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 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:compared with the conventional index of microcirculatory resistance (IMR) in a cohort of individuals with INOCA. METHODS/UNASSIGNED:was calculated retrospectively, blinded to CFT results. CMD was defined by IMR ≥25 or CFR <2.5. RESULTS/UNASSIGNED:and IMR. CONCLUSIONS/UNASSIGNED:appears unreliable for identifying CMD in patients with INOCA.

BACKGROUND:Patients with heart failure (HF) often have difficulty obtaining life-saving medications due to coverage barriers, such as prior authorizations and high out-of-pocket costs. To promote better coverage for high value therapies and inform policymakers about cost effectiveness, the American Heart Association/American College of Cardiology/Heart Failure Society of America added Value Statements to HF guidelines. We assessed whether these guidelines influenced Medicare drug coverage policies for 2 life-saving, costly HF medications: angiotensin receptor neprilysin inhibitors (ARNI-guideline "high value") and sodium glucose cotransporter-2 inhibitors (SGLT2i-guideline "intermediate value"). METHODS:We performed an observational study using Medicare prescription drug plan formulary files from April 2020 to April 2023 to separately assess for changes in coverage barriers to ARNI and SGLT2i after Value Statement publication (April 2022), and subsequent Medicare plan online update (October 2022). The primary outcome was the percentage of plans each month with any barrier to drug coverage (prior authorizations, tier ≥3 out-of-pocket cost-sharing, step therapy, or no coverage). Analyses used interrupted time series and difference-in-differences approaches. Difference-in-differences analyses used direct oral anticoagulants as a control due to their comparable cost and use as ARNI and SGLT2i, but without a Value Statement. RESULTS:Among 7396 Medicare drug plans, monthly rates of any coverage barrier ranged from 94.3% to 97.4% for ARNI and 93.2% to 96.6% for SGLT2i. Most barriers were due to tier ≥3 out-of-pocket cost-sharing requirements (ARNI: 94.3%-95.8%; SGLT2i: 93.2%-95.6%). Coverage barriers remained stable in April 2022 and declined slightly in October 2022. In difference-in-differences analyses, the presence of a Value Statement was associated with a ~1 percentage point decline in coverage barriers for both ARNI (difference-in-differences estimate, -1.07% [95% CI, -1.44% to -0.70%]) and SGLT2i (-1.32% [95% CI, -1.63% to -1.00%]). CONCLUSIONS:Coverage barriers to ARNI and SGLT2i were common and changed only slightly after publication of Value Statements in HF guidelines. There is a critical need for robust strategies to improve access to life-saving HF medications.

Pulmonary hypertension (PH) is a frequent complication of Philadelphia-negative myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). However, its prognostic significance is understudied, thus we aimed to evaluate the effect of PH identified by echocardiography on risk of progression to secondary MF or acute leukemia in MPN patients. We conducted a multicenter, retrospective cohort study of MPN patients with ≥ 1 echocardiogram from 2010-2023. PH was defined as pulmonary artery systolic pressure (PASP) ≥ 40 mmHg. Outcomes were progression to secondary myelofibrosis or leukemia, major adverse cardiovascular event (MACE) and all-cause death. Multivariable Fine-Gray competing-risk regression was used to estimate subhazard ratio (SHR) of hematologic progression and MACE. 555 patients were included (42.7% PV, 41.1% ET, 16.2% MF) or which 195 (35.1%) had PH. Over a median follow-up period of 51.2 months, PH was associated with increased risk of secondary MF progression (aSHR 2.40, 95% CI 1.25-4.59), leukemia progression (aSHR 3.06, 95% CI 1.13 - 8.25), and MACE (aSHR 1.59, 95% CI 1.01- 2.49) but not all-cause death (aHR 1.48, 95% CI 0.96-2.26). Among patients with PH, absence of left heart disease (LHD) was associated with higher risk of secondary MF progression among patients with ET or PV (aSHR 2.76, 95% CI 1.19 - 6.38) and leukemia progression among patients with MF (aSHR 7.18, 95% CI 1.59-32.46). Prospective studies are needed to assess the role of echocardiography on MPNspecific prognostication.

