Dysregulated Efferocytosis in CAD: TNF-α and TGF-β Silencing Reveals Functional Divergence in M1 and M2 Macrophages

The U.S. multi-societal chest pain guideline – A quick look into a long-awaited document

Prevalence of Depression in Patients With Chest Pain and Non-Obstructive Coronary Artery Disease

792 Acute Coronary Syndrome in Patients With Normal or Non-Obstructive Coronary Artery Disease: Patient Characteristics and Long-Term Outcomes

Management of acute coronary syndrome (ACS) patients with nonobstructive epicardial coronary artery disease (CAD) remains poorly understood. Acute coronary syndrome patients with nonobstructive CAD are less likely to receive effective cardiac medications upon discharge from the hospital. We identified patients hospitalized with ACS that underwent coronary angiography and had a 6-month follow-up. Patients were grouped by CAD severity: nonobstructive CAD (<50% blockage in all vessels) or obstructive CAD (> or =50% blockage in > or = 1 vessels). Data were collected on demographics, medications at discharge, and adverse outcomes at 6 months, for all patients. Of the 2264 ACS patients included in the study: 123 patients had nonobstructive CAD and 2141 had obstructive CAD. Cardiac risk factors including hypertension and diabetes were common among patients with nonobstructive CAD. Men and women with nonobstructive CAD were less likely to receive cardiac medications compared to patients with obstructive CAD including aspirin (87.8% vs 95.0%, P = 0.001), beta-blockers (74.0% vs 89.2%, P < 0.001), or statins (69.1% vs 81.2%, P = 0.001). No gender-related differences in discharge medications were observed for patients with nonobstructive CAD. However, women with nonobstructive CAD had similar rates of cardiac-related rehospitalization as men with obstructive CAD (23.3% and 25.9%, respectively). Patients with nonobstructive CAD are less likely to receive evidence-based medications compared to patients with obstructive CAD, despite the presence of CAD risk factors and occurrence of an ACS event. Further research is warranted to determine if receipt of effective cardiac medications among patients with nonobstructive CAD would reduce cardiac-related events.

Coronary computed tomography angiography (CCTA) is increasingly used to detect coronary artery disease (CAD), but long-term follow-up studies are still scarce. To evaluate the prognostic value of CCTA in patients with suspected CAD. A total of 1205 consecutive CCTA patients with chest pain were classified as normal coronary arteries, non-obstructive CAD, or obstructive CAD. The primary outcome was major adverse cardiac event (MACE), defined as a composite outcome including cardiac death, myocardial infarction, unstable angina pectoris, or late revascularization (after >90 days). Over 7.5 years follow-up (median = 3.1 years), Kaplan-Meier estimates demonstrated a MACE in 1.0%, 4.6%, and 20.7% in normal coronary arteries, non-obstructive CAD, and obstructive CAD, respectively. Log rank test for pairwise comparisons showed significant differences between non-obstructive CAD and normal coronary arteries ( P = 0.023) and between obstructive CAD and normal coronary arteries ( P < 0.001). In a multivariable analysis, adjusting for classical risk factors, non-obstructive CAD and obstructive CAD were independent predictors of MACE, with hazard ratios (HR) of 3.22 ( P = 0.041) and 25.18 ( P < 0.001), respectively. Patients with normal coronary arteries have excellent long-term prognosis, but the risk for MACE increases with non-obstructive and obstructive CAD. Both non-obstructive and obstructive CAD are independently associated with future ischemic events.

