Non-obstructive Coronary Artery Disease Patients Research Articles

Men with nonobstructive coronary disease have higher burden of ischemic heart disease detected by cardiopulmonary exercise test.

Nonobstructive coronary artery disease (NOCAD), characterized by the presence of myocardial ischemic symptoms and signs without obstructive coronaries, is a common clinical condition, but it is less well understood. Few studies have analyzed the gender differences in inducible myocardial ischemia assessed by cardiopulmonary exercise test (CPET) in NOCAD. We conducted a study of 289 NOCAD patients (mean age 60, 56% women) with ischemic symptoms and confirmed ⫹50% coronaries stenoses by coronary angiography who underwent symptom-limited CPET. We assessed ischemic response using predicted % peak VO2 , O2 pulse trajectory, and exercise ECG test. Men with NOCAD had significantly lower predicted % peak VO2 (62% vs. 73%), higher proportions of flattening pattern (16% vs. 2%), and downward patterns of O2 pulse trajectory (2% vs. 0%) (p < .0001) compared with women. In contrast, women with NOCAD had a higher prevalence of shallow patterns of O2 pulse trajectory (21% vs. 6%, p < .0001). Men with NOCAD had a higher risk ischemic profile (medium risk: 63% vs. 54%, high risk: 18% vs. 4%, p < .0001). After adjustment, men with NOCAD had significantly lower predicted % peak VO2 (β -27.4, 95% CI -30.74 to -24.07), higher risk for abnormal O2 pulse trajectories (OR 4.21, 95% CI 1.93 to 9.19), and myocardial ischemia risk per CPET parameters (OR 3.14, 95% CI 1.78 to 5.54) (p < .0001). Men with NOCAD had a higher risk profile for ischemic heart disease per CPET. Therefore, they should receive rigorous management and follow-up to prevent cardiovascular events.

The association between coronary artery calcium score and myocardial blood flow in non-obstructive coronary artery disease patients

The association between coronary artery calcium score and myocardial blood flow in non-obstructive coronary artery disease patients

Impaired retinal microcirculation in patients with non-obstructive coronary artery disease.

To quantitatively investigate alterations of retinal microcirculation in patients with non-obstructive coronary artery disease (NOCAD) using optical coherence tomography angiography (OCTA), and to identify the ability of retinal microcirculation parameters in differentiating coronary artery disease (CAD) subtypes. All participants with angina pectoris underwent coronary computed tomography angiography. Patients with lumen diameter reduction of 20-50% in all major coronary arteries were defined as NOCAD, while patients with at least one major coronary artery lumen diameter reduction ≥ 50% were recruited as obstructive coronary artery disease (OCAD). Participants without a history of ophthalmic or systemic vascular disease were recruited as healthy controls. Retinal neural-vasculature was measured quantitatively by OCTA, including peripapillary retinal nerve fiber layer (RNFL) thickness and vessel density (VD) of the optic disc, superficial vessel plexus (SVP), deep vessel plexus (DVP), and foveal density (FD 300). p<0.017 is considered significant in multiple comparisons. A total of 185 participants (65 NOCAD, 62 OCAD, and 58 controls) were enrolled. Except for the DVP fovea (p=0.069), significantly reduced VD in all other regions of SVP and DVP was detected in both the NOCAD and OCAD groups compared to control group (all p<0.017), while a more significant decrease was found in OCAD compared to NOCAD. Multivariate regression analysis showed that lower VD in superior hemi part of whole SVP (OR: 0.582, 95% CI: 0.451-0.752) was an independent risk factor for NOCAD compared to controls, while lower VD in the whole SVP (OR: 0.550, 95% CI: 0.421-0.719) was an independent risk factor for OCAD compared to NOCAD. Using the integration of retinal microvascular parameters, the area under the receiver operating characteristic curve (AUC) for NOCAD versus control and OCAD versus NOCAD were 0.840 and 0.830, respectively. Significant retinal microcirculation impairment, while milder than that in OCAD was observed in NOCAD patients, indicating retinal microvasculature assessment might provide a new systemic microcirculation observation window for NOCAD. Furthermore, retinal microvasculature may serve as a new indicator to assess the severity of CAD with good performance of retinal microvascular parameters in identifying different CAD subtypes.

Prognostic value of coronary CTA-based classifications for predicting major events without obstructive coronary artery disease