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.

PURPOSE/OBJECTIVE:Patients with ischemia with no obstructive coronary arteries (INOCA) and myocardial infarction with no obstructive coronary arteries (MINOCA) may benefit from cardiac rehabilitation. Episodes of INOCA can be caused by different mechanisms including coronary microvascular dysfunction and coronary artery spasm, while episodes of MINOCA can be caused by plaque disruption (rupture or erosion), coronary artery spasm, or coronary embolism. Both conditions affect women more than men. REVIEW METHODS/METHODS:The current review evaluates available evidence on exercise and cardiac rehabilitation in patients with INOCA and MINOCA. SUMMARY/CONCLUSIONS:Small studies have shown that exercise training can result in improvements in endothelial function, myocardial perfusion, exercise capacity, and overall wellbeing and quality of life in patients with INOCA. Structured cardiac rehabilitation programs have also been shown to improve symptoms of angina, physical functioning, and quality of life for patients with INOCA. Studies of cardiac rehabilitation among patients with MINOCA have found that only one third participate in cardiac rehabilitation, but among those who do, observational studies and a randomized controlled trial demonstrate a lower risk of major adverse cardiovascular events (such as all-cause mortality and nonfatal myocardial infarction) with cardiac rehabilitation. However, given that INOCA and MINOCA are conditions that predominantly affect women and may be caused by non-atherosclerotic mechanisms, tailoring of traditional cardiac rehabilitation programs (eg, education components) may be desirable to meet the specific needs of these patients. Future studies should explore the effectiveness of tailored cardiac rehabilitation programs with novel delivery methods to optimize programs for patients with INOCA and MINOCA.

BACKGROUND:Limited contemporary evidence exists on risk prediction by stress imaging and exercise electrocardiography (ECG) among patients with chronic coronary syndromes (CCS). Objectives From the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) study, prognosis was examined by core laboratory-defined stress imaging and exercise ECG findings in CCS patients. METHODS:A total of 5,179 patients (qualifying by stress nuclear imaging [n = 2,567], echocardiography [n = 1,085], cardiac magnetic resonance [CMR] [n = 257], and ECG [n = 1,270]) were randomized. Cox models assessed associations between trial endpoints and the number of scarred and ischemic segments, rest/stress left ventricular ejection fraction (LVEF), and ST-segment depression. HRs and 95% CIs were calculated per millimeter, segment, or 5% of LVEF. We examined prognostic models for the following trial endpoints: 1) the trial's primary endpoint of cardiovascular (CV) death, myocardial infarction (MI), resuscitated cardiac arrest, or hospitalization for unstable angina or heart failure; 2) CV death; 3) spontaneous MI; 4) procedural MI; and 5) type 2 MI. RESULTS:The number of scarred segments (HR: 1.07 [95% CI: 1.02-1.13]; P = 0.0209), rest LVEF (HR: 0.88 [95% CI: 0.83-0.93]; P < 0.001), and stress LVEF (HR: 0.87 [95% CI: 0.83-0.91]; P < 0.001) predicted the trial's primary endpoint of CV death, MI, resuscitated cardiac arrest, or hospitalization for unstable angina or heart failure. The extent of scar and rest/stress LVEF on echocardiography and nuclear imaging predicted several trial endpoints. The number of ischemic segments predicted spontaneous (HR: 1.08 [95% CI: 1.03-1.14]; P = 0.0104) and procedural MI (HR: 1.14 [95% CI: 1.03-1.25]; P = 0.0015) but was of borderline significance for the trial's primary endpoint (P = 0.0746). Ischemia extent by CMR predicted the trial's primary endpoint (P = 0.0068) and spontaneous MI (P = 0.0042). CONCLUSIONS:ISCHEMIA trial findings from 320 worldwide centers revealed that stress imaging and exercise ECG measures exhibited a variable association with key trial endpoints delineating risk patterns for ischemia and infarction. Stress CMR ischemia predicted several trial endpoints, supporting an expanded role in the evaluation of patients with CCS (ISCHEMIA [International Study of Comparative Health Effectiveness With Medical and Invasive Approaches]; NCT01471522).