Faculty Bibliography

BACKGROUND/UNASSIGNED:Myeloproliferative neoplasms (MPN) are a group of chronic leukemias that are associated with pulmonary hypertension (PH), which has been associated with increased risk adverse outcomes. The echocardiographic characterization of PH in MPN has not been reported, and the prognostic significance of PH among patients with MPN remains unclear. METHODS/UNASSIGNED:Multicenter, retrospective cohort study of patients with MPN with ≥1 echocardiogram from 2010 to 2023. The echocardiographic probability of PH was determined according to the guidelines. The outcomes were hematologic progression and major adverse cardiovascular events. Exploratory analysis included outcomes among patients with right heart catheterization after the first echocardiogram, with PH defined as mean pulmonary artery pressure of >20 mm Hg. Multivariable Fine-Gray competing risk regression was used to estimate the subhazard ratio of hematologic progression and major adverse cardiovascular events. RESULTS/UNASSIGNED:=0.048). CONCLUSIONS/UNASSIGNED:Among patients with MPN, echocardiographic probability of PH was associated with an increased risk of hematologic progression. Prospective studies are needed to assess the optimal use of echocardiography on MPN-specific prognostication.

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:In the ISCHEMIA Trial, 5179 patients with stable coronary disease were randomized to initial invasive or conservative management. METHODS:PCI was recommended with a SYNTAX score 0-22 (low) and CABG with a SYNTAX score ≥33 (high). Either could be recommended for intermediate scores. The composite primary outcome was cardiovascular death, MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. There were two cohorts in this analysis. The descriptive cohort included patients who underwent CABG or PCI within 180 days of randomization and had no primary outcome before revascularization. The comparative cohort excluded participants with prior CABG, single vessel disease, SYNTAX score ≥ 45, and without core laboratory assessment. We focused on the intermediate (23-32) SYNTAX comparative group for which either CABG or PCI could be recommended. RESULTS:For 1935 patients in the descriptive cohort (485 CABG, 1450 PCI), the SYNTAX score was 27.3 ± 11.0 in the CABG group and 15.3 ± 8.6 in the PCI group, p<0.0001. Most patients with low SYNTAX scores underwent PCI (87.1%), while most with high SYNTAX scores underwent CABG (72.6%). For the 1203 patients (385 CABG, 818 PCI) in the entire comparative cohort, the adjusted 4-year primary event rate was 14.5% for CABG and 13.2% for PCI (difference 1.3%, 95% CI, -4.9% to 7.7%). For the 346 patients (163 CABG, 183 PCI) in the intermediate SYNTAX group, the adjusted 4-year primary event rate was 10.6% for CABG and 18.3% for PCI (difference -7.6%, 95% CI, -16.1% to 0.9%). CONCLUSIONS:Selection of revascularization method resulted in more PCI in the low SYNTAX group and more CABG in the high SYNTAX group. There was no statistical evidence of a difference between PCI and CABG in the intermediate SYNTAX group but the CIs are broad, reflecting uncertainty. GOV IDENTIFIER/UNASSIGNED:NCT01471522; https://clinicaltrials.gov/ct2/show/NCT01471522.

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:Randomized trials of chronic total occlusion (CTO) revascularization vs medical therapy have yielded inconsistent results. OBJECTIVES/OBJECTIVE:The aim of this study was to evaluate outcomes with an initial invasive strategy (INV) vs an initial conservative strategy (CON) in patients with coronary computed tomographic angiography (CCTA)-determined CTO in the ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) trial. METHODS:Participants in ISCHEMIA who underwent CCTA evaluated for CTO by the core laboratory (3,113 of 5,179 randomized patients [60%]) were categorized into subgroups with (100% stenosis) and without (<100% stenosis) CTO. Primary analysis compared outcomes in those randomized to INV vs CON using an intention-to-treat approach. Secondary analyses compared outcomes using inverse probability weighting to model successful CTO revascularization (REV) in all INV participants vs CON participants. RESULTS:Of the 3,113 CCTA-evaluable participants, 1,470 had at least 1 CTO (752 INV and 718 CON). INV did not reduce cardiovascular (CV) death or myocardial infarction (MI) (5-year difference -3.5%; 95% CI: -7.8% to 0.8%) and resulted in more procedural MIs (2.5%; 95% CI: 1.0%-4.0%) but fewer spontaneous MIs (-6.3%; 95% CI: -9.7% to -3.2%) than CON. CTO REV modeled across INV had a high probability (>90%) of any lower CV death or MI, MI, spontaneous MI, unstable angina, and heart failure counterbalanced by a higher rate of procedural MI. CTO REV significantly improved angina-related quality of life (mean difference 4.6 points), Rose Dyspnea Scale score (rescaled) (mean difference 5.3 points), and EQ-5D visual analog scale score (4.6 points). CONCLUSIONS:In the ISCHEMIA trial, the risks and benefits of INV compared with CON were similar among patients with and without CCTA-determined CTO (more frequent procedural MI, less frequent spontaneous MI, and significantly improved angina and dyspnea-related quality of life). In an observational comparison, successful CTO REV was associated with a high probability of lower CV death or MI (driven by lower MI) compared with CON. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).