We aim to explore the classifications based on coronary computed tomography angiography (CTA) for predicting the risk of major adverse cardiovascular events (MACE) in patients with suspected non-obstructive coronary artery disease (CAD) and compare with traditional non-obstructive CAD (NOCAD) classification, Duke prognostic NOCAD index, Non-obstructive coronary artery disease reporting and data system (NOCAD-RADS). 4378 consecutive non-obstructive CAD patients were assessed by coronary CTA for traditional NOCAD classification, Duke prognostic NOCAD index, NOCAD-RADS and a new classification (stenosis proximal involvement, SPI) from two medical centrals. We defined proximal involvement as any plaque was present in the main or proximal segments of coronary artery (left main, left anterior descending artery, left circumflex artery, or right coronary artery). The main outcome was MACE. During a median follow-up of 3.7 years, a total of 310 patients experienced MACE event. Kaplan–Meier survival curves showed the cumulative events increased significantly associated with traditional NOCAD, Duke NOCAD index, NOCAD-RADS and SPI classifications (all P < 0.001). In multivariate Cox regressions, the risk for the events increased from HR 1.20 (95% CI 0.78–1.83, P = 0.408) for SPI 1 to 1.35 (95% CI 1.05–1.73, P = 0.019) for SPI 2, using SPI 0 as the reference group. Coronary CTA based SPI classification provided important prognostic information for all cause-mortality risk and MACE prediction in patients with non-obstructive CAD, which was non-inferior than traditional NOCAD, Duke NOCAD Index and NOCAD-RADS classifications. The plaque location information by coronary CTA may provide additional risk prediction in patients with non-obstructive CAD.

Impaired peripheral microvascular reactivity in patients with nonobstructive coronary artery disease

This study aimed to determine whether peripheral microvascular reactivity is impaired in patients with nonobstructive coronary artery disease (NOCAD). Stable patients presenting with angina were recruited and, based on results from coronary angiography, were categorized into OCAD (coronary stenosis of ≥50%) and NOCAD (stenosis <50%) groups. A control group with no history of angina was also recruited. Forearm skin microvascular reactivity was measured using the laser Doppler blood perfusion monitor and the process of postocclusive skin reactive hyperemia (PORH). Patients were categorized into OCAD (n = 42), NOCAD (n = 40), and control (n = 39) groups. Compared with the control group, the PORH perfusion percent change (PORH% change) was significantly lower in the OCAD and NOCAD groups. No significant differences were noted between the OCAD and NOCAD groups. Additionally, the NOCAD group without any coronary obstruction takes a longer time to reach peak perfusion and had lower PORH% change compared with the nonangina control group. Angina patients with NOCAD have microvascular dysfunction as demonstrated by reduced magnitude of reperfusion with an ischemic stimulus. NOCAD patients without coronary obstruction also displayed a slower response to reperfusion.

158 AIR POLLUTION AND CORONARY VASOMOTOR DISORDERS IN PATIENTS WITH MYOCARDIAL ISCHEMIA AND NON-OBSTRUCTIVE CORONARY ARTERY DISEASE

Abstract Background Coronary vasomotor abnormalities are important causes of myocardial ischemia in patients with non-obstructive coronary artery disease (NOCAD). However, the role of air pollution in determining coronary vasomotor disorders has never been investigated. Objectives We aimed to evaluate the association between long-term exposure to particulate matter 2.5 (PM2.5) and 10 (PM10), and coronary vasomotor disorders in NOCAD patients. Methods Patients with myocardial ischemia and NOCAD undergoing coronary angiography and intracoronary provocation test with acetylcholine (ACh) were prospectively studied. Both patients with chronic myocardial ischemia (INOCA) and myocardial infarction with non-obstructive coronary arteries (MINOCA) were enrolled. Based on each case's home address, exposure to PM2.5 and PM10 was assessed. Results We included 287 patients (median age 62.0 years [52.0-70.0], 149 [51.9%] males): 161 (56.1%) INOCA and 126 (43.9%) MINOCA. One hundred seventy-six patients (61.3%) had positive provocation test. Exposure to PM2.5 and PM10 was higher in patients with a positive provocation test (p&amp;lt;0.001). At multivariate logistic regression analysis, PM2.5 and PM10 were independent predictors of a positive provocation test (p=0.001 and p=0.029, respectively). Interestingly, among these patients, PM2.5 and PM10 were both independent predictors of MINOCA (p&amp;lt;0.001 and p=0.001, respectively) as clinical presentation, while PM2.5 was independently associated with the occurrence of epicardial spasm as opposed to microvascular spasm (p=0.001). Conclusions Higher exposure to PM2.5 and PM10 in patients with myocardial ischemia and NOCAD is associated with coronary vasomotor abnormalities. In particular, PM2.5 is an independent risk factor for the occurrence of epicardial spasm and MINOCA as clinical presentation.

Air pollution and coronary vasomotor disorders in patients with myocardial ischemia and non-obstructive coronary arteries

