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Coronary Microvascular Dysfunction Is Associated With a Proinflammatory Circulating Transcriptome in Patients With Nonobstructive Coronary Arteries

Smilowitz, Nathaniel R; Schlamp, Florencia; Hausvater, Anaïs; Joa, Amanda; Serrano-Gomez, Claudia; Farid, Ayman; Hochman, Judith S; Barrett, Tessa; Reynolds, Harmony R; Berger, Jeffrey S
PMID: 38299358
ISSN: 1524-4636
CID: 5627252

Body Mass Index and Clinical and Health Status Outcomes in Chronic Coronary Disease and Advanced Kidney Disease in the ISCHEMIA-CKD Trial

Mathew, Roy O; Kretov, Evgeny I; Huang, Zhen; Jones, Philip G; Sidhu, Mandeep S; O'Brien, Sean M; Prokhorikhin, Aleksei A; Rangaswami, Janani; Newman, Jonathan; Stone, Gregg W; Fleg, Jerome L; Spertus, John A; Maron, David J; Hochman, Judith S; Bangalore, Sripal; ,
OBJECTIVE:This study aimed to assess whether an obesity paradox (lower event rates with higher body mass index [BMI]) exists in participants with advanced chronic kidney disease (CKD) and chronic coronary disease in the International Study of Comparative Health Effectiveness of Medical and Invasive Approaches (ISCHEMIA)-CKD, and whether BMI modified the effect of initial treatment strategy. METHODS:). Associations between BMI and the primary outcome of all-cause death or myocardial infarction (D/MI), and all-cause death, cardiovascular death, and MI individually were estimated. Associations with health status were also evaluated using the Seattle Angina Questionnaire-7, the Rose Dyspnea Scale, and the EuroQol-5D Visual Analog Scale. RESULTS:was marginally associated with D/MI (HR 1.43 [1.00-2.04]) and greater dyspnea throughout follow-up (P < .05 at all time points). Heterogeneity of treatment effect between baseline BMI was not evident for any outcome. CONCLUSIONS:In the ISCHEMIA-CKD trial, an obesity paradox was not detected. Higher BMI was associated with worse dyspnea, and a trend toward increased D/MI and MI risk. Larger studies to validate these findings are warranted.
PMID: 37925061
ISSN: 1555-7162
CID: 5607182

REPLY: Interpreting the Impact of Complete Revascularization in the ISCHEMIA Trial [Letter]

Stone, Gregg W; Ali, Ziad A; Hochman, Judith S; Maron, David J
PMID: 38267120
ISSN: 1558-3597
CID: 5625012

COVID-19 Convalescent Plasma Therapy: Long-term Implications

Yoon, Hyunah; Li, Yi; Goldfeld, Keith S; Cobb, Gia F; Sturm-Reganato, Caroline L; Ostrosky-Zeichner, Luis; Jayaweera, Dushyantha T; Philley, Julie V; Desruisseaux, Mahalia S; Keller, Marla J; Hochman, Judith S; Pirofski, Liise-Anne; Ortigoza, Mila B; ,
BACKGROUND/UNASSIGNED:The long-term effect of coronavirus disease 2019 (COVID-19) acute treatments on postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) is unknown. The CONTAIN-Extend study explores the long-term impact of COVID-19 convalescent plasma (CCP) therapy on postacute sequelae of SARS-CoV-2 infection (PASC) symptoms and general health 18 months following hospitalization. METHODS/UNASSIGNED:The CONTAIN-Extend study examined 281 participants from the original CONTAIN COVID-19 trial (CONTAIN-RCT, NCT04364737) at 18 months post-hospitalization for acute COVID-19. Symptom surveys, global health assessments, and biospecimen collection were performed from November 2021 to October 2022. Multivariable logistic and linear regression estimated associations between the randomization arms and self-reported symptoms and Patient-Reported Outcomes Measurement Information System (PROMIS) scores and adjusted for covariables, including age, sex, race/ethnicity, disease severity, and CONTAIN enrollment quarter and sites. RESULTS/UNASSIGNED:There were no differences in symptoms or PROMIS scores between CCP and placebo (adjusted odds ratio [aOR] of general symptoms, 0.95; 95% CI, 0.54-1.67). However, females (aOR, 3.01; 95% CI, 1.73-5.34), those 45-64 years (aOR, 2.55; 95% CI, 1.14-6.23), and April-June 2020 enrollees (aOR, 2.39; 95% CI, 1.10-5.19) were more likely to report general symptoms and have poorer PROMIS physical health scores than their respective reference groups. Hispanic participants (difference, -3.05; 95% CI, -5.82 to -0.27) and Black participants (-4.48; 95% CI, -7.94 to -1.02) had poorer PROMIS physical health than White participants. CONCLUSIONS/UNASSIGNED:CCP demonstrated no lasting effect on PASC symptoms or overall health in comparison to the placebo. This study underscores the significance of demographic factors, including sex, age, and timing of acute infection, in influencing symptom reporting 18 months after acute hypoxic COVID-19 hospitalization.
PMID: 38269049
ISSN: 2328-8957
CID: 5625122

