Faculty Bibliography

BACKGROUND:Research comparing the prognostic value of stress cardiac magnetic resonance (CMR) to other stress modalities in patients with coronary disease is limited. OBJECTIVES/OBJECTIVE:The authors compared the prognostic value of stress CMR vs alternative testing by either single-photon emission computed tomography or stress echocardiography (SPECT/echo) in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial. METHODS:CMR vs SPECT/echo was compared in 3,909 patients randomized in ISCHEMIA after sites' interpretation of moderate to severe ischemia. Ischemia and infarct extent, measured by either CMR or SPECT/echo, were each associated with the trial's primary outcome of cardiovascular death, nonfatal myocardial infarction (MI), or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest, at a median follow-up of 3.37 years (Q1-Q3: 2.20-4.56 years). RESULTS:Compared with SPECT/echo (n = 5,627), CMR participants (n = 313) were not different in key demographic factors but were more likely to have severe ischemia (57% vs 38%; P < 0.001) and to be randomized (n = 257, 82%, vs n = 3,652, 65%; P < 0.001). Ischemia severity (no/mild, moderate, severe) by CMR core laboratory was associated with cumulative 4-year event rates of all trial-specific endpoints, including the primary outcome (P = 0.042), cardiovascular death/MI (P = 0.041), and nonfatal MI (P = 0.03), but SPECT/echo ischemia severity was not. No/mild, moderate, and severe ischemia by CMR were associated with 0%, 14%, and 23% 4-year primary outcome rates, respectively, compared with 18%, 15%, and 16%, by SPECT/echo. After adjustment for age, estimated glomerular filtration rate, and diabetes, the association between ischemia extent and the primary endpoint differed by imaging modality, with each additional ischemic segment on CMR associated with a 13% increase in hazard (interaction P = 0.02). In participants assigned to initial conservative management who had no/mild ischemia on imaging, 4-year rates of invasive referral and coronary revascularization were lower in the CMR than SPECT/echo group (16.7% and 0%, respectively, for CMR; and 31% and 13.3%, respectively, for SPECT/echo). CONCLUSIONS:Ischemia severity by CMR had a stronger association with all ISCHEMIA trial endpoints compared with SPECT/echo.

Coronary artery disease remains a common cause of morbidity and mortality for patients with heart failure, both in the acute and chronic settings. The management decisions for these patients are complex and are often driven by the clinical setting (ie, acute vs chronic disease) and predominant symptoms (angina vs heart failure). However, there remain significant gaps in the knowledge/evidence around optimal timing and implementation of medical therapy and the role and selection of patients for revascularization. Suggested considerations for clinical practice are provided based on the current body of evidence with emphasis on ongoing gaps in knowledge for future clinical research in this area.

Coronary endothelial dysfunction plays a key role in the pathogenesis of acute coronary syndromes. During myocardial infarction (MI), activated platelets release prothrombotic and proinflammatory factors, contributing to vascular injury and dysfunction. To investigate platelet-mediated endothelial dysfunction, endothelial cells (ECs) were treated with platelet-released factors from patients with MI and non-MI controls undergoing coronary angiography. RNA sequencing revealed that MI platelets induced EC mitochondrial dysfunction, confirmed by reduced mitochondrial membrane potential and disrupted mitochondrial networks. Integrating platelet transcriptomic data, we identified the C-C motif chemokine ligand 3 (CCL3) as significantly up-regulated in MI platelets and a key mediator of EC mitochondrial dysfunction. Blocking its receptor, CCR5, attenuated CCL3 effects. In an independent cohort of 261 patients with established cardiovascular disease, higher circulating CCL3 levels were associated with incident major adverse cardiovascular events. Together, these findings establish a mechanistic link between platelet activation and coronary endothelial dysfunction in MI.

BACKGROUND:Coronary microvascular dysfunction (CMD) is present in approximately 40% of patients with ischemia with no obstructive coronary arteries (INOCA) and has been associated with inflammation. We investigated associations between measures of inflammation of the coronary perivascular adipose tissue assessed by coronary computed tomography angiography (CCTA) and results of invasive coronary function testing (CFT) to diagnose CMD. METHODS:Adults referred for clinically indicated invasive coronary angiography who had less than 50% stenosis in all epicardial arteries were prospectively enrolled. CMD was defined as a coronary flow reserve (CFR) less than 2.5 or index of microvascular resistance (IMR) greater than or equal to 25 using bolus thermodilution in the left anterior descending (LAD) coronary artery. Coronary perivascular fat attenuation index was assessed by CCTA in the right coronary artery (RCA) and LAD. T tests were used to evaluate differences in perivascular FAI by CMD status. RESULTS:A total of 31 participants underwent CFT and CCTA. The mean age was 58 ± 11.7 years, 77% were female, and 61% were white. CMD was present in 15 participants (48%). No differences in perivascular FAI were observed in patients with and without CMD, either in the RCA [-74.2 ± 9.8 vs. -69.9 ± 10.3 Hounsfield units (HU), P = 0.24] or LAD (-76.4 ± 10.2 vs. -74.8 ± 12.7 HU, P = 0.69). Perivascular FAI was not correlated with CFR or IMR measurements in the RCA or LAD. CONCLUSION/CONCLUSIONS:There were no associations between CMD diagnosed by invasive CFT and perivascular FAI by CCTA in patients with INOCA. Further research is needed to understand the relationship between vascular inflammation and CMD in INOCA.