Abstract Background Coronary vasomotor abnormalities are an important cause of myocardial ischemia in patients with non-obstructive coronary artery disease (NOCAD). However, the role of air pollution in determining vasomotor disorders has never been investigated. Purpose In this study, we evaluated the association between long-term exposure to particulate matter (PM) PM2.5 and PM10 and coronary vasomotor disorders in NOCAD patients. Methods Patients with myocardial ischemia and NOCAD undergoing intracoronary provocative test with acetylcholine (ACh) were prospectively enrolled. The test was considered positive for epicardial coronary spasm in the presence of focal or diffuse epicardial coronary diameter reduction ≥90% in comparison with the relaxed state following intracoronary nitroglycerin administration given to relieve the spasm, associated with the reproduction of the patient's symptoms and ischaemic ECG shifts. Both patients with chronic myocardial ischemia (INOCA) and myocardial infarction with non-obstructive coronary arteries (MINOCA) were enrolled. Based on each case's home address, exposure to PM2.5 and PM10 was assessed. Only patients with &amp;gt;2 years of available data on air pollution exposure prior to coronary angiography were included. Results We enrolled 287 patients (median age 62.0 years [52.0–70.0], 149 [51.9%] males): 161 (56.1%) INOCA and 126 (43.9%) MINOCA. One hundred seventy-six patients (61.3%) had positive provocative test. Exposure to PM2.5 (Figure 1) and PM10 was higher in patients with a positive provocative test (p&amp;lt;0.001). PM2.5 and PM10 were independent predictors of a positive coronary provocative test after adjustment for confounders. Interestingly, among patients with a positive provocative test, PM2.5 and PM10 were both independent predictors of MINOCA (p&amp;lt;0.001 and p=0.001, respectively; Figure 2) as clinical presentation, while only PM2.5 was independently associated with the occurrence of epicardial spasm as opposed to microvascular spasm (p&amp;lt;0.001). Conclusions We provide novel insights into the missing link between air pollution and ischemic heart disease. In particular, higher exposure to air pollution in patients with myocardial ischemia and NOCAD is associated with coronary vasomotor abnormalities, and PM2.5 is an independent risk factor for the occurrence of epicardial spasm and for MINOCA as clinical presentation. Funding Acknowledgement Type of funding sources: None.

Air Pollution and Coronary Vasomotor Disorders in Patients With Myocardial Ischemia and Unobstructed Coronary Arteries

BackgroundCoronary vasomotor abnormalities are important causes of myocardial ischemia in patients with nonobstructive coronary artery disease (NOCAD). However, the role of air pollution in determining coronary vasomotor disorders has never been investigated. ObjectivesWe aimed to evaluate the association between long-term exposure to particulate matter 2.5 (PM2.5) and 10 (PM10), and coronary vasomotor disorders in NOCAD patients. MethodsPatients with myocardial ischemia and NOCAD undergoing coronary angiography and intracoronary provocation test with acetylcholine were prospectively studied. Both patients with chronic myocardial ischemia and nonobstructive coronary arteries and myocardial infarction with nonobstructive coronary arteries (MINOCA) were enrolled. Based on each case’s home address, exposure to PM2.5 and PM10 was assessed. ResultsWe included 287 patients (median age, 62.0 years [IQR: 52.0-70.0 years], 149 [51.9%] males); there were 161 (56.1%) myocardial ischemia and nonobstructive coronary arteries and 126 (43.9%) MINOCA cases. One hundred seventy-six patients (61.3%) had positive provocation test. Exposure to PM2.5 and PM10 was higher in patients with a positive provocation test (P < 0.001). At multivariate logistic regression analysis, PM2.5 and PM10 were independent predictors of a positive provocation test (P = 0.001 and P = 0.029, respectively). Interestingly, among these patients, PM2.5 and PM10 were both independent predictors of MINOCA (P < 0.001 and P = 0.001, respectively) as clinical presentation, whereas PM2.5 was independently associated with the occurrence of epicardial spasm as opposed to microvascular spasm (P = 0.001). ConclusionsHigher exposure to PM2.5 and PM10 in patients with myocardial ischemia and NOCAD is associated with coronary vasomotor abnormalities. In particular, PM2.5 is an independent risk factor for the occurrence of epicardial spasm and MINOCA as clinical presentation.

ARTERIAL STIFNESS AND SYMPATHETIC OVERDRIVE IN HYPERTENSIVE PATIENTS WITH ANGINA AND NON-OBSTRUCTIVE CORONARY ARTERY DISEASE

Objective: Existing data support that hypertension is related to sympathetic overdrive and arterial stiffness. Non-obstructive coronary artery disease (CAD) is frequent among hypertensive patients with angina. Nowadays, there are scarce evidence on the role of sympathetic nervous system (SNS) in the above population. The aim of this preliminary analysis of our study was to assess whether hypertensive patients with angina and non-obstructive CAD, hypertensives without angina and normotensive controls are characterized by different level of SNS activation and arterial stifness. Design and method: We studied 13 hypertensive patients with angina and non-obstructive CAD in coronary angiography [9 females, mean age: 61.2 ± 9.9 years, office blood pressure (BP): 159/96 ± 14/10 mmHg], 16 treated hypertensive patients without angina (9 females, mean age: 59.5 ± 7.5 years, office BP:142/88 mmHg) and 11 normotensive controls (8 females, mean age: 51.8 ± 11 years, BP:125/87 mmHg). In all participants, sympathetic drive was assessed by muscle sympathetic nerve activity (MSNA) estimated by microneurography and arterial stiffness, measured with heart rate-corrected aortic augmentation index (Aix@75), calculated by analyzing the ambulatory blood pressure monitoring (ABPM) waveforms. Results: Hypertensives with angina and non-obstructive CAD (n = 13) compared to hypertensive patients without angina (n = 16) and normotensive individuals (n = 11) exhibited higher levels of MSNA (59.6 ± 6.6 vs 43 ± 8.4 vs 45 ± 9.5 bursts per minute, respectively; p &lt; 0.01 for all) and 24-h BP (146/85 ± 18/11 vs 141/83 ± 7/10 vs 125/81 ± 7/6 mmHg, respectively; p &lt; 0.001 for all). Hypertensives with and without angina did not differ regarding renal function based on eGFR (p = NS). Moreover, there were no differences in left ventricular mass index, total cholesterol and low-density lipoprotein between hypertensive patients with and without angina and no gender related effects on MSNA and Aix@75 (p = NS). Furthermore, patients with angina and non-obstructive CAD patients compared to hypertensives without angina were characterized by increased levels of Aix@75 (36.13 ± 7.4 vs 22.5 ± 11.7, p &lt; 0.05). Conclusions: Patients with hypertension and non-obstructive CAD are characterized by higher MSNA and increased Aix levels compared to hypertensives without angina and normotensive controls. These preliminary results suggest that therapies targeting sympathetic overdrive and vascular stiffening could provide additional clinical benefit in this special category of hypertensive patients.