Little is known about cardiac adverse events among patients with nonobstructive coronary artery disease (CAD). To compare myocardial infarction (MI) and mortality rates between patients with nonobstructive CAD, obstructive CAD, and no apparent CAD in a national cohort. Retrospective cohort study of all US veterans undergoing elective coronary angiography for CAD between October 2007 and September 2012 in the Veterans Affairs health care system. Patients with prior CAD events were excluded. Angiographic CAD extent, defined by degree (no apparent CAD: no stenosis >20%; nonobstructive CAD: ≥1 stenosis ≥20% but no stenosis ≥70%; obstructive CAD: any stenosis ≥70% or left main [LM] stenosis ≥50%) and distribution (1, 2, or 3 vessel). The primary outcome was 1-year hospitalization for nonfatal MI after the index angiography. Secondary outcomes included 1-year all-cause mortality and combined 1-year MI and mortality. Among 37,674 patients, 8384 patients (22.3%) had nonobstructive CAD and 20,899 patients (55.4%) had obstructive CAD. Within 1 year, 845 patients died and 385 were rehospitalized for MI. Among patients with no apparent CAD, the 1-year MI rate was 0.11% (n = 8, 95% CI, 0.10%-0.20%) and increased progressively by 1-vessel nonobstructive CAD, 0.24% (n = 10, 95% CI, 0.10%-0.40%); 2-vessel nonobstructive CAD, 0.56% (n = 13, 95% CI, 0.30%-1.00%); 3-vessel nonobstructive CAD, 0.59% (n = 6, 95% CI, 0.30%-1.30%); 1-vessel obstructive CAD, 1.18% (n = 101, 95% CI, 1.00%-1.40%); 2-vessel obstructive CAD, 2.18% (n = 110, 95% CI, 1.80%-2.60%); and 3-vessel or LM obstructive CAD, 2.47% (n = 137, 95% CI, 2.10%-2.90%). After adjustment, 1-year MI rates increased with increasing CAD extent. Relative to patients with no apparent CAD, patients with 1-vessel nonobstructive CAD had a hazard ratio (HR) for 1-year MI of 2.0 (95% CI, 0.8-5.1); 2-vessel nonobstructive HR, 4.6 (95% CI, 2.0-10.5); 3-vessel nonobstructive HR, 4.5 (95% CI, 1.6-12.5); 1-vessel obstructive HR, 9.0 (95% CI, 4.2-19.0); 2-vessel obstructive HR, 16.5 (95% CI, 8.1-33.7); and 3-vessel or LM obstructive HR, 19.5 (95% CI, 9.9-38.2). One-year mortality rates were associated with increasing CAD extent, ranging from 1.38% among patients without apparent CAD to 4.30% with 3-vessel or LM obstructive CAD. After risk adjustment, there was no significant association between 1- or 2-vessel nonobstructive CAD and mortality, but there were significant associations with mortality for 3-vessel nonobstructive CAD (HR, 1.6; 95% CI, 1.1-2.5), 1-vessel obstructive CAD (HR, 1.9; 95% CI, 1.4-2.6), 2-vessel obstructive CAD (HR, 2.8; 95% CI, 2.1-3.7), and 3-vessel or LM obstructive CAD (HR, 3.4; 95% CI, 2.6-4.4). Similar associations were noted with the combined outcome. In this cohort of patients undergoing elective coronary angiography, nonobstructive CAD, compared with no apparent CAD, was associated with a significantly greater 1-year risk of MI and all-cause mortality. These findings suggest clinical importance of nonobstructive CAD and warrant further investigation of interventions to improve outcomes among these patients.