Global Longitudinal Strain as Predictor of Inducible Ischemia in No Obstructive Coronary Artery Disease in the CIAO-ISCHEMIA Study

Davis, Esther F; Crousillat, Daniela R; Peteiro, Jesus; Lopez-Sendon, Jose; Senior, Roxy; Shapiro, Michael D; Pellikka, Patricia A; Lyubarova, Radmila; Alfakih, Khaled; Abdul-Nour, Khaled; Anthopolos, Rebecca; Xu, Yifan; Kunichoff, Dennis M; Fleg, Jerome L; Spertus, John A; Hochman, Judith; Maron, David; Picard, Michael H; Reynolds, Harmony R; ,
BACKGROUND:Global longitudinal strain (GLS) is a sensitive marker for identifying subclinical myocardial dysfunction in obstructive coronary artery disease (CAD). Little is known about the relationship between GLS and ischemia in patients with myocardial ischemia and no obstructive CAD (INOCA). OBJECTIVES/OBJECTIVE:To investigate the relationship between resting GLS and ischemia on stress echocardiography (SE) in patients with INOCA. METHODS:Left ventricular GLS was calculated offline on resting SE images at enrollment (n = 144) and 1-year follow-up (n = 120) in the CIAO-ISCHEMIA (Changes in Ischemia and Angina over One year in International Study of Comparative Health Effectiveness with Medical and Invasive Approaches trial screen failures with no obstructive CAD on computed tomography [CT] angiography) study, which enrolled participants with moderate or severe ischemia by local SE interpretation (≥3 segments with new or worsening wall motion abnormality and no obstructive (<50% stenosis) on coronary computed tomography angiography. RESULTS:Global longitudinal strain values were normal in 83.3% at enrollment and 94.2% at follow-up. Global longitudinal strain values were not associated with a positive SE at enrollment (GLS = -21.5% positive SE vs GLS = -19.9% negative SE, P = .443) or follow-up (GLS = -23.2% positive SE vs GLS = -23.1% negative SE, P = .859). Significant change in GLS was not associated with positive SE in follow-up (P = .401). Regional strain was not associated with colocalizing ischemia at enrollment or follow-up. Changes in GLS and number of ischemic segments from enrollment to follow-up showed a modest but not clinically meaningful correlation (β = 0.41; 95% CI, 0.16, 0.67; P = .002). CONCLUSIONS:In this cohort of INOCA patients, resting GLS values were largely normal and did not associate with the presence, severity, or location of stress-induced ischemia. These findings may suggest the absence of subclinical myocardial dysfunction detectable by echocardiographic strain analysis at rest in INOCA.
PMID: 37722490
ISSN: 1097-6795
CID: 5603252

Biomarkers and cardiovascular events in patients with stable coronary disease in the ISCHEMIA Trials