The relation of RAAS activity and endothelin-1 levels to coronary atherosclerotic burden and microvascular dysfunction in chest pain patients

Background and aimsIn this study, we investigated whether increased renin angiotensin aldosterone system (RAAS) activation and endothelin-1 levels are related to coronary artery calcium (CAC) score, total plaque volume (TPV), high risk plaque, hyperemic myocardial blood flow (MBF) and coronary microvascular dysfunction (CMD). MethodsIn a prospective, observational, cross-sectional cohort, renin as a marker for RAAS activation and endothelin-1 were measured in peripheral venous blood of 205 patients (64% men; age 58 ± 8.7 years) with suspected coronary artery disease (CAD) who underwent coronary computed tomography angiography (CCTA), [15O]H2O positron emission tomography (PET) perfusion imaging and invasive fractional flow reserve (FFR) measurements. Patients were categorized into three groups based on FFR (≤0.80) and hyperemic MBF <2.3 ml/min/g: [1] obstructive CAD (n = 92), [2] CMD (n = 26) or [3] no or non-obstructive CAD (n = 85). ResultsAfter correction for baseline characteristics, including RAAS inhibiting therapy, renin associated positively with CAC score and TPV, but not with hyperemic MBF (p < 0.01; p = 0.02 and p = 0.23). Patients with high risk plaque displayed higher levels of renin (mean logarithmic renin 1.25 ± 0.43 vs. 1.12 ± 0.35 pg/ml; p = 0.04), but not endothelin-1. Compared to no or non-obstructive CAD patients, renin was significantly elevated in obstructive CAD patients but not in CMD patients (mean logarithmic renin 1.06 ± 0.34 vs. 1.23 ± 0.36; p < 0.01 and 1.06 ± 0.34 vs. 1.16 ± 0.41 pg/ml; p = 0.65). Endothelin-1 did not differ between the three patient groups. ConclusionsOur report provides evidence that RAAS activity measured by renin concentration is elevated in patients with coronary atherosclerosis and high risk plaque but not in patients with CMD, whereas endothelin-1 is not related to either.

Abstract 11723: Depression and Obesity Are Associated with Chest Pain in Patients with Non-Obstructive Coronary Artery Disease

Introduction: Chest pain in patients with non-obstructive coronary artery disease (NO-CAD) is a major clinical problem impacting the quality of life and can present a therapeutic challenge for providers. The objective of this study was to identify clinical factors associated with chest pain frequency in NO-CAD patients. Mainly, we investigated the hypothesis that increased body mass index (BMI) and depression are associated with increased chest pain frequency in NO-CAD patients. Methods: We identified a sample of 439 patients with NO-CAD (mean age 55.3 years, 50% women, 72% white) in the Emory Cardiovascular Biobank, a database of patients who underwent coronary angiography for suspected myocardial ischemia. Sociodemographic variables, clinical risk factors like BMI, and Patient Health Questionnaire 9 (PHQ9) results - a depression screening tool - were collected. We measured chest pain frequency through a questionnaire that asked patients how many times they had chest pain, chest tightness, or angina over the preceding four weeks. Within the sample, 180 patients (41%) reported no chest pain, chest tightness, or angina, and 259 patients (69%) reported one or more instances of chest pain, chest tightness, or angina in the preceding four weeks. We compared these two groups using t-test, Mann-Whitney U test, and multivariate logistic regression analyses. Results: The sample mean BMI was 30.6 ± 6.6 kg/m 2 . The median PHQ9 score was 3.0, with scores ranging from 0 to 27 and 34% having minimal to major depressive symptoms. Compared to those with no chest pain, patients with chest pain had higher BMI (31.5 ± 7.1 vs 29.4 ± 5.6 kg/m 2 , p=0.001) and higher PHQ9 scores (median [interquartile range]: 4 [1,8] vs 1 [0,3], p&lt;0.001). Furthermore, higher BMI and PHQ9 scores were associated with higher odds of chest pain (odds ratio [95% confidence interval]: 1.041 [1.004-1.079] and 1.104 [1.044-1.168], respectively). Conclusions: In patients with NO-CAD, higher BMI and PHQ9 scores were associated with higher chest pain frequency. Thus, weight and depression optimization could reduce symptoms and improve quality of life in NO-CAD patients; however, this needs further study.