BACKGROUND:Guideline-directed medical therapy (GDMT) with multiple risk factor goals is recommended for patients with chronic coronary disease (CCD), yet achieving all GDMT goals is uncommon. The relative importance of these goals and timing of their attainment on cardiovascular events is uncertain. OBJECTIVES/OBJECTIVE:This study aims to describe the relationship between achieving specific GDMT goals, when they are achieved, and clinical outcomes. METHODS:This was an observational study of participants with CCD in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial. The primary outcome was cardiovascular (CV) death or myocardial infarction (MI). GDMT goals were systolic blood pressure (SBP) <130 mm Hg, low-density lipoprotein cholesterol <70 mg/dL, not smoking, and antiplatelet therapy. Frequency of GDMT goals met at baseline and during follow-up is described. Bayesian joint modeling for longitudinal goal status and time-to-event analyses characterized the relative importance of specific GDMT goal attainment and timing with CV death/MI. RESULTS:All 5,179 ISCHEMIA participants were included. Among 4,914 participants with complete data on all 4 GDMT goals at baseline, 386 (9%), 2,073 (42%), 1,843 (38%), and 612 (12%) met 0-1, 2, 3, and 4 GDMT goals, respectively. The 4-year cumulative event rate for CV death/MI was highest for participants who attained no GDMT goals (24.5%; 95% credible interval [CrI]: 13.5%-42.2%) and lowest for those who attained all goals at baseline and remained at goal during follow-up (8.7%; 95% CrI: 6.7%-10.9%). SBP goal attainment was associated with a significant absolute event reduction in CV death/MI (-5.1%; 95% CrI: -11.3% to -1.0%), followed by antiplatelet therapy (-11.2%; 95% CrI: -29.1% to 0.8%), achieving low-density lipoprotein cholesterol <70 mg/dL (-2.0%; 95% CrI: -6.0% to 2.4%), and not smoking (-1.7%; 95% CrI: -9.3% to 4.2%). Ten millimeters of mercury lower SBP during follow-up was associated with 10% relative risk reduction of CV death/MI (RR [relative risk] = 0.90; 95% CrI: 0.82-0.98), after adjusting for other GDMT goals and baseline characteristics. CONCLUSIONS:Among participants with CCD, early attainment and maintenance of GDMT goals, especially SBP, were associated with fewer cardiovascular events. Compared with no GDMT goals at target, having all 4 GDMT goals at target at baseline was associated with an absolute 16% fewer CV deaths and MIs. (ISCHEMIA [International Study of Comparative Health Effectiveness With Medical and Invasive Approaches]; NCT01471522).

AIM/OBJECTIVE:To investigate how psychosocial stress contributes to accelerated thrombosis, focusing on platelet activation and hyperreactivity. The specific objective was to identify novel platelet regulators involved in stress-mediated thrombosis, with a particular emphasis on the tetraspanin CD37. METHODS AND RESULTS/RESULTS:To explore how stress contributes to platelet hyperreactivity, platelets were isolated from (1) mice that experienced chronic variable stress and stress-free controls (n=8/group) and (2) human subjects with self-reported high and no stress levels (n=18/group), followed by RNA-sequencing. By comparing mutually expressed transcripts, a subset of genes differentially expressed following psychosocial stress was identified in both human and mouse platelets. In both mice and humans, platelet CD37 positively associates with platelet aggregation responses that underlie thrombosis, with Cd37-/- platelets exhibiting impaired integrin αIIbβ3 signaling, characterized by reduced platelet fibrinogen spreading and decreased agonist-induced αIIbβ3 activation. Consistent with a role for CD37 in regulating platelet activation responses, chimeric mice that received Cd37-/- bone marrow experienced a significantly increased time to vessel occlusion in the carotid artery FeCl3 model compared to mice reconstituted with wild-type bone marrow. CD37 deficiency did not alter hemostasis, as platelet count, coagulation metrics, prothrombin time, and partial thromboplastin time did not differ in Cd37-/- mice relative to wild-type mice. Consistent with this, bleeding time did not differ between wild-type and Cd37-/- mice following tail tip transection. CONCLUSIONS:This study provides new insights into the platelet-associated mechanisms underlying stress-mediated thrombosis. Identifying CD37 as a novel regulator of platelet activation responses offers potential therapeutic targets for reducing the thrombotic risk associated with psychosocial stress. The findings also contribute to understanding how psychosocial stress accelerates thrombotic events and underscore the importance of platelet activation in this process.