The relationship between autoantibodies to oxidized low density lipoprotein (OxLDL) and coronary artery disease (CAD) remains controversial. IgM and IgG OxLDL autoantibodies to malondialdehyde (MDA)-modified LDL, copper oxidized low density lipoprotein (CuOxLDL), and oxidized cholesterol linoleate (OxCL), as well as apolipoprotein B-100 immune complexes (apoB-ICs), were measured in 504 patients undergoing clinically indicated coronary angiography. Patients were followed for cardiovascular events for a median of 4 years. In univariate analysis, IgM OxLDL autoantibodies and IgM apoB-ICs were inversely associated with the presence of angiographically determined CAD, whereas IgG OxLDL autoantibodies and IgG apoB-ICs were positively associated. In logistic regression analysis, compared with the first quartile, patients in the fourth quartile of IgM OxLDL autoantibodies and apoB-ICs showed a lower probability of angiographically determined CAD (>50% diameter stenosis). Odds ratios and (95% confidence intervals) were as follows: MDA-LDL, 0.51 (0.32-0.82; P = 0.005); CuOxLDL, 0.63 (0.39-1.01; P = 0.05); OxCL, 0.63 (0.39-1.01; P = 0.05); and apoB-IC, 0.55 (0.34-0.88; P = 0.013). These relationships were accentuated in the setting of hypercholesterolemia, with the highest IgM levels showing the lowest risk of CAD for the same level of hypercholesterolemia. Multivariable analysis revealed that neither IgM or IgG OxLDL autoantibodies nor apoB-ICs were independently associated with angiographically determined CAD or cardiovascular events. In conclusion, IgG and IgM OxLDL biomarkers have divergent associations with CAD in univariate analysis but are not independent predictors of CAD or clinical events.

Aim of the study To analyze the association of biological markers levels of endothelial dysfunction and fibrosis with macro- and microcirculation alterations in patients with obstructive and nonobstructive coronary artery disease (CAD) and type 2 diabetes mellitus (DM). Methods 52 patients with CAD were enrolled and divided into 4 groups: 19 patients with nonobstructive CAD (1–49% stenosis) without DM (1 group: 4 men, age 64.89±7.61, body mass index (BMI) 28.14±3.69 kg/m2); 13 patients with obstructive CAD (≥50% stenosis) without DM (2 group: 9 men, age 66.92±7.02, BMI 30.4±5.91 kg/m2); 10 patients with obstructive CAD (3 group: 4 men, age 63.4±10.37, BMI 31.7±4.81kg/m2) and 10 patients with nonobstructive CAD with DM (4 group: 3 men, age 64.6±5.32, BMI 33.74±3.25 kg/m2). Patients were matched for age, sex and BMI. All patients underwent coronary angiography or coronary computed tomography angiography. Biological markers levels (E-selectin, ng/ml; tissue inhibitor of metalloproteinase 1 (TIMP-1), ng/ml) were measured using ELISA. To determine arterial damage in both macro- and microcirculation, digital reactive hyperemia photoplethysmography were performed. Endothelial function of small (Occlusion Index, OI) and large vessels (Phase Shear, PS, ms) were analyzed. Vascular remodeling of aorta (Stiffness Index, aSI, m/s) and arterioles (Reflection Index, RI, %) were studied. Results The elevation of E-selectin (1 – 21.6 [18.7; 30.4]; 2 – 31.5 [20.1; 36.9]; 3 – 42.25 [29.9; 55.3]; 4 – 42.1 [33.1; 46.5]) and TIMP-1 (1 – 416 [376; 481]; 2 – 478 [381; 539]; 3 – 534 [490; 579]; 4 – 590 [520; 782]) levels were found in all groups. Statistical analysis revealed significant differences between TIMP-1 (p1–3=0.004; p1–4=0.003) and E-Selectin (p1–3=0.013; p1–4=0.01) levels. Remodeling of large vessels was detected only in patients with obstructive CAD without DM and nonobstructive CAD with DM (2 – aSI, 9.05 [7.08; 10.58]; 3 – aSI, 8.2 [7.6; 11]). Patients in all groups had endothelial dysfunction of large vessels (PS, 1 – 5.1 [1.75; 7.75]; 2 – 6.45 [5.53; 9.03]; 3 – 7.65 [13.4; 9.5]; 4 – 4.6 [0.7; 8.1] and arterioles (IO; 1 – 1.5 [1.38; 1.78]; 2 – 1.4 [1.26; 1.53]; 3 – 1.4 [1.2; 1.7]; 4 – 1.3 [1.2; 2.0]). Structural disorders of arterioles were found in all groups, except for patients with obstructive CAD without DM (RI, 1 – 36.95 [23.4; 52.65]; 2 – 28.25 [23.35; 53.75]; 3 – 41.15 [26.5; 55]; 4 – 44.7 [20; 54.5]. The data did not show significant differences between the study groups. Conclusions The data showed that biological markers levels of endothelial dysfunction and fibrosis were increased in all groups. Significant differences revealed between the levels of E-selectin and TIMP-1 in patients with nonobstructive CAD without DM and patients with CAD and DM, regardless of the degree of stenosis. All patients had functional changes of large vessels and arterioles regardless of the severity of coronary artery atherosclerosis and presence of DM. Funding Acknowledgement Type of funding sources: None.