Abstract 12511: Differential Regulation of Circulating Damage-Associated Molecular Patterns in Patients With Coronary Artery Ectasia

Introduction: Coronary artery ectasia (CAE) defined as localized or diffuse non-obstructive coronary lesions is a rare but well-recognized pathological entity of the coronary arteries and characterized as a variant of coronary atherosclerosis. CAE commonly coexists with coronary artery disease (CAD). Although inflammation appears to be involved, the pathophysiology behind CAE remains unclear. Danger-associated molecular patterns (DAMPs) are altered metabolism products of necrotic or stressed cells, which are deemed as alarm signals by the innate immune system. Inflammatory agents are DAMP generators and DAMPs create a pro-inflammatory state. Hypothesis: We aimed to investigate the different patterns of serum DAMPs in patients with CAE, obstructive CAD and normal coronary arteries and the prognostic role of these in the pathogenesis of CAE. Methods: In this prospective cross-sectional study, 28 patients with CAE and nonobstructive CAD were enrolled in the study, 19 patients with obstructive CAD but without CAE, and 18 control subjects with normal coronary arteries that have been matched with the CAE patients for age and sex were also enrolled in our study population. Venous blood samples of the participants were collected for serum DAMP evaluation. Results: Patients with CAE and non-obstructive CAD had increased (30-35%) serum levels of the DAMPs, the receptor for advanced glycation end products (RAGE) ligand S100B and the toll-like receptor 4 ligand heat shock protein (HSP)70 compared to control subjects and patients with CAD. Additionally, CAE and non-obstructive CAD patients had decreased (30-40%) serum levels of potential DAMPs, the antioxidant DJ-1 and soluble (s)RAGE, a decoy molecule that bind excess RAGE ligands, compared to control subjects and CAD patients. Positive correlations were observed between S100B and HSP70 (p=00564), and DJ-1 and sRAGE (p=0.00461). All evaluated serum DAMPs were not different in CAD patients compared to control subjects. Conclusion: The differential regulation of the DAMPs S100B, HSP70, DJ-1 and sRAGE in CAE versus CAD makes them attractive novel biomarkers as therapeutic targets and therapeutics.

Abstract 9563: Preventive Therapy Changes Following Coronary Computed Tomography Angiography versus Invasive Coronary Angiography in Patients With Nonobstructive Coronary Artery Disease

Introduction: Coronary computed tomography angiography (CCTA) in SCOT-HEART led to increased preventive therapy for coronary artery disease (CAD). We hypothesized that atherosclerosis on CCTA would lead to greater preventive therapy changes compared to invasive coronary angiography (ICA). Methods: We studied 429 consecutive patients with available electronic health records and nonobstructive CAD (1-69% epicardial stenosis) by CCTA for assessment of chest pain or exertional dyspnea (n=143), ICA (n=142), or no CAD on CCTA (n=144). Changes in preventive therapies were assessed at 6 weeks and 6 months. Statin intensification was defined as change to greater LDL-lowering capacity. Intensification of antiplatelet agents, ACEI/ARB, or beta-blockers was defined as increased dose. Pairwise comparisons were made with Bonferroni adjustment. Results: There was no difference in age or gender in nonobstructive CAD patients ( Table ). ICA patients had more baseline therapies. Six week statin initiation was more common (p=0.006) in CCTA nonobstructive group, but not statin intensification (p=0.24) ( Table ). Six month LDL lowering was observed in CCTA (114±40 to 94±39 mg/dL, p&lt;0.001), but not ICA (95±41 to 87±36 mg/dL, p=0.10) nonobstructive patients. Younger age (OR 0.96; 95% CI 0.93-0.99, p=0.006), but not modality (CCTA compared to ICA OR 1.12; 95% CI 0.60-2.07, p=0.73) was associated with statin initiation or intensification at 6 weeks in nonobstructive patients. Greater change in therapies was found in nonobstructive patients by both modalities vs normal coronaries ( Table ). Conclusions: Nonobstructive CAD on CCTA is associated with greater statin initiation, but not intensification, at 6 weeks and lowering of LDL compared to ICA. Antiplatelet, beta-blocker, or ACEI/ARB prescriptions were not different in nonobstructive CAD by CCTA vs ICA. More preventive therapy changes occurred in nonobstructive CAD by either modality vs normal coronaries.