Newman, Jonathan D; Anthopolos, Rebecca; Ruggles, Kelly V; Cornwell, Macintosh; Reynolds, Harmony R; Bangalore, Sripal; Mavromatis, Kreton; Held, Claes; Wallentin, Lars; Kullo, Iftikar J; McManus, Bruce; Newby, L Kristin K; Rosenberg, Yves; Hochman, Judith S; Maron, David J; Berger, Jeffrey S; ,
IMPORTANCE:Biomarkers may improve prediction of cardiovascular events for patients with stable coronary artery disease (CAD), but their importance in addition to clinical tests of inducible ischemia and CAD severity is unknown. OBJECTIVES:To evaluate the prognostic value of multiple biomarkers in stable outpatients with obstructive CAD and moderate or severe inducible ischemia. DESIGN AND SETTING:The ISCHEMIA and ISCHEMIA CKD trials randomized 5,956 participants with CAD to invasive or conservative management from July 2012 to January 2018; 1,064 participated in the biorepository. MAIN OUTCOME MEASURES:Primary outcome was cardiovascular death, myocardial infarction (MI), or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. Secondary outcome was cardiovascular death or MI. Improvements in prediction were assessed by cause-specific hazard ratios (HR) and area under the receiver operating characteristics curve (AUC) for an interquartile increase in each biomarker, controlling for other biomarkers, in a base clinical model of risk factors, left ventricular ejection fraction (LVEF) and ischemia severity. Secondary analyses were performed among patients in whom core-lab confirmed severity of CAD was ascertained by computed cardiac tomographic angiography (CCTA). EXPOSURES:Baseline levels of interleukin-6 (IL-6), high sensitivity troponin T (hsTnT), growth differentiation factor 15 (GDF-15), N-terminal pro-B-type natriuretic peptide (NT-proBNP), lipoprotein a (Lp[a]), high sensitivity C-reactive protein (hsCRP), Cystatin C, soluble CD 40 ligand (sCD40L), myeloperoxidase (MPO), and matrix metalloproteinase 3 (MMP3). RESULTS:Among 757 biorepository participants, median (IQR) follow-up was 3 (2-5) years, age was 67 (61-72) years, and 144 (19%) were female; 508 had severity of CAD by CCTA available. In an adjusted multimarker model with hsTnT, GDF-15, NT-proBNP and sCD40L, the adjusted HR for the primary outcome per interquartile increase in each biomarker was 1.58 (95% CI 1.22, 2.205), 1.60 (95% CI 1.16, 2.20), 1.61 (95% 1.22, 2.14), and 1.46 (95% 1.12, 1.90), respectively. The adjusted multimarker model also improved prediction compared with the clinical model, increasing the AUC from 0.710 to 0.792 (P < .01) and 0.714 to 0.783 (P < .01) for the primary and secondary outcomes, respectively. Similar findings were observed after adjusting for core-lab confirmed atherosclerosis severity. CONCLUSIONS AND RELEVANCE:Among ISCHEMIA biorepository participants, biomarkers of myocyte injury/distension, inflammation, and platelet activity improved cardiovascular event prediction in addition to risk factors, LVEF, and assessments of ischemia and atherosclerosis severity. These biomarkers may improve risk stratification for patients with stable CAD.
PMID: 37604357
ISSN: 1097-6744
CID: 5598422

Therapeutic Heparin in non-ICU patients Hospitalized for COVID-19 in the ACTIV-4a Trial: Effect on 3 Month Symptoms and Quality of Life