Background Mismatches between the severity of coronary stenosis and the presence of ischemia by invasive fractional flow reserve (FFR) are frequently reported. Purpose To investigate whether plaque characteristics as evaluated with coronary computed tomography angiography (CCTA) may explain this discordance in nonobstructive versus obstructive coronary artery disease (CAD). Methods From the CREDENCE trial, 612 patients with suspected CAD at 13 sites (64±10 years, 70% men) underwent CCTA with semi-automated whole heart quantification and invasive coronary angiography with 3-vessel FFR measurements. Obstructive CAD was visually defined as ≥50% stenosis. The primary endpoint of coronary vessel-specific ischemia was defined as FFR ≤0.80. Generalized estimating equations were calculated to evaluate the effect of plaque characteristics on coronary vessel-specific ischemia. Interactions were tested by obstructive CAD, adjusted for age. Results Among 1,686 vessels, ischemia was present in 436 (26%) vessels. In both nonobstructive and obstructive CAD, the majority of plaque characteristics were associated with coronary vessel-specific ischemia (p≤0.005, Figure 1). In nonobstructive CAD, odds for ischemia were significantly higher for total percent atheroma volume (PAV, p&amp;lt;0.001), calcified PAV (p&amp;lt;0.001), noncalcified PAV &amp;lt;350 and &amp;lt;130 HU (p≤0.043), the number of lesions at a bifurcation (p=0.009) and the number of lesions with high-risk plaque (HRP, p=0.033) when compared with obstructive CAD. Conclusion Our findings reveal that ischemia by FFR is documented in the setting of both nonobstructive and obstructive CAD on CCTA. Detection of atherosclerotic plaque characteristics associated with ischemia can potentially improve diagnostic certainty and guide management of symptomatic patients with nonobstructive CAD. Figure 1. Odds ratios for ischemia. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health - National Heart, Lung, and Blood Institute

Sex differences in long-term outcomes of patients across the spectrum of coronary artery disease

Background There is growing evidence that women with ischemia and no obstructive coronary artery disease (INOCA) have an increased risk of major adverse cardiovascular events (MACE). Half of these women continue to experience persistent chest pain (PChP); however longer-term outcomes are unknown. Purpose To investigate the relationships between PChP at 1-year with obstructive and nonobstructive coronary artery disease (CAD) and longer-term all-cause mortality, MACE and angina hospitalization in women with suspected myocardial ischemia. Methods We studied 673 women with chest pain undergoing coronary angiography for suspected myocardial ischemia in the National Heart, Lung, and Blood Institute Women's Ischemia Syndrome Evaluation (WISE) study. PChP was defined as self-reported continuing chest pain at 1-year, obstructive CAD as &amp;gt;50 stenosis in any coronary artery and non-obstructive CAD was further divided as &amp;lt;20% stenosis and 20–50% stenosis in any coronary artery. The Kaplan-Meier method was used to estimate cumulative incidence rates of all-cause mortality, MACE, and angina hospitalization. Proportional hazards regression estimated adjusted hazard ratios of mortality, MACE and angina hospitalization in relation to PChP at 1-year in obstructive and nonobstructive CAD. Results The median age was 58 years, 45% had PChP, and 39% had obstructive CAD with a median follow-up time of 9 years (range 1 to 11) for mortality and 5 years (range 0 to 9) for MACE and anginal hospitalization. There was no difference in mortality or MACE in women with PChP compared to women without PChP in any of the 3 groups (&amp;lt;20%, 20–50%, or &amp;gt;50% CAD), however differences were noted in long-term angina hospitalization (Figure 1). Notably,angina hospitalization rates in women with PChP and nonobstructive CAD were 2.2 times those of women without PChP, and comparable to those of women with obstructive CAD and no PChP (p&amp;lt;0.0001). Conclusions Among women undergoing coronary angiography for suspected myocardial ischemia, women with nonobstructive CAD and PChP have rates of angina hospitalization comparable to patients with obstructive CAD without PChP. Thus, PChP increases the hazard of long term anginal hospitalization regardless of the presence or absence of obstructive CAD. Given the economic burden of angina hospitalization, further studies are needed to determine whether aggressive treatment in women with PChP without obstructive CAD changes outcomes and impact on the health care system. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Institute of Health (NIH)