Prognostic significance of plaque location in non-obstructive coronary artery disease: from the CONFIRM registry

Obstructive coronary artery disease (CAD) in proximal coronary segments is associated with a poor prognosis. However, the relative importance of plaque location regarding the risk for major adverse cardiovascular events (MACE) in patients with non-obstructive CAD has not been well defined. From the Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter (CONFIRM) registry, 4644 patients without obstructive CAD were included in this study. The degree of stenosis was classified as 0 (no) and 1-49% (non-obstructive). Proximal involvement was defined as any plaque present in the left main or the proximal segment of the left anterior descending artery, left circumflex artery, and right coronary artery. Extensive CAD was defined as segment involvement score of >4. During a median follow-up of 5.2 years (interquartile range 4.1-6.0), 340 (7.3%) MACE occurred. Within the non-obstructive CAD group (n = 2065), proximal involvement was observed in 1767 (85.6%) cases. When compared to non-obstructive CAD patients without proximal involvement, those with proximal involvement had an increased MACE risk (log-rank P = 0.033). Multivariate Cox analysis showed when compared to patients with no CAD, proximal non-obstructive CAD was associated with increased MACE risk [hazard ratio (HR) 1.90, 95% confidence interval (CI) 1.47-2.45, P < 0.001] after adjusting for extensive CAD and conventional cardiovascular risk factors; however, non-proximal non-obstructive CAD did not increase MACE risk (HR 1.26, 95% CI 0.79-2.01, P = 0.339). Independent of plaque extent, proximal coronary involvement was associated with increased MACE risk in patients with non-obstructive CAD. The plaque location information by coronary computed tomography angiography may provide additional risk prediction over CAD extent in patients with non-obstructive CAD.

Machine learning aids clinical decision-making in patients presenting with angina and non-obstructive coronary artery disease.

The current gold standard comprehensive assessment of coronary microvascular dysfunction (CMD) is through a limited-access invasive catheterization lab procedure. We aimed to develop a point-of-care tool to assist clinical guidance in patients presenting with chest pain and/or an abnormal cardiac functional stress test and with non-obstructive coronary artery disease (NOCAD). This study included 1893 NOCAD patients (<50% angiographic stenosis) who underwent CMD evaluation as well as an electrocardiogram (ECG) up to 1-year prior. Endothelial-independent CMD was defined by coronary flow reserve (CFR) ≤2.5 in response to intracoronary adenosine. Endothelial-dependent CMD was defined by a maximal percent increase in coronary blood flow (%ΔCBF) ≤50% in response to intracoronary acetylcholine infusion. We trained algorithms to distinguish between the following outcomes: CFR ≤2.5, %ΔCBF ≤50, and the combination of both. Two classes of algorithms were trained, one depending on ECG waveforms as input, and another using tabular clinical data. Mean age was 51 ± 12 years and 66% were females (n = 1257). Area under the curve values ranged from 0.49 to 0.67 for all the outcomes. The best performance in our analysis was for the outcome CFR ≤2.5 with clinical variables. Area under the curve and accuracy were 0.67% and 60%. When decreasing the threshold of positivity, sensitivity and negative predictive value increased to 92% and 90%, respectively, while specificity and positive predictive value decreased to 25% and 29%, respectively. An artificial intelligence-enabled algorithm may be able to assist clinical guidance by ruling out CMD in patients presenting with chest pain and/or an abnormal functional stress test. This algorithm needs to be prospectively validated in different cohorts.

Machine learning aids clinical decision making in patients presenting with angina and non-obstructive coronary artery disease

Abstract Background Coronary microvascular dysfunction (CMD) is associated with an increased risk of cardiovascular morbidity and mortality. The current gold-standard comprehensive assessment of CMD is through a limited-access invasive catheterization lab procedure. Purposes We aimed to develop a point-of-care tool to assist clinical guidance in patients presenting with chest pain and/or an abnormal functional stress test and with non-obstructive coronary artery disease (NOCAD) based on demographic data and resting ECG waveforms. Methods This study included 1,893 NOCAD patients (&amp;lt;50% angiographic stenosis) who underwent CMD evaluation as well as a standard ECG up to 1 year prior. Microvascular endothelial-independent dysfunction was defined by abnormal coronary flow reserve (CFR) &amp;lt;2.5 in response to intracoronary adenosine administration. Microvascular endothelial dysfunction was defined by a maximal percent increase in coronary blood flow (%ΔCBF) ≤50% in response to intracoronary acetylcholine infusion. We trained algorithms to distinguish between the following outcomes: CFR ≤2.5, ΔCBF (%) ≤50, and the combination of both. Two classes of algorithms were trained, one depending on ECG waveforms as input, and another using tabular style clinical data. The optimal classification threshold was determined by maximizing Youden's J. Results Mean age was 51±12 years and 66% were females (n=1,257). AUC values ranged from 0.49 to 0.67 for all the outcomes. The best performance in our analysis was for the outcome CFR ≤2.5 via logistic regression on tabular variables. AUC and accuracy were 0.67 and 60%; while sensitivity and NPV were 70% and 85%. Specificity and PPV were 56% and 0.35%. When decreasing the threshold from the “optimal” one (24%) to 15%, sensitivity and NPV increased to 92% and 90% respectively, while specificity and PPV decreased to 25% and 29% respectively (Figure 2). Conclusion An AI-enabled algorithm may be able to assist clinical guidance by ruling out CMD in patients presenting with chest pain and/or an abnormal functional stress test. This algorithm needs to be prospectively validated in different cohorts. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): The James Nutter Family &amp; Maria Long Family Fellowship in Cardiovascular Research and Mayo Clinic Figure 1Figure 2

Long-term outcomes in patients with normal coronary arteries, nonobstructive, or obstructive coronary artery disease on invasive coronary angiography.