Greenstein, Yonatan Y; Hubel, Kinsley; Froess, Joshua; Wisniewski, Stephen R; Venugopal, Vidya; Lai, Yu-Hsuan; Berger, Jeff S; Chang, Steven Y; Colovos, Christos; Shah, Faraaz; Kornblith, Lucy Z; Lawler, Patrick R; Gaddh, Manila; Guerrero, Raquel Morillo; Nkemdirim, William; Lopes, Renato D; Reynolds, Harmony R; Amigo, Jose Seijas; Wahid, Lana; Zahra, Ajani; Goligher, Ewan C; Zarychanski, Ryan; Leifer, Eric; Huang, David T; Neal, Matthew D; Hochman, Judith S; Cushman, Mary; Gong, Michelle N
BACKGROUND:Therapeutic-dose heparin decreased days requiring organ support in non-critically ill patients hospitalized for COVID-19 but its impact on persistent symptoms or quality of life (QoL) is unclear. RESEARCH QUESTION/OBJECTIVE:In the ACTIV-4a trial, was randomization of patients hospitalized for COVID-19 illness to therapeutic-dose vs. prophylactic heparin associated with less symptoms and better QoL at 90-days? STUDY DESIGN AND METHODS/METHODS:This was an open-label randomized controlled trial at 34 hospitals in the US and Spain. 727 non-critically ill patients hospitalized for COVID-19 from September 2020 to June 2021 were randomized to therapeutic-dose vs. prophylactic heparin. Only patients with 90-day data on symptoms and QoL were analyzed. We ascertained symptoms and QoL by EQ-5D-5L at 90-day follow-up in a pre-planned analysis for the ACTIV-4a trial. Individual domains assessed by the EQ-5D-5L were mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Univariate and multivariate analysis were performed. RESULTS:Among 571 patients, 288 (50.4%) reported at least one symptom. In 410 patients, 148 (36.1%) reported moderate to severe impairment in one or more domains of EQ-5D-5L. Presence of 90-day symptoms were associated with moderate-severe impairment in the EQ-5D-5L domains of mobility (adjusted odds ratio (aOR) 2.37, 95% CI 1.22-4.59), usual activity (aOR 3.66, 95% CI 1.75-7.65), pain (aOR 2.43, 95% CI 1.43-4.12), and anxiety (aOR 4.32, 95% CI 2.06-9.02), compared to patients reporting no symptoms There were no differences in symptoms or the overall EQ-5D-5L index score between treatment groups. Therapeutic-dose heparin was associated with less moderate-severe impairment in all physical functioning domains (mobility, self-care, usual activities) but was independently significant only in the self-care domain (aOR 0.32, CI 0.11-0.96). INTERPRETATION/CONCLUSIONS:In a randomized controlled trial of hospitalized non-critically ill patients with COVID-19, therapeutic-dose heparin was associated with less severe impairment in the self-care domain of EQ-5D-5L. However, this type of impairment was uncommon, affecting 23 individuals. CLINICAL TRIAL REGISTRATION/BACKGROUND:NCT04505774.
PMID: 37979717
ISSN: 1931-3543
CID: 5608182

Impact of Complete Revascularization in the ISCHEMIA Trial

Stone, Gregg W; Ali, Ziad A; O'Brien, Sean M; Rhodes, Grace; Genereux, Philippe; Bangalore, Sripal; Mavromatis, Kreton; Horst, Jennifer; Dressler, Ovidiu; Poh, Kian Keong; Nath, Ranjit K; Moorthy, Nagaraja; Witkowski, Adam; Dwivedi, Sudhanshu K; Bockeria, Olga; Chen, Jiyan; Smanio, Paola E P; Picard, Michael H; Chaitman, Bernard R; Berman, Daniel S; Shaw, Leslee J; Boden, William E; White, Harvey D; Fremes, Stephen E; Rosenberg, Yves; Reynolds, Harmony R; Spertus, John A; Hochman, Judith S; Maron, David J
BACKGROUND:Anatomic complete revascularization (ACR) and functional complete revascularization (FCR) have been associated with reduced death and myocardial infarction (MI) in some prior studies. The impact of complete revascularization (CR) in patients undergoing an invasive (INV) compared with a conservative (CON) management strategy has not been reported. OBJECTIVES/OBJECTIVE:Among patients with chronic coronary disease without prior coronary artery bypass grafting randomized to INV vs CON management in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial, we examined the following: 1) the outcomes of ACR and FCR compared with incomplete revascularization; and 2) the potential impact of achieving CR in all INV patients compared with CON management. METHODS:ACR and FCR in the INV group were assessed at an independent core laboratory. Multivariable-adjusted outcomes of CR were examined in INV patients. Inverse probability weighted modeling was then performed to estimate the treatment effect had CR been achieved in all INV patients compared with CON management. RESULTS:ACR and FCR were achieved in 43.4% and 58.4% of 1,824 INV patients. ACR was associated with reduced 4-year rates of cardiovascular death or MI compared with incomplete revascularization. By inverse probability weighted modeling, ACR in all 2,296 INV patients compared with 2,498 CON patients was associated with a lower 4-year rate of cardiovascular death or MI (difference -3.5; 95% CI: -7.2% to 0.0%). In comparison, the event rate difference of cardiovascular death or MI for INV minus CON in the overall ISCHEMIA trial was -2.4%. Results were similar but less pronounced with FCR. CONCLUSIONS:The outcomes of an INV strategy may be improved if CR (especially ACR) is achieved. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).
PMID: 37462593
ISSN: 1558-3597
CID: 5535622

