Faculty Bibliography

PURPOSE/OBJECTIVE:To report on the presentation, treatment, and visual outcome of stromal keratitis (SK) in the Zoster Eye Disease Study (ZEDS). DESIGN/METHODS:Secondary analysis of SK endpoint of randomized clinical trial. SUBJECTS/METHODS:Herpes Zoster Ophthalmicus (HZO) patients were randomized in a double-masked clinical trial of oral valacyclovir 1g daily or placebo for 1 year. They were followed prospectively every 3 months for 18 months for endpoints of SK, iritis (IR), endothelial keratitis (EK), or dendritiform epithelial keratitis (DEK). METHODS:Presentation of recurrent, new, or worsening SK was evaluated retrospectively by treatment assignment, randomization strata, and use of topical steroids. Investigators had been allowed discretionary treatment of endpoints including open label valacyclovir and topical steroids. Visual outcome and treatment with open label oral valacyclovir and topical steroids were evaluated. MAIN OUTCOME MEASURES/METHODS:Use of open label valacyclovir and topical steroid treatment of recurrent, new, or worsening SK, and visual acuity at 12 months. RESULTS:Recurrent, new, or worsening SK occurred in 105/527(20%) participants. Randomization group was not associated with this complication. Mean best corrected visual acuity at enrollment was logMAR 0.10±0.14 with no difference at 1 year, logMAR 0.13±0.2, and no difference between valacyclovir and placebo groups at enrollment or at 1 year. Among the 105 instances of SK, 79(75%) were recognized at scheduled study visits rather than at episodic visits. In only 11/105(10%) of recurrent, new, or worsening SK, did masked investigators opt to treat with open label oral antiviral. At the time of SK complication, 52/105(50%) were on topical steroid, but 47/52(90%) on topical steroids were using 1x daily or less, 21/47(45%) high potency and 26/47(55%) low potency (p=0.47). Of 48/105(47%) on no topical steroids at recurrent, new, or worsening SK, 18/48(38%) had discontinued steroids in the prior 3 months. 38/48(75%) on no topical steroids at complication SK were subsequently treated with high potency steroids 2x daily or more. Of 26/52(50%) on low potency steroids at complication SK, 23/26(88%) were treated with increase in frequency only. CONCLUSIONS:Individuals with ocular complications of HZO who develop SK generally maintain very good vision without use of oral antiviral therapy when monitored closely and SK is recognized and treated. Low potency topical steroids should be considered for treatment and ongoing suppression of SK in HZO.

AIMS/OBJECTIVE:To assess whether baseline functional performance assessed by exercise treadmill stress testing (EST) has additive value to coronary computed tomography angiography (CCTA) for risk stratification among patients with chronic coronary disease (CCD) and moderate or severe ischemia. METHODS AND RESULTS/RESULTS:We performed a subgroup analysis of the ISCHEMIA trial including participants who underwent EST and CCTA. EST data and severity of coronary artery disease (CAD) on CCTA were evaluated by core laboratories, blinded to clinical data and results of the other test. The primary outcome for this analysis was all-cause death. Secondary outcomes were cardiovascular death, cardiovascular death or myocardial infarction (MI), MI and a composite of cardiovascular death, MI, or hospitalization for heart failure, unstable angina, or resuscitated cardiac arrest. EST and number of vessels diseased on CCTA were both interpretable in 1864 patients (median age 62 years, IQR 55-68, 83% males). During a median follow-up of 3.1 years, 69 patients died. Higher peak metabolic equivalents (METs) achieved on the qualifying stress test was associated with lower all-cause death (HR 0.86, CI 0.76-0.98; p=0.025). The addition of peak METs to CAD severity improved the predictive ability of the all-cause death and CV death models by 10-20% and 8-13% respectively, depending on the metrics used for CCTA. Adding peak METs to CCTA anatomical models resulted in better prediction of MI by 11-17%, cardiovascular death or MI by 10-14%, and 5-component composite outcome by 12-16%. CONCLUSION/CONCLUSIONS:Peak METs on EST, a marker of functional performance, added prognostic value to models including CCTA anatomical findings in patients with CCD and moderate or severe ischemia.

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.