BackgroundNormal or near normal coronary arteries (NNCA) or nonobstructive coronary artery disease (CAD) are commonly found on invasive coronary angiography (ICA).HypothesisWe aimed to determine long‐term outcomes by severity of CAD in a contemporary cohort of patients undergoing ICA for evaluation for ischemic heart disease.MethodsWe assessed a consecutive cohort of 925 patients who underwent non‐emergent ICA over 24 months. Cardiac death (CD), nonfatal myocardial infarction (NFMI), late revascularization, and medication use were assessed.ResultsFollow‐up data was available in 850 patients. Of patients without heart failure, at a median of 6.0 years, there was a significant decrease in survival free from CD or NFMI, and from all cardiac events, for those with obstructive CAD compared with patients with NNCAs or nonobstructive CAD (p < .001 for both). No differences between NNCA and nonobstructive CAD patients in rates of CD or NFMI (2.0% vs. 2.1%/year, p = .58) or all cardiac events (2.4% vs. 2.9%/year, p = .84) were observed.ConclusionLong‐term follow‐up in a contemporary cohort of consecutive patients undergoing non‐emergent ICA for detection of CAD showed no difference in annual rates of CD or NFMI, or total cardiac events, in patients with NNCAs versus those with nonobstructive CAD, whereas patients with obstructive CAD had significantly more events. Event rates were low and similar by gender. Use of aspirin, lipid lowering therapy, and beta‐blockers increased in all subgroups after ICA. We speculate this may explain the low incidence of subsequent cardiac events, and similar event rates in patients with NNCA and nonobstructive CAD, even in patients presenting with non‐ST‐elevation MI.

The interplay between myocardial bridging and coronary spasm in patients with myocardial infarction and non-obstructive coronary arteries: pathogenic and prognostic implications

Abstract Funding Acknowledgements Type of funding sources: None. Background Myocardial bridging (MB) is associated with endothelial dysfunction and may represent a cause of angina in patients with non-obstructive coronary artery disease (NOCAD). Purpose Herein, we assessed the interplay between MB and coronary vasomotor disorders, evaluating also their prognostic relevance in patients with myocardial infarction and non-obstructive coronary arteries (MINOCA) or stable NOCAD. Methods We prospectively enrolled consecutive NOCAD patients undergoing intracoronary acetylcholine provocative test to assess the presence of epicardial or microvascular spasm in patients with suspected angina or MINOCA. Myocardial bridging was diagnosed by coronary angiography. The incidence of major adverse cardiac events (MACE), defined as the composite of cardiac death, non-fatal MI and rehospitalisation for unstable angina, was assessed at follow-up. We also assessed angina status using Seattle Angina Questionnaires (SAQ). Results We enrolled 310 patients (mean age 60.6 ± 11.9; 136 [43.9%] men; 169 [54.5%] stable NOCAD and 141 [45.5%] MINOCA). MB was found in 53 (17.1%) patients. MB was an independent predictor of spasm and MINOCA (p &amp;lt; 0.05). At follow-up (median 22 months, interquartile range [13-32]), patients with MB had a higher rate of MACE and a lower SAQ score (all p &amp;lt; 0.001) compared with patients without MB. The rate of MACE was considerably higher in patients with both spasm and MB than in the remaining patients (12/42 [28.6%] vs. 13/268 [4.8%], p &amp;lt; 0.001). Conclusion Among patients with NOCAD coronary spasm associated with MB predicts a worse clinical presentation with MINOCA and a worse clinical outcome at medium-long term follow-up, thus identifying a high-risk subset of patients with MB with relevant therapeutic implications. MB and clinical outcomesCharacteristicsOverall population(n= 310)Presence of Myocardial bridging(n= 53)Absence of Myocardial bridging(n = 257)p valueMACE [n, (%)]25 (8.1)12 (22.6)13 (5.1)&amp;lt;0.001CV Death [n, (%)]1 (0.3)0 (0.0)1 (0.4)0.649MI occurrence [n, (%)]6 (1.9)2 (3.8)4 (1.6)0.286Hospitalization for unstable angina [n, (%)]18 (5.8)10 (18.9)8 (3.1)&amp;lt; 0.001Recurrent angina [n, (%)]70 (22.6)20 (37.7)50 (19.4)0.004SAQ [median (IQR)]82 [78; 88]78 [68; 84]84 [78; 88]&amp;lt; 0.001Follow-up time [months, median (IQR)]22 [15;32]20 [15; 28]23 [15; 34]0.10CV Cardiovascular; MI: Myocardial Infarction; IQR: InterQuartile Range; MACE: Major Adverse Cardiovascular Event; SAQ: Seattle Angina Questionnaire.Abstract Figure Outcomes

Cost-effectiveness of imaging strategies to diagnose and select patients with non-obstructive coronary artery disease for statin treatment in the United Kingdom