BackgroundMechanisms of myocardial ischemia in obstructive and non-obstructive coronary artery disease (CAD), and the interplay between clinical, functional, biological and psycho-social features, are still far to be fully elucidated.ObjectivesTo develop a machine-learning (ML) model for the supervised prediction of obstructive versus non-obstructive CAD.MethodsFrom the EVA study, we analysed adults hospitalized for IHD undergoing conventional coronary angiography (CCA). Non-obstructive CAD was defined by a stenosis < 50% in one or more vessels. Baseline clinical and psycho-socio-cultural characteristics were used for computing a Rockwood and Mitnitski frailty index, and a gender score according to GENESIS-PRAXY methodology. Serum concentration of inflammatory cytokines was measured with a multiplex flow cytometry assay. Through an XGBoost classifier combined with an explainable artificial intelligence tool (SHAP), we identified the most influential features in discriminating obstructive versus non-obstructive CAD.ResultsAmong the overall EVA cohort (n = 509), 311 individuals (mean age 67 ± 11 years, 38% females; 67% obstructive CAD) with complete data were analysed. The ML-based model (83% accuracy and 87% precision) showed that while obstructive CAD was associated with higher frailty index, older age and a cytokine signature characterized by IL-1β, IL-12p70 and IL-33, non-obstructive CAD was associated with a higher gender score (i.e., social characteristics traditionally ascribed to women) and with a cytokine signature characterized by IL-18, IL-8, IL-23.ConclusionsIntegrating clinical, biological, and psycho-social features, we have optimized a sex- and gender-unbiased model that discriminates obstructive and non-obstructive CAD. Further mechanistic studies will shed light on the biological plausibility of these associations.Clinical trial registrationNCT02737982.Graphical abstract

We sought to compare the complementary prognostic value of exercise treadmill testing (ETT) and coronary computed tomographic angiography (CTA) among patients referred for both exams. We studied 582 patients without known coronary artery disease (CAD) who were clinically referred for ETT and CTA within 6 months. Patients were followed for cardiovascular (CV) death, non-fatal myocardial infarction (MI), or late revascularization (>90 days), stratified by Duke Treadmill Score (DTS) and CAD severity (≥50% stenosis). Mean age was 54 ± 13 years (63% male). In median follow-up of 40 months, there were 3 CV deaths, 7 non-fatal MIs, and 26 late revascularizations. ETT was inconclusive in 23%, positive in 31%, and negative in 46%. CTA demonstrated no CAD in 37%, non-obstructive CAD in 28%, and obstructive CAD in 35%. Among low-risk ETT patients (n = 326), there were 3 MI, 10 late revascularizations, and the frequent presence of non-obstructive (32%, n = 105) and obstructive CAD (27%, n = 88). When present, ETT features (i.e., angina, DTS, ischaemic electrocardiogram changes, and exercise capacity) individually failed to predict CV death/MI after adjustment for Morise score. Conversely, both obstructive CAD [HR 4.9 (1.0-23.3), P = 0.048] and CAD extent by segment involvement score >4 [HR 3.9 (1.0-15.2), P = 0.049] predicted increased risk for CV death or MI. Patients with a low-risk ETT have an excellent prognosis at 40 months, despite the frequent presence of non-obstructive (32%) and obstructive (27%) CAD. In patients with an intermediate- to high-risk ETT (DTS <5), CTA can provide incremental risk stratification for future CV events.