BACKGROUND/UNASSIGNED:In ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches), an invasive strategy demonstrated better health status outcomes than a conservative strategy in patients with chronic coronary disease (CCD). Some previous studies have shown greater health status benefits with coronary artery bypass grafting (CABG) than percutaneous coronary intervention (PCI). Whether the health status benefits of invasive management in ISCHEMIA were driven primarily by participants treated with CABG is unknown. METHODS/UNASSIGNED:The aim of this analysis was to describe the health status outcomes of participants treated with a conservative strategy (n=2232) compared with invasively managed participants treated with PCI (n=1198) or CABG (n=340) in ISCHEMIA. The Seattle Angina Questionnaire-7 summary score (SAQ-SS) and angina frequency score (SAQ-AF) were the primary outcomes, with higher scores indicating better health status. Proportional odds models comparing 1- and 3-year outcomes were fit, adjusting for demographic, clinical, and angiographic characteristics. RESULTS/UNASSIGNED:SAQ-SS in the conservative, PCI, and CABG groups increased by 9.9±18.1, 15.7±19.3, and 16.1±19.1 points at 1 year and 11.5±20.2, 16.5±21.8, and 15.0±19.4 points at 3 years, respectively. Freedom from angina in the conservative, PCI, and CABG groups was noted in 61.4%, 73.3%, and 82.4% at 1 year and 70.4%, 76.1%, 81.4% at 3 years, respectively. In risk-adjusted analyses, PCI and CABG were each associated with a higher SAQ-SS and SAQ-AF at 1 and 3 years compared with conservative management. SAQ-AF was higher with CABG than PCI at 1 year (odds ratio, 1.54 [95% CI, 1.03, 2.31]), but no differences between CABG and PCI were observed in SAQ-SS (odds ratio, 1.11 [95% CI, 0.78, 1.57]) or SAQ-AF (odds ratio, 0.94 [95% CI, 0.58, 1.54]) at 3 years. CONCLUSIONS/UNASSIGNED:In ISCHEMIA, both PCI and CABG were associated with better 3-year health status than conservative management. Better angina relief with CABG than PCI was seen at 1, but not 3, years. REGISTRATION/UNASSIGNED:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522.

BACKGROUND:Clinical trials typically report average health status outcomes by treatment at single points in time, as opposed to participants' trajectories (or journeys) over time. Although ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) demonstrated better mean health status at discrete times with an invasive treatment among those with baseline angina, the patterns of individual participants' angina over time are unknown. OBJECTIVES/OBJECTIVE:The purpose of this study was to identify patterns of individual participants' angina over time after invasive or conservative management strategies for chronic coronary disease. METHODS:In this secondary analysis of the ISCHEMIA trial, which enrolled participants with chronic coronary disease and moderate to severe ischemia from July 2012 to January 2018, we used ordinal latent trajectory analysis to assess angina frequency over a 2-year period, separately for participants assigned to the initial invasive and initial conservative arms. Angina frequency was defined using the SAQ-AF (Seattle Angina Questionnaire Angina Frequency) score, recategorized as daily/weekly (0-60 points), monthly (61-99 points), and no angina (100 points). Participants without baseline angina were excluded. RESULTS:Among 2,977 participants with baseline angina, 1,505 (50.6%) were randomized to initial invasive and 1,472 (49.4%) to initial conservative management; baseline characteristics were well balanced between groups. Six distinct patterns of angina trajectories were identified in each arm and were qualitatively similar: 1) rapid resolution; 2) gradual resolution; 3) early improvement with persistent infrequent angina; 4) severe angina with improvement; 5) modest angina with minimal change; and 6) severe angina without improvement. In the invasive group, the most common patterns included rapid resolution (27.1%) and early improvement with persistent infrequent angina (32.1%), whereas the conservative group more often showed modest angina with minimal change (42.1%) and fewer cases of rapid resolution (12.8%) or early improvement with persistent infrequent angina (10.2%). CONCLUSIONS:Patients with chronic coronary disease and angina experienced diverse symptom trajectories, ranging from rapid resolution to severe or persistent angina. A greater proportion of conservatively managed patients experienced unfavorable angina patterns over 2 years compared with those treated invasively. When health status is monitored over time, such patterns may help identify patients with persistent symptoms who could benefit from additional therapy. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).

Ischemic heart disease is the leading cause of heart failure with reduced ejection fraction in the developed world. An evolution of background medical therapy over the past decade has spurred improvement in symptoms and a reduction in morbidity and mortality with ischemic cardiomyopathy. However, there is still ongoing debate about the role and impact of revascularization. Much of the societal guidance regarding revascularization with coronary artery bypass grafting in ischemic cardiomyopathy comes from the STICH trial (Surgical Treatment for Ischemic Heart Failure) which predates improvements in medical therapy. More recently, the REVIVED-BCIS2 trial (Revascularization for Ischemic Ventricular Dysfunction-British Cardiovascular Intervention Society) failed to show a benefit of percutaneous coronary intervention on heart failure hospitalization and mortality in ischemic cardiomyopathy over contemporary medical therapy alone. Yet, there are outstanding questions regarding the role and modality of revascularization required to improve outcomes. We review current data and future directions in the management of ischemic cardiomyopathy and the potential role of revascularization.