Chronic Coronary Disease Guidelines

Rao, Sunil V; Reynolds, Harmony R; Hochman, Judith S
PMID: 37471475
ISSN: 1524-4539
CID: 5535992

Effect of the P-selectin Inhibitor Crizanlizumab on Survival Free of Organ Support in Patients Hospitalized for COVID-19: A Randomized Controlled Trial

Solomon, Scott D; Lowenstein, Charles J; Bhatt, Ankeet S; Peikert, Alexander; Vardeny, Orly; Kosiborod, Mikhail N; Berger, Jeffrey S; Reynolds, Harmony R; Mavromichalis, Stephanie; Barytol, Anya; Althouse, Andrew D; Luther, James F; Leifer, Eric S; Kindzelski, Andrei L; Cushman, Mary; Gong, Michelle N; Kornblith, Lucy Z; Khatri, Pooja; Kim, Keri S; Baumann Kreuziger, Lisa; Wahid, Lana; Kirwan, Bridget-Anne; Geraci, Mark W; Neal, Matthew D; Hochman, Judith S
BACKGROUND:COVID-19 has been associated with endothelial injury and resultant microvascular inflammation and thrombosis. Activated endothelial cells release and express P-selectin and von Willebrand Factor (VWF), both of which are elevated in severe COVID-19 and may be implicated in the disease pathophysiology. We hypothesized that crizanlizumab, a humanized monoclonal antibody to P-selectin, would reduce morbidity and mortality in patients hospitalized for COVID-19. METHODS:An international, adaptive randomized-controlled platform trial, funded by the NHLBI, randomly assigned 422 patients hospitalized with COVID-19, with either moderate or severe illness, to receive either a single infusion of the P-selectin inhibitor crizanlizumab (at a dose of 5 mg/kg) plus standard-of-care, or standard-of-care alone, in an open-label 1:1 ratio. The primary outcome was organ support-free days, evaluated on an ordinal scale consisting of the number of days alive free of organ support through the first 21 days after trial entry. RESULTS:The study was stopped for futility by the data safety monitoring committee. Among 421 randomized patients with known 21-day outcome, 163 (77%) patients randomized to the crizanlizumab plus standard-of-care arm did not require any respiratory or cardiovascular organ support compared with 169 (80%) in the standard-of-care only arm. The adjusted OR for the effect of crizanlizumab on organ support-free days was 0.70 (95% CrI, 0.43 to 1.16), where OR>1 indicates treatment benefit, yielding a posterior probability of futility Pr(OR<1.2) of 98% and a posterior probability of inferiority Pr(OR<1.0) of 91%. Overall, there were 37 deaths (17.5%) in the crizanlizumab arm and 27 (12.8%) deaths in the standard-of-care arm (HR=1.42, 95% CrI 0.90-2.36, Pr(HR>1) = 0.934). CONCLUSIONS:Crizanlizumab, a P-selectin inhibitor, did not result in improvement in organ-support free days in patients hospitalized with COVID-19.
PMID: 37356038
ISSN: 1524-4539
CID: 5540042