Coronary sinus (CS) Reducer implantation shows favorable results in alleviating angina symptoms in patients with obstructive coronary artery disease (CAD) with non-revascularizable lesions. Whether CS Reducer is effective also in patients without obstructive epicardial CAD remains unsettled. We sought to assess the potential benefits of the CS narrowing in patients without obstructive presenting with refractory angina. Consecutive refractory angina patients, with objective evidence of myocardial ischemia despite optimal medical therapy (OMT), who underwent CS Reducer implantation, were enrolled in an international registry. Study cohort was divided into two groups: patients with non-obstructive CAD (< 50% narrowing in all epicardial coronary arteries or a negative intracoronary fractional flow reserve test in case of intermediate lesions), and patients with obstructive CAD. The study outcome was the improvement of the Canadian Cardiovascular Society (CCS) angina score at 12-month follow-up in both groups of patients. Of 285 enrolled patients with successful CS Reducer implantation, 46 patients (16%) had non-obstructive CAD and 239 patients (84%) had obstructive CAD. Baseline CCS angina score was similar in both groups (2.9 ± 0.5 vs. 2.9 ± 0.6, p = 0.884). At 12-month follow-up, the improvement in CCS angina score was similar in both groups (-1.4 ± 0.8 vs. -1.3 ± 0.9 vs. p = 0.67). Both groups had the same CCS angina score at 12-month follow-up (1.6 ± 0.8 p = 0.80). Improvement of ≥ 2 CCS classes were 41.9% and 45.1% in patients with non-obstructive and obstructive CAD, respectively, p = 0.6746. In patients with refractory angina and myocardial ischemia, CS Reducer implantation improves angina symptoms in patients with myocardial ischemia with and without obstructive CAD.

In recent decades, there has been an appropriate focus on ensuring gender equity in the quantity and quality of evidence to guide female-specific, optimal management strategies for suspected and known ischemic heart disease (IHD). The evolving evidence supports a multifactorial pathophysiology of coronary atherosclerosis that includes obstructive coronary artery disease (CAD) and dysfunction of the coronary microvasculature and endothelium, and therefore, the term IHD best encompasses this varied pathophysiology in women. An overwhelming body of evidence has documented undertreatment and undertesting of women, leading to higher case fatality rates and increased morbid complications among women.1–3 Accordingly, to increase our knowledge base, women were given the status of a priority population, which resulted in federal policy to include proportional representation of females in clinical trials and registries.4 The past decade provided abundant evidence to guide clinical decision making regarding diagnostic testing for suspected IHD. In 2005, the American Heart Association (AHA) published an evidence synthesis on the use of CAD imaging for the evaluation of symptomatic women with suspected myocardial ischemia.5 Numerous reports have since provided additional high-quality evidence, including data on coronary computed tomographic angiography (CCTA) and cardiac magnetic resonance imaging (CMR), which in 2005 were considered research techniques.5 The present statement provides an update to the 2005 document and synthesizes contemporary evidence on appropriate symptomatic female candidates for diagnostic testing, as well as sex-specific data on the diagnostic and prognostic accuracy for exercise treadmill testing (ETT) with electrocardiography, stress echocardiography, stress myocardial perfusion imaging (MPI) with single-photon emission computed tomography (SPECT) or positron emission tomography (PET), stress CMR, and CCTA.5 Within this document, quality evidence is synthesized, and important gaps in knowledge about the assessment of IHD risk in women are identified. The 2005 document included sections on the evaluation of asymptomatic …