angina according to the Canadian Cardiovascular Society (CCS) Angina Score for stable angina. Conclusions These results suggest, that decreased adiponectin levels are indicative for symptomatic CAD, but are not further influenced by the progression of this disease.

A functional variant of the iNOS gene flanking region is associated with LAD coronary artery disease: an autopsy study.

Recent studies using reporter gene constructs have indicated significant differences in the promoter activity of inducible nitric oxide synthase (iNOS) gene variants. Although the exact role of iNOS in atherogenesis is unclear, it is possible that this variation site may influence the extent of coronary artery disease (CAD). We amplified these (AAAT) repeat variants from the NOS2A gene (denoted iNOS R4 and iNOS R5) from 325 Finnish men included in the Helsinki Sudden Death Study, and studied their association with indices of stenosis and atherosclerosis of the left anterior descending artery (LAD), right coronary artery (RCA) and left circumflex artery (LCX). In order to understand the effect of iNOS genotype on different stages of CAD, our study population was divided into age groups. In the LAD, the progression of atherosclerosis seemed to be more pronounced in the 4/5 genotype carriers than in those with the 4/4 genotype when the different age groups were compared. More specifically, statistically significant differences between the genotypes were found in the subgroup of men aged > 55 years. In this group, men carrying the rare R4/5 genotype presented higher mean values of stenosis percentages (55% vs. 42%, P = 0.008), larger areas of fatty streaks (10.4% vs. 5.9%; P = 0.01) and complicated lesions (3.5% vs. 1.3%; P = 0.001) compared with the R4/4 carriers. No significant association of iNOS genotypes with stenosis and atherosclerosis of RCA and LCX was found. It appears unlikely the R4/5 genotype plays a major role in the pathogenesis of CAD, as it was not associated with stenosis and atherosclerosis in RCA and LCX. However this genotype may have some role in more pronounced CAD, as seen in the LAD.

Multidetector-row computed tomography of the coronary arteries: predictive value and quantitative assessment of non-calcified vessel-wall changes.

The aim of this study was to quantitatively assess non-calcified coronary artery plaques and to determine their predictive value for the detection of coronary artery disease (CAD). A total of 179 patients underwent a calcium screening examination and a contrast-enhanced multidetector-row computed tomography angiography (MDCT) of the coronary arteries for various indications. The traditional calcium scores were evaluated and all examinations were reviewed for the presence of non-calcified plaques with an attenuation of 0-130 Hounsfield units (HU). The number, mean attenuation, and volume of these non-calcified plaques were recorded. All patients also underwent conventional catheter angiography. Coronary calcium was detected in 73% (131 of 179) of the patients. Overall incidence of purely non-calcified plaques was 30% (53 of 179). In 27% of the patients (48 of 179) no calcium was detected; however, 15% of these patients without calcifications showed non-calcified plaques (7 of 48). Significant correlations were found between the volume of calcified plaques, volume of non-calcified plaques, and total plaque volume. There were significant differences in plaque composition comparing different risk factor profiles and different stages of CAD. Volumetric assessment of non-calcified coronary artery plaques is feasible using contrast-enhanced MDCT. Screening for non-calcified plaques identifies patients with signs of CAD that are missed in a calcium screening examination.