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): The project leading to this publication has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 668142. Background Patients with non-obstructive coronary artery disease (NOCAD) are at a higher risk of cardiovascular events compared to those with normal arteries. Plaque rupture is associated with increased adverse events and statin therapy seems to be beneficial for plaque stabilisation. Coronary Computed Tomography Angiography (CCTA) is currently the non-invasive imaging modality of choice for the morphological evaluation of NOCAD in the United Kingdom (UK). However, CCTA provides limited information regarding the vulnerability of plaques to rupture and the selection of patients for preventive statin treatment. Currently being tested on patients, Spectral Photon-Counting CT (SPCCT) may provide increased accuracy for vulnerable plaque detection and, in turn, improved selection of patients for statin treatment. Purpose We investigated the potential cost-effectiveness of SPCCT (compared to a set of CCTA-based strategies) in identifying NOCAD patients with rupture-prone plaques for preventive statin treatment. Methods A decision tree and a Markov trace were developed to model the expected outcomes (costs and quality-adjusted life-years (QALYs)) for a hypothetical UK cohort of 50-year-old male patients with stable chest pain and no history of CAD. Input data were obtained from the literature. Deterministic and probabilistic sensitivity analyses were performed. The impact of a pairwise variation of SPCCT sensitivity and specificity was analysed. Furthermore, five competing imaging strategies were compared in terms of their lifetime costs and effects: 1) CCTA and treat NOCAD based on imaging results, 2) CCTA and treat all NOCAD, 3) CCTA and do not treat NOCAD, 4) SPCCT with high specificity and treat NOCAD based on imaging results, and 5) SPCCT with high sensitivity and treat NOCAD based on imaging results. Results Our deterministic and probabilistic results showed that an improved imaging test would add value compared to CCTA. While increased specificity (to 95%) is favorable at a lower willingness to pay (WTP) (up to ∼£9,000 per QALY), increased sensitivity (to 95%) is more likely to be favorable at a higher WTP (∼£9,000 to £120,000 per QALY). The role of a CCTA-treat-none strategy and a CCTA-treat-all strategy is minimal and potential only at really low (&amp;lt;£2,000 per QALY) and high (&amp;gt;£120,000 per QALY) WTP, respectively. The uncertainty around these results is highly correlated to the uncertainty around the long-term risk for NOCAD patients to experience myocardial infarction or stroke. Conclusion An improved imaging test based on higher sensitivity in identifying rupture-prone coronary plaques in NOCAD patients seems to have value in guiding the decision of preventive statin treatment in the UK. However, additional data regarding the efficacy of statins and of combined treatments for NOCAD patients are needed before the cost-effectiveness of SPCCT can be precisely estimated in this population.

AGEs exacerbates coronary microvascular dysfunction in NoCAD by activating endoplasmic reticulum stress-mediated PERK signaling pathway

ObjectiveThe current study was aimed to investigate the involvement of endoplasmic reticulum stress (ERS)-mediated protein kinase R-like endoplasmic reticulum kinase (PERK) signaling in advanced glycation end products (AGEs)-exacerbated coronary microvascular dysfunctions (CMD) in non-obstructive coronary artery disease (NoCAD). Methods and materialsob/ob−/− mice were used as NoCAD animal model which were exposed to AGEs by intraperitoneal injections. Animal CMD was evaluated by coronary flow velocity reserve (CFVR). A viral vector carrying perk-siRNA was used to silence PERK in vivo and in vitro studies. Cell apoptosis was detected by TUNEL. Immunofluorescent staining was used to assess CD42c-positive cell number in cardiac sections and NFATc4 translocation in CMECs. Real-time PCR and Western blotting were used to evaluate the gene expression levels. Cytokine and AGEs concentrations were determined by ELISA. Enzymatic activity of CaN was measured by a colorimetric method. A registered cross sectional study consisted of 77 patients diagnosed as NoCAD was used to analyze the association between diabetes and CMD which was measured by index of microvascular resistance (IMR) with a pressure wire system. ResultsSignificant CMD was found in NoCAD mice compared with healthy control. AGEs exposure exacerbated CMD in NoCAD animals which was improved by PERK silencing. Phosphorylation of PERK, nuclear translocation of nuclear factor of activated T-cells (NFAT)c4, enzymatic activity of calcineurin (CaN), expression levels of Fas/FasL, production of interleukin (IL)6, tumor necrosis factor (TNF)α, cyclooxygenase (COX)2, thromboxane B (TXB)2 as well as apoptosis were suppressed by PERK silencing in cardiac microcirculation endothelial cells (CMECs) isolated from AGEs-exposed NoCAD mice and AGEs-treated primary CMECs. PERK silencing also reduced CD42c-postive cells number in cardiac tissue from AGEs-exposed NoCAD mice. ConclusionDiabetes was associated with CMD in NoCAD. AGEs fostered in diabetes exacerbated CMD by activating ERS-mediated PERK/CaN/NFATc4 signaling in CMECs. IMR values increased significantly in NoCAD patients complicated with diabetes, which were significantly and positively correlated with serum AGEs